Micrograph showing CLL

Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).

Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.

The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.

Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.

Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.

Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.

The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).

At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.

There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).

The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).

The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.

Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.

Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.

Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.

The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.

The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.

“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.

This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.

Micrograph showing CLL

Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).

Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.

The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.

Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.

Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.

Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.

The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).

At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.

There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).

The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).

The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.

Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.

Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.

Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.

The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.

The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.

“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.

This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.

Micrograph showing CLL

Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).

Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.

The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.

Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.

Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.

Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.

The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).

At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.

There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).

The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).

The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.

Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.

Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.

Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.

The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.

The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.

“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.

This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.

In older patients with chronic lymphocytic leukemia (CLL), first-line treatment with ibrutinib resulted in a long-term progression-free survival benefit versus chemotherapy, according to extended follow-up results of a phase 3 trial.

The quality of response to ibrutinib continued to improve over time in the study, including a substantial increase in the proportion of patients achieving complete response, the updated results of the RESONATE-2 trial show.

Rates of serious adverse events decreased over time in the study, while common reasons for initiating treatment, such as marrow failure and disease symptoms, all improved to a greater extent than with chlorambucil, reported Paul M. Barr, MD, of the University of Rochester (N.Y.) and colleagues.

“These data support the use of ibrutinib in the first-line treatment of CLL as a chemotherapy-free option that can be taken continuously, achieving long-term disease control for the majority of patients, including those with high-risk features,” Dr. Barr and coauthors said in the journal Haematologica.

Previously reported primary results of the RESONATE-2 trial, which showed an 84% reduction in risk of death for ibrutinib versus chlorambucil with a median follow-up of 18 months, led to the approval of ibrutinib for first-line CLL treatment, the authors said.

The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized 1:1 to ibrutinib or chlorambucil.

Out of 136 ibrutinib-treated patients, 107 (79%) remained on therapy at this extended analysis, which had a median follow-up of 29 months.

The extended analysis also showed an 88% reduction in risk of progression or death for those patients randomized to ibrutinib (P less than .0001), with significant improvements in subgroups evaluated, which include groups typically considered high risk, according to Dr. Barr and colleagues.

The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months, to 15% at 24 months, and to 18% with a maximum of 36 months’ follow-up, they said.

The overall response rate for ibrutinib was 92% in this extended analysis, with comparable findings in high-risk subgroups, including those with del(11q) at 100% and unmutated IGHV at 95%, according to the report.

Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42% versus 7% with chlorambucil. Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients versus 52% for chlorambucil, with complete resolution in 56% of ibrutinib-treated patients and 22% of chlorambucil-treated patients.

Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time. Rates of grade 3 or greater neutropenia, anemia, and thrombocytopenia were 8.1%, 5.9%, and 2.2%, respectively, in the first 12 months of treatment; those decreased to 0%, 1%, and 0% in the third year.

The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up; however, investigators said ibrutinib dose reductions and discontinuations because of this adverse effect were uncommon and less frequent with extended treatment.

“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.

The study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.

SOURCE: Barr PM, et al. Haematologica. 2018;103(9):1502-10.

In older patients with chronic lymphocytic leukemia (CLL), first-line treatment with ibrutinib resulted in a long-term progression-free survival benefit versus chemotherapy, according to extended follow-up results of a phase 3 trial.

The quality of response to ibrutinib continued to improve over time in the study, including a substantial increase in the proportion of patients achieving complete response, the updated results of the RESONATE-2 trial show.

Rates of serious adverse events decreased over time in the study, while common reasons for initiating treatment, such as marrow failure and disease symptoms, all improved to a greater extent than with chlorambucil, reported Paul M. Barr, MD, of the University of Rochester (N.Y.) and colleagues.

“These data support the use of ibrutinib in the first-line treatment of CLL as a chemotherapy-free option that can be taken continuously, achieving long-term disease control for the majority of patients, including those with high-risk features,” Dr. Barr and coauthors said in the journal Haematologica.

Previously reported primary results of the RESONATE-2 trial, which showed an 84% reduction in risk of death for ibrutinib versus chlorambucil with a median follow-up of 18 months, led to the approval of ibrutinib for first-line CLL treatment, the authors said.

The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized 1:1 to ibrutinib or chlorambucil.

Out of 136 ibrutinib-treated patients, 107 (79%) remained on therapy at this extended analysis, which had a median follow-up of 29 months.

The extended analysis also showed an 88% reduction in risk of progression or death for those patients randomized to ibrutinib (P less than .0001), with significant improvements in subgroups evaluated, which include groups typically considered high risk, according to Dr. Barr and colleagues.

The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months, to 15% at 24 months, and to 18% with a maximum of 36 months’ follow-up, they said.

The overall response rate for ibrutinib was 92% in this extended analysis, with comparable findings in high-risk subgroups, including those with del(11q) at 100% and unmutated IGHV at 95%, according to the report.

Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42% versus 7% with chlorambucil. Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients versus 52% for chlorambucil, with complete resolution in 56% of ibrutinib-treated patients and 22% of chlorambucil-treated patients.

Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time. Rates of grade 3 or greater neutropenia, anemia, and thrombocytopenia were 8.1%, 5.9%, and 2.2%, respectively, in the first 12 months of treatment; those decreased to 0%, 1%, and 0% in the third year.

The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up; however, investigators said ibrutinib dose reductions and discontinuations because of this adverse effect were uncommon and less frequent with extended treatment.

“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.

The study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.

SOURCE: Barr PM, et al. Haematologica. 2018;103(9):1502-10.

In older patients with chronic lymphocytic leukemia (CLL), first-line treatment with ibrutinib resulted in a long-term progression-free survival benefit versus chemotherapy, according to extended follow-up results of a phase 3 trial.

The quality of response to ibrutinib continued to improve over time in the study, including a substantial increase in the proportion of patients achieving complete response, the updated results of the RESONATE-2 trial show.

Rates of serious adverse events decreased over time in the study, while common reasons for initiating treatment, such as marrow failure and disease symptoms, all improved to a greater extent than with chlorambucil, reported Paul M. Barr, MD, of the University of Rochester (N.Y.) and colleagues.

“These data support the use of ibrutinib in the first-line treatment of CLL as a chemotherapy-free option that can be taken continuously, achieving long-term disease control for the majority of patients, including those with high-risk features,” Dr. Barr and coauthors said in the journal Haematologica.

Previously reported primary results of the RESONATE-2 trial, which showed an 84% reduction in risk of death for ibrutinib versus chlorambucil with a median follow-up of 18 months, led to the approval of ibrutinib for first-line CLL treatment, the authors said.

The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized 1:1 to ibrutinib or chlorambucil.

Out of 136 ibrutinib-treated patients, 107 (79%) remained on therapy at this extended analysis, which had a median follow-up of 29 months.

The extended analysis also showed an 88% reduction in risk of progression or death for those patients randomized to ibrutinib (P less than .0001), with significant improvements in subgroups evaluated, which include groups typically considered high risk, according to Dr. Barr and colleagues.

The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months, to 15% at 24 months, and to 18% with a maximum of 36 months’ follow-up, they said.

The overall response rate for ibrutinib was 92% in this extended analysis, with comparable findings in high-risk subgroups, including those with del(11q) at 100% and unmutated IGHV at 95%, according to the report.

Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42% versus 7% with chlorambucil. Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients versus 52% for chlorambucil, with complete resolution in 56% of ibrutinib-treated patients and 22% of chlorambucil-treated patients.

Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time. Rates of grade 3 or greater neutropenia, anemia, and thrombocytopenia were 8.1%, 5.9%, and 2.2%, respectively, in the first 12 months of treatment; those decreased to 0%, 1%, and 0% in the third year.

The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up; however, investigators said ibrutinib dose reductions and discontinuations because of this adverse effect were uncommon and less frequent with extended treatment.

“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.

The study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.

SOURCE: Barr PM, et al. Haematologica. 2018;103(9):1502-10.

Green is just as good – make that better – than blue at identifying sentinel lymph nodes in women with cervical and uterine cancers, results of the multicenter FILM (Fluorescence Imaging for Lymphatic Mapping) study indicate.

Among 176 patients randomly assigned to first have lymphatic mapping with indocyanine green fluorescent dye visualized with near infrared imaging followed by isosulfan blue dye visualized with white light, or the two modalities in the reverse order, indocyanine green identified 50% more lymph nodes in both modified intention-to-treat and per-protocol analyses, reported Michael Frumovitz, MD, from the University of Texas MD Anderson Cancer Center in Houston and colleagues.

“Indocyanine green dye with near-infrared imaging identified significantly more sentinel nodes and more bilateral sentinel nodes than did isosulfan blue dye. It also identified all sentinel nodes with metastatic disease, whereas isosulfan blue dye missed a large proportion of them,” they wrote in the Lancet Oncology.

The FILM study was designed to determine whether fluorescent indocyanine green dye would be noninferior to isosulfan blue dye for accurately identifying sentinel lymph nodes in patients with cancer.

Although several single-center retrospective studies have reported on the use of interstitial injection of indocyanine green for lymphatic mapping in various solid tumors, including uterine and cervical cancers, there were no published studies comparing indocyanine green mapping to isosulfan blue mapping, the standard of care, the authors noted.

They enrolled 180 women aged 18 or older with clinical stage I endometrial or cervical cancers who were undergoing curative surgery and randomly assigned them as described above to have lymphatic mapping with each of the imaging modalities assigned in random order.

The patients but not the operators were masked as to the order of randomization.

Of the 180 patients enrolled, 176 received the intervention, and 13 of these patients were excluded because of major protocol violations, leaving 163 for a per-protocol analysis.

In the per-protocol analysis, 517 sentinel nodes were identified in the 163 patients, and of these, 478 (92%) were confirmed to be lymph nodes on pathological examination. This sample included 219 of 238 nodes identified with both blue and green dyes, all seven nodes revealed by blue dye alone, and 252 of 265 nodes identified by only green dye. Seven sentinel lymph nodes that were not identified by either dye were removed because they were enlarged or appeared suspicious on visual inspection.

In total, green dye identified 97% of lymph nodes in the per-protocol population, and blue dye identified 47%, an absolute difference of 50% (P less than .0001).

In the modified intention-to-treat population, which included all 176 patients randomized and treated, 545 nodes were identified, and 513 (94%) were confirmed to be lymph nodes on pathology. In this sample, 229 (92%) of 248 nodes showed both blue and green, nine nodes were blue only, and 266 (95%) of 279 were green only. Nine sentinel lymph nodes that were not revealed by either blue or green were removed for appearing suspicious or enlarged visually.

In total, in the modified-ITT analysis, 495 of 513 (96%) nodes were identified with the green dye and 238 (46%) were identified with the blue dye, again for an absolute difference of 50% (P less than .0001).

Based on the results of the study, the green dye’s maker, Novadaq Technologies, is submitting an application to the Food and Drug Administration for on-label use of interstitial injection of indocyanine green combined with near-infrared imaging for lymphatic mapping.

The study was funded by Novadaq. Dr. Frumovitz reported grants from Novadaq/Stryker during the conduct of the study, as well as personal fees; grants from Navidea; personal fees from Johnson & Johnson; and personal fees from Genentech outside the submitted work. The other authors declared no competing interests.

SOURCE: Frumovitz M et al. Lancet Oncol. 2018 Aug 21. doi: 10.1016/S1470-2045(18)30448-0.

Green is just as good – make that better – than blue at identifying sentinel lymph nodes in women with cervical and uterine cancers, results of the multicenter FILM (Fluorescence Imaging for Lymphatic Mapping) study indicate.

Among 176 patients randomly assigned to first have lymphatic mapping with indocyanine green fluorescent dye visualized with near infrared imaging followed by isosulfan blue dye visualized with white light, or the two modalities in the reverse order, indocyanine green identified 50% more lymph nodes in both modified intention-to-treat and per-protocol analyses, reported Michael Frumovitz, MD, from the University of Texas MD Anderson Cancer Center in Houston and colleagues.

“Indocyanine green dye with near-infrared imaging identified significantly more sentinel nodes and more bilateral sentinel nodes than did isosulfan blue dye. It also identified all sentinel nodes with metastatic disease, whereas isosulfan blue dye missed a large proportion of them,” they wrote in the Lancet Oncology.

The FILM study was designed to determine whether fluorescent indocyanine green dye would be noninferior to isosulfan blue dye for accurately identifying sentinel lymph nodes in patients with cancer.

Although several single-center retrospective studies have reported on the use of interstitial injection of indocyanine green for lymphatic mapping in various solid tumors, including uterine and cervical cancers, there were no published studies comparing indocyanine green mapping to isosulfan blue mapping, the standard of care, the authors noted.

They enrolled 180 women aged 18 or older with clinical stage I endometrial or cervical cancers who were undergoing curative surgery and randomly assigned them as described above to have lymphatic mapping with each of the imaging modalities assigned in random order.

The patients but not the operators were masked as to the order of randomization.

Of the 180 patients enrolled, 176 received the intervention, and 13 of these patients were excluded because of major protocol violations, leaving 163 for a per-protocol analysis.

In the per-protocol analysis, 517 sentinel nodes were identified in the 163 patients, and of these, 478 (92%) were confirmed to be lymph nodes on pathological examination. This sample included 219 of 238 nodes identified with both blue and green dyes, all seven nodes revealed by blue dye alone, and 252 of 265 nodes identified by only green dye. Seven sentinel lymph nodes that were not identified by either dye were removed because they were enlarged or appeared suspicious on visual inspection.

In total, green dye identified 97% of lymph nodes in the per-protocol population, and blue dye identified 47%, an absolute difference of 50% (P less than .0001).

In the modified intention-to-treat population, which included all 176 patients randomized and treated, 545 nodes were identified, and 513 (94%) were confirmed to be lymph nodes on pathology. In this sample, 229 (92%) of 248 nodes showed both blue and green, nine nodes were blue only, and 266 (95%) of 279 were green only. Nine sentinel lymph nodes that were not revealed by either blue or green were removed for appearing suspicious or enlarged visually.

In total, in the modified-ITT analysis, 495 of 513 (96%) nodes were identified with the green dye and 238 (46%) were identified with the blue dye, again for an absolute difference of 50% (P less than .0001).

Based on the results of the study, the green dye’s maker, Novadaq Technologies, is submitting an application to the Food and Drug Administration for on-label use of interstitial injection of indocyanine green combined with near-infrared imaging for lymphatic mapping.

The study was funded by Novadaq. Dr. Frumovitz reported grants from Novadaq/Stryker during the conduct of the study, as well as personal fees; grants from Navidea; personal fees from Johnson & Johnson; and personal fees from Genentech outside the submitted work. The other authors declared no competing interests.

SOURCE: Frumovitz M et al. Lancet Oncol. 2018 Aug 21. doi: 10.1016/S1470-2045(18)30448-0.

Green is just as good – make that better – than blue at identifying sentinel lymph nodes in women with cervical and uterine cancers, results of the multicenter FILM (Fluorescence Imaging for Lymphatic Mapping) study indicate.

Among 176 patients randomly assigned to first have lymphatic mapping with indocyanine green fluorescent dye visualized with near infrared imaging followed by isosulfan blue dye visualized with white light, or the two modalities in the reverse order, indocyanine green identified 50% more lymph nodes in both modified intention-to-treat and per-protocol analyses, reported Michael Frumovitz, MD, from the University of Texas MD Anderson Cancer Center in Houston and colleagues.

“Indocyanine green dye with near-infrared imaging identified significantly more sentinel nodes and more bilateral sentinel nodes than did isosulfan blue dye. It also identified all sentinel nodes with metastatic disease, whereas isosulfan blue dye missed a large proportion of them,” they wrote in the Lancet Oncology.

The FILM study was designed to determine whether fluorescent indocyanine green dye would be noninferior to isosulfan blue dye for accurately identifying sentinel lymph nodes in patients with cancer.

Although several single-center retrospective studies have reported on the use of interstitial injection of indocyanine green for lymphatic mapping in various solid tumors, including uterine and cervical cancers, there were no published studies comparing indocyanine green mapping to isosulfan blue mapping, the standard of care, the authors noted.

They enrolled 180 women aged 18 or older with clinical stage I endometrial or cervical cancers who were undergoing curative surgery and randomly assigned them as described above to have lymphatic mapping with each of the imaging modalities assigned in random order.

The patients but not the operators were masked as to the order of randomization.

Of the 180 patients enrolled, 176 received the intervention, and 13 of these patients were excluded because of major protocol violations, leaving 163 for a per-protocol analysis.

In the per-protocol analysis, 517 sentinel nodes were identified in the 163 patients, and of these, 478 (92%) were confirmed to be lymph nodes on pathological examination. This sample included 219 of 238 nodes identified with both blue and green dyes, all seven nodes revealed by blue dye alone, and 252 of 265 nodes identified by only green dye. Seven sentinel lymph nodes that were not identified by either dye were removed because they were enlarged or appeared suspicious on visual inspection.

In total, green dye identified 97% of lymph nodes in the per-protocol population, and blue dye identified 47%, an absolute difference of 50% (P less than .0001).

In the modified intention-to-treat population, which included all 176 patients randomized and treated, 545 nodes were identified, and 513 (94%) were confirmed to be lymph nodes on pathology. In this sample, 229 (92%) of 248 nodes showed both blue and green, nine nodes were blue only, and 266 (95%) of 279 were green only. Nine sentinel lymph nodes that were not revealed by either blue or green were removed for appearing suspicious or enlarged visually.

In total, in the modified-ITT analysis, 495 of 513 (96%) nodes were identified with the green dye and 238 (46%) were identified with the blue dye, again for an absolute difference of 50% (P less than .0001).

Based on the results of the study, the green dye’s maker, Novadaq Technologies, is submitting an application to the Food and Drug Administration for on-label use of interstitial injection of indocyanine green combined with near-infrared imaging for lymphatic mapping.

The study was funded by Novadaq. Dr. Frumovitz reported grants from Novadaq/Stryker during the conduct of the study, as well as personal fees; grants from Navidea; personal fees from Johnson & Johnson; and personal fees from Genentech outside the submitted work. The other authors declared no competing interests.

SOURCE: Frumovitz M et al. Lancet Oncol. 2018 Aug 21. doi: 10.1016/S1470-2045(18)30448-0.

CASE REPORT

A 74-year-old woman presented with a painful lesion on the left lower leg that was getting larger and more edematous and erythematous over the last 5 months. She experienced numbness and burning of the left lower leg 1 year prior to the development of the lesion. A review of her medical history revealed an otherwise healthy woman with no constitutional symptoms of fever, chills, nausea, vomiting, diarrhea, or chest pain. The patient did not exhibit mucosal, genital, or nail involvement. Physical examination revealed a group of four 1-cm, ill-defined, irregularly bordered, violaceous plaques on the left anterior tibial leg with faint surrounding erythematous to violaceous patches (Figure 1). The plaques were tender to palpation with no bleeding or drainage.

An 8.0-mm punch biopsy of the lesion was obtained. Hematoxylin and eosin staining on low-power magnification demonstrated a diffuse lymphocytic inflammatory infiltrate in the dermis and subcutis. Notable sparing of the subepidermal area (free grenz zone) was present (Figure 2A). On higher power, centroblasts and immunoblasts were visualized alongside extravasated red blood cells (Figure 2B). A diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCLLT) was made. Various immunohistochemical stains confirmed the diagnosis, including B-cell lymphoma 2 (BCL-2)(Figure 3A) and multiple myeloma oncogene 1 (MUM-1)(Figure 3B), which were highly positive in our patient. The patient had a negative bone marrow biopsy and positron emission tomography scan. She was started on rituximab infusions and multiple radiation treatments. At 2-year follow-up the lymphoma continued to recur despite radiation therapy.

COMMENT

Incidence and Clinical Characteristics

Primary cutaneous DLBCLLT is an intermediately aggressive form of primary cutaneous B-cell lymphoma (CBCL) that accounts for approximately 10% to 20% of all primary CBCLs and 1% to 3% of all cutaneous lymphomas.¹ Diffuse large B-cell lymphoma, leg type primarily affects elderly patients (median age, 70 years). Women are more commonly affected. Clinically, primary cutaneous DLBCLLT presents as red-brown to bluish nodules or tumors on one or both distal legs. Although referred to as leg-type diffuse large B-cell lymphoma, 10% to 15% of patients have lesions in anatomic areas other than the legs, most commonly the trunk.

Histopathology

The diagnosis of DLBCLLT is best made histologically. There is a dense inflammatory infiltrate present in the dermis and subcutis that may extend upward into the dermoepidermal junction. Often a subepidermal free grenz zone may be seen, and adnexal structures may be destroyed. This infiltrate is composed of confluent sheets of large round cells including centroblasts and immunoblasts.² Centroblasts are large cells that have nuclei with several small nucleoli adhering to the membrane, while immunoblasts are large round cells containing nuclei with large central nucleoli. Both centroblasts and immunoblasts stain positively for BCL-2. Centrocytes typically are absent. Staining for BCL-2 can be important in distinguishing DLBCLLT from other forms of CBCL. Diffuse large B-cell lymphoma, leg type also can demonstrate clusters of large atypical cells in the epidermis simulating epidermotropism and Pautrier microabscesses. Neoplastic cells in this condition may express monoclonal surface and cytoplasmic immunoglobulins. Primary cutaneous DLBCLLT typically is positive for B-cell markers CD20 and CD79a. Additionally, MUM-1/IRF4 (interferon regulatory factor 4) and forkhead box protein 1 (FOXP1) are strongly expressed by most patients, which helps distinguish it from other forms of CBCL.

Treatment

Diffuse large B-cell lymphoma, leg type is a relatively aggressive form of CBCL that requires more aggressive treatment than the conservative watchful waiting of some of the more indolent forms of primary CBCL. One regimen involves using cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Local chemotherapy or radiation with rituximab is another treatment option.^1,2 In patients with severe comorbidities, rituximab alone may be administered. The prognosis for DLBCLLT is not as favorable as other types of primary CBCL, with an estimated 5-year survival rate of approximately 50%.²

Differential Diagnosis

Lymphomas are malignancies of the lymphocytes that may be subdivided depending on the organ of origin. Both primary nodal lymphomas and primary cutaneous lymphomas exist. Primary nodal lymphomas arise from the lymph nodes and are divided into Hodgkin and non-Hodgkin lymphomas. There are 2 major types of primary cutaneous lymphomas: cutaneous T-cell lymphoma (CTCL) and CBCL. Most primary cutaneous lymphomas are CTCLs, accounting for 75% to 80%.³

Pseudolymphoma
Pseudolymphoma is an inflammatory condition that may histologically mimic cutaneous lymphoma but has a benign clinical course. Pseudolymphoma is not a specific disease but rather is a reactive lymphoproliferative response to a known or unknown stimulus.⁴ Pseudolymphoma can be broken down into 2 or 3 major categories: cutaneous B-cell pseudolymphoma; cutaneous T-cell pseudolymphoma; and debatably lymphomatoid papulosis, a chronic, self-remitting, papulonecrotic condition that resembles lymphoma histologically but clinically appears benign. It is unknown if lymphomatoid papulosis represents a pseudolymphoma or a true lymphoma. Lymphomatoid papulosis may represent an early indolent form of CTCL.⁴

Pseudolymphomas can be triggered by a variety of causes. Most cases are idiopathic, and a causative stimulus is never identified. Drugs are known to cause many cases of pseudolymphoma, either by a causing a hypersensitivity reaction or by depressing immunosurveillance.⁵ Pseudolymphomas may result from exogenous stimuli such as jewelry, tattoo dyes, injectable fillers (eg, silicone), insect bites, vaccines, and trauma.^6,7 Lastly, infections in the form of Borrelia, varicella, and molluscum contagiosum can potentially cause pseudolymphomas.⁴

Clinically, pseudolymphomas may demonstrate a B-cell or T-cell pattern. In cutaneous B-cell pseudolymphomas, asymptomatic solitary erythematous, violaceous, or flesh-colored nodules appear on the face, followed by the chest and arms. Cutaneous T-cell pseudolymphomas present with erythematous patches that are more likely to be symptomatic.⁴

Histologically, pseudolymphomas also are classified as demonstrating B-cell or T-cell patterns. The nodular inflammatory infiltrate of cutaneous B-cell pseudolymphoma corresponds with its clinically apparent nodules. It can be distinguished from lymphoma in that it is not solely a lymphocytic infiltrate but rather a mixed infiltrate including histiocytes, lymphocytes, eosinophils, and plasma cells. Additionally, cutaneous B-cell pseudolymphoma does not penetrate the dermis as deeply as CBCL.⁸ Cutaneous T-cell pseudolymphoma is more difficult to distinguish from CTCL because it also demonstrates a bandlike lymphocytic infiltrate in the papillary dermis with epidermotropism.⁹

Treatment must address the underlying cause of pseudolymphoma for resolution. Other treatment options include surgery, cryotherapy, local radiotherapy, topical steroids, and topical immunomodulators. Spontaneous resolution also can occur. The prognosis is better when a known trigger is eliminated, though idiopathic pseudolymphomas may be chronic in nature. It is important to rule out concurrent cutaneous lymphoma or rare transformation into cutaneous lymphoma.

Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas are a diverse group of neoplasms that account for most cutaneous lymphomas seen by dermatologists. In 1806, the first case of CTCL in the form of mycosis fungoides (MF) was described by Jean Louis Alibert. Mycosis fungoides represents the most common form of CTCL, accounting for approximately 50% of all primary cutaneous lymphomas.¹⁰ Mycosis fungoides was named after its morphological resemblance to mushrooms. Although not all cases exhibit a classic progression, MF is known for its stepwise progression from patch stage to tumor stage.

Clinically, lesions typically begin as patches that progress to plaques and finally tumors. This progression may not always occur and often can take years to decades to progress. Patches are characterized by erythematous, finely scaling lesions that may be easily confused with eczema or psoriasis. Lesions occur primarily in a swimming trunk distribution.

Mycosis fungoides histologically demonstrates a bandlike lymphocytic infiltrate with epidermotropism, which occurs when lymphocytes infiltrate the epidermis without spongiosis. These lymphocytes are larger, darker, and more angulated than normal lymphocytes. Intraepidermal nests of these atypical lymphocytes creating Pautrier microabscesses may be present. Tumor-stage lesions demonstrate diminished epidermotropism with dense sheets of lymphocytes in the dermis, and fat cells with cerebriform nuclei are present.

Therapies for MF may control the disease but may not prolong patients’ lives. Topical corticosteroids, phototherapy, and radiotherapy are options for skin-targeting therapies. Systemic chemotherapy and biological response modifiers also are viable treatment options. Prognosis for MF is poor.

There are a few notable variants of MF that are important to consider. Sézary syndrome is an erythrodermic variant of MF characterized by atypical Sézary cells. Clinically, it presents with generalized erythroderma with leonine facies, facial edema, and alopecia with associated symptoms of burning and pruritus. Histologically, Sézary syndrome is similar to MF with an increased CD4:CD8 ratio.¹⁰ Sézary syndrome may be treated with methotrexate or photopheresis, but the prognosis remains poor with an average survival of 5 years.

Cutaneous B-Cell Lymphoma
There are 5 types of primary CBCL: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, other; precursor B-cell lymphoblastic lymphoma; and primary cutaneous DLBCLLT, which was seen in our patient.¹¹

Primary cutaneous follicle center lymphoma is an indolent neoplastic proliferation in the skin. Clinically, it presents with solitary or grouped pinkish purple papules, plaques, or nodules on the trunk with surrounding patches of erythema.³ Lesions located on the back are referred to as Crosti lymphoma. Histopathology reveals a lymphocytic infiltrate with a diffuse follicular pattern and large round centroblasts, centrocytes, and immunoblasts with epidermal sparing. Tumor cells stain positively for κ or λ light chains, as well as CD20, CD79a, and B-cell lymphoma 6 (BCL-6); however, staining for the protein product of BCL-2 may be negative, which differentiates this form of CBCL from primary nodal B-cell lymphoma. Staining for MUM-1 may be negative, which contrasts with the strong expression seen in DLBCLLT. The follicular pattern of follicle center lymphoma stains positive for CD10, but the diffuse pattern may be CD10 negative. The prognosis for primary cutaneous follicle center lymphoma is favorable, but the recurrence rate is up to 50%.³ Treatment includes local radiotherapy or surgical excision.

Primary cutaneous marginal zone B-cell lymphoma is another indolent primary CBCL subtype that is closely related to mucosa-associated lymphoid tissue lymphomas and arises in areas of acrodermatitis chronica atrophicans and Borrelia infection. Clinically, it presents with recurrent, asymptomatic, red-brown papules, plaques, and nodules of the arms and legs. Histologically, there is a patchy infiltrate in the dermis and subcutis with sparing of the epidermis with pale-staining cells with indented nuclei, along with plasma cells and eosinophils. Primary cutaneous marginal zone B-cell lymphoma typically does not demonstrate epidermotropism. Centrocyte cells stain positively for CD20, CD79a, and BCL-2. The prognosis of primary cutaneous marginal zone B-cell lymphoma is favorable. Treatment is similar to primary cutaneous follicle center lymphoma with surgical excision, radiotherapy, and surveillance being the main modalities.

Primary cutaneous diffuse large B-cell lymphoma, other is an intermediately aggressive form of primary CBCL that is thought to be related to primary cutaneous DLBCLLT. Clinically, it presents with indurated erythematous to violaceous plaques on the trunk and thighs that may resemble a vascular tumor or panniculitis.^2,12 Histopathologically, this form of lymphoma presents with a round cell morphology without BCL-2 expression, which distinguishes it from DLBCLLT. If limited to skin, the prognosis is better than the systemic form but is still less favorable than other forms of CBCL.

Precursor B-cell lymphoblastic lymphoma is an extremely rare type of CBCL that potentially can occur in the skin. It primarily affects children and young adults. Clinically, it presents as a solitary large erythematous tumor of the head. Histologically, monomorphic proliferation of medium-sized cells with round nuclei that demonstrate a starry sky pattern with multiple mitotic cells can be observed.¹³ Immunohistochemical markers such as CD43, CD10, CD20, and CD79a may be positive. The disease is very aggressive with poor prognosis if left untreated.

CONCLUSION

We present a rare case of primary cutaneous DLBCLLT. Our case demonstrates the classic presentation of primary cutaneous DLBCLLT in a 74-year-old woman with a tumor on the lower left leg. Histologically, a dense dermal and subcutis infiltrate of centroblasts and immunoblasts with a grenz zone was present. Immunostaining in our patient was consistent with characteristic findings in the literature, staining highly positive for BCL-2 and MUM-1. Primary cutaneous DLBCLLT is an extremely rare and unique form of cutaneous lymphoma that can have potentially fatal consequences if undiagnosed; therefore, clinicians must take great care to make the correct diagnosis based on a knowledge of the clinical and immunohistochemical findings of DLBCLLT.

CASE REPORT

A 74-year-old woman presented with a painful lesion on the left lower leg that was getting larger and more edematous and erythematous over the last 5 months. She experienced numbness and burning of the left lower leg 1 year prior to the development of the lesion. A review of her medical history revealed an otherwise healthy woman with no constitutional symptoms of fever, chills, nausea, vomiting, diarrhea, or chest pain. The patient did not exhibit mucosal, genital, or nail involvement. Physical examination revealed a group of four 1-cm, ill-defined, irregularly bordered, violaceous plaques on the left anterior tibial leg with faint surrounding erythematous to violaceous patches (Figure 1). The plaques were tender to palpation with no bleeding or drainage.

An 8.0-mm punch biopsy of the lesion was obtained. Hematoxylin and eosin staining on low-power magnification demonstrated a diffuse lymphocytic inflammatory infiltrate in the dermis and subcutis. Notable sparing of the subepidermal area (free grenz zone) was present (Figure 2A). On higher power, centroblasts and immunoblasts were visualized alongside extravasated red blood cells (Figure 2B). A diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCLLT) was made. Various immunohistochemical stains confirmed the diagnosis, including B-cell lymphoma 2 (BCL-2)(Figure 3A) and multiple myeloma oncogene 1 (MUM-1)(Figure 3B), which were highly positive in our patient. The patient had a negative bone marrow biopsy and positron emission tomography scan. She was started on rituximab infusions and multiple radiation treatments. At 2-year follow-up the lymphoma continued to recur despite radiation therapy.

COMMENT

Incidence and Clinical Characteristics

Primary cutaneous DLBCLLT is an intermediately aggressive form of primary cutaneous B-cell lymphoma (CBCL) that accounts for approximately 10% to 20% of all primary CBCLs and 1% to 3% of all cutaneous lymphomas.¹ Diffuse large B-cell lymphoma, leg type primarily affects elderly patients (median age, 70 years). Women are more commonly affected. Clinically, primary cutaneous DLBCLLT presents as red-brown to bluish nodules or tumors on one or both distal legs. Although referred to as leg-type diffuse large B-cell lymphoma, 10% to 15% of patients have lesions in anatomic areas other than the legs, most commonly the trunk.

Histopathology

The diagnosis of DLBCLLT is best made histologically. There is a dense inflammatory infiltrate present in the dermis and subcutis that may extend upward into the dermoepidermal junction. Often a subepidermal free grenz zone may be seen, and adnexal structures may be destroyed. This infiltrate is composed of confluent sheets of large round cells including centroblasts and immunoblasts.² Centroblasts are large cells that have nuclei with several small nucleoli adhering to the membrane, while immunoblasts are large round cells containing nuclei with large central nucleoli. Both centroblasts and immunoblasts stain positively for BCL-2. Centrocytes typically are absent. Staining for BCL-2 can be important in distinguishing DLBCLLT from other forms of CBCL. Diffuse large B-cell lymphoma, leg type also can demonstrate clusters of large atypical cells in the epidermis simulating epidermotropism and Pautrier microabscesses. Neoplastic cells in this condition may express monoclonal surface and cytoplasmic immunoglobulins. Primary cutaneous DLBCLLT typically is positive for B-cell markers CD20 and CD79a. Additionally, MUM-1/IRF4 (interferon regulatory factor 4) and forkhead box protein 1 (FOXP1) are strongly expressed by most patients, which helps distinguish it from other forms of CBCL.

Treatment

Diffuse large B-cell lymphoma, leg type is a relatively aggressive form of CBCL that requires more aggressive treatment than the conservative watchful waiting of some of the more indolent forms of primary CBCL. One regimen involves using cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Local chemotherapy or radiation with rituximab is another treatment option.^1,2 In patients with severe comorbidities, rituximab alone may be administered. The prognosis for DLBCLLT is not as favorable as other types of primary CBCL, with an estimated 5-year survival rate of approximately 50%.²

Differential Diagnosis

Lymphomas are malignancies of the lymphocytes that may be subdivided depending on the organ of origin. Both primary nodal lymphomas and primary cutaneous lymphomas exist. Primary nodal lymphomas arise from the lymph nodes and are divided into Hodgkin and non-Hodgkin lymphomas. There are 2 major types of primary cutaneous lymphomas: cutaneous T-cell lymphoma (CTCL) and CBCL. Most primary cutaneous lymphomas are CTCLs, accounting for 75% to 80%.³

Pseudolymphoma
Pseudolymphoma is an inflammatory condition that may histologically mimic cutaneous lymphoma but has a benign clinical course. Pseudolymphoma is not a specific disease but rather is a reactive lymphoproliferative response to a known or unknown stimulus.⁴ Pseudolymphoma can be broken down into 2 or 3 major categories: cutaneous B-cell pseudolymphoma; cutaneous T-cell pseudolymphoma; and debatably lymphomatoid papulosis, a chronic, self-remitting, papulonecrotic condition that resembles lymphoma histologically but clinically appears benign. It is unknown if lymphomatoid papulosis represents a pseudolymphoma or a true lymphoma. Lymphomatoid papulosis may represent an early indolent form of CTCL.⁴

Pseudolymphomas can be triggered by a variety of causes. Most cases are idiopathic, and a causative stimulus is never identified. Drugs are known to cause many cases of pseudolymphoma, either by a causing a hypersensitivity reaction or by depressing immunosurveillance.⁵ Pseudolymphomas may result from exogenous stimuli such as jewelry, tattoo dyes, injectable fillers (eg, silicone), insect bites, vaccines, and trauma.^6,7 Lastly, infections in the form of Borrelia, varicella, and molluscum contagiosum can potentially cause pseudolymphomas.⁴

Clinically, pseudolymphomas may demonstrate a B-cell or T-cell pattern. In cutaneous B-cell pseudolymphomas, asymptomatic solitary erythematous, violaceous, or flesh-colored nodules appear on the face, followed by the chest and arms. Cutaneous T-cell pseudolymphomas present with erythematous patches that are more likely to be symptomatic.⁴

Histologically, pseudolymphomas also are classified as demonstrating B-cell or T-cell patterns. The nodular inflammatory infiltrate of cutaneous B-cell pseudolymphoma corresponds with its clinically apparent nodules. It can be distinguished from lymphoma in that it is not solely a lymphocytic infiltrate but rather a mixed infiltrate including histiocytes, lymphocytes, eosinophils, and plasma cells. Additionally, cutaneous B-cell pseudolymphoma does not penetrate the dermis as deeply as CBCL.⁸ Cutaneous T-cell pseudolymphoma is more difficult to distinguish from CTCL because it also demonstrates a bandlike lymphocytic infiltrate in the papillary dermis with epidermotropism.⁹

Treatment must address the underlying cause of pseudolymphoma for resolution. Other treatment options include surgery, cryotherapy, local radiotherapy, topical steroids, and topical immunomodulators. Spontaneous resolution also can occur. The prognosis is better when a known trigger is eliminated, though idiopathic pseudolymphomas may be chronic in nature. It is important to rule out concurrent cutaneous lymphoma or rare transformation into cutaneous lymphoma.

Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas are a diverse group of neoplasms that account for most cutaneous lymphomas seen by dermatologists. In 1806, the first case of CTCL in the form of mycosis fungoides (MF) was described by Jean Louis Alibert. Mycosis fungoides represents the most common form of CTCL, accounting for approximately 50% of all primary cutaneous lymphomas.¹⁰ Mycosis fungoides was named after its morphological resemblance to mushrooms. Although not all cases exhibit a classic progression, MF is known for its stepwise progression from patch stage to tumor stage.

Clinically, lesions typically begin as patches that progress to plaques and finally tumors. This progression may not always occur and often can take years to decades to progress. Patches are characterized by erythematous, finely scaling lesions that may be easily confused with eczema or psoriasis. Lesions occur primarily in a swimming trunk distribution.

Mycosis fungoides histologically demonstrates a bandlike lymphocytic infiltrate with epidermotropism, which occurs when lymphocytes infiltrate the epidermis without spongiosis. These lymphocytes are larger, darker, and more angulated than normal lymphocytes. Intraepidermal nests of these atypical lymphocytes creating Pautrier microabscesses may be present. Tumor-stage lesions demonstrate diminished epidermotropism with dense sheets of lymphocytes in the dermis, and fat cells with cerebriform nuclei are present.

Therapies for MF may control the disease but may not prolong patients’ lives. Topical corticosteroids, phototherapy, and radiotherapy are options for skin-targeting therapies. Systemic chemotherapy and biological response modifiers also are viable treatment options. Prognosis for MF is poor.

There are a few notable variants of MF that are important to consider. Sézary syndrome is an erythrodermic variant of MF characterized by atypical Sézary cells. Clinically, it presents with generalized erythroderma with leonine facies, facial edema, and alopecia with associated symptoms of burning and pruritus. Histologically, Sézary syndrome is similar to MF with an increased CD4:CD8 ratio.¹⁰ Sézary syndrome may be treated with methotrexate or photopheresis, but the prognosis remains poor with an average survival of 5 years.

Cutaneous B-Cell Lymphoma
There are 5 types of primary CBCL: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, other; precursor B-cell lymphoblastic lymphoma; and primary cutaneous DLBCLLT, which was seen in our patient.¹¹

Primary cutaneous follicle center lymphoma is an indolent neoplastic proliferation in the skin. Clinically, it presents with solitary or grouped pinkish purple papules, plaques, or nodules on the trunk with surrounding patches of erythema.³ Lesions located on the back are referred to as Crosti lymphoma. Histopathology reveals a lymphocytic infiltrate with a diffuse follicular pattern and large round centroblasts, centrocytes, and immunoblasts with epidermal sparing. Tumor cells stain positively for κ or λ light chains, as well as CD20, CD79a, and B-cell lymphoma 6 (BCL-6); however, staining for the protein product of BCL-2 may be negative, which differentiates this form of CBCL from primary nodal B-cell lymphoma. Staining for MUM-1 may be negative, which contrasts with the strong expression seen in DLBCLLT. The follicular pattern of follicle center lymphoma stains positive for CD10, but the diffuse pattern may be CD10 negative. The prognosis for primary cutaneous follicle center lymphoma is favorable, but the recurrence rate is up to 50%.³ Treatment includes local radiotherapy or surgical excision.

Primary cutaneous marginal zone B-cell lymphoma is another indolent primary CBCL subtype that is closely related to mucosa-associated lymphoid tissue lymphomas and arises in areas of acrodermatitis chronica atrophicans and Borrelia infection. Clinically, it presents with recurrent, asymptomatic, red-brown papules, plaques, and nodules of the arms and legs. Histologically, there is a patchy infiltrate in the dermis and subcutis with sparing of the epidermis with pale-staining cells with indented nuclei, along with plasma cells and eosinophils. Primary cutaneous marginal zone B-cell lymphoma typically does not demonstrate epidermotropism. Centrocyte cells stain positively for CD20, CD79a, and BCL-2. The prognosis of primary cutaneous marginal zone B-cell lymphoma is favorable. Treatment is similar to primary cutaneous follicle center lymphoma with surgical excision, radiotherapy, and surveillance being the main modalities.

Primary cutaneous diffuse large B-cell lymphoma, other is an intermediately aggressive form of primary CBCL that is thought to be related to primary cutaneous DLBCLLT. Clinically, it presents with indurated erythematous to violaceous plaques on the trunk and thighs that may resemble a vascular tumor or panniculitis.^2,12 Histopathologically, this form of lymphoma presents with a round cell morphology without BCL-2 expression, which distinguishes it from DLBCLLT. If limited to skin, the prognosis is better than the systemic form but is still less favorable than other forms of CBCL.

Precursor B-cell lymphoblastic lymphoma is an extremely rare type of CBCL that potentially can occur in the skin. It primarily affects children and young adults. Clinically, it presents as a solitary large erythematous tumor of the head. Histologically, monomorphic proliferation of medium-sized cells with round nuclei that demonstrate a starry sky pattern with multiple mitotic cells can be observed.¹³ Immunohistochemical markers such as CD43, CD10, CD20, and CD79a may be positive. The disease is very aggressive with poor prognosis if left untreated.

CONCLUSION

We present a rare case of primary cutaneous DLBCLLT. Our case demonstrates the classic presentation of primary cutaneous DLBCLLT in a 74-year-old woman with a tumor on the lower left leg. Histologically, a dense dermal and subcutis infiltrate of centroblasts and immunoblasts with a grenz zone was present. Immunostaining in our patient was consistent with characteristic findings in the literature, staining highly positive for BCL-2 and MUM-1. Primary cutaneous DLBCLLT is an extremely rare and unique form of cutaneous lymphoma that can have potentially fatal consequences if undiagnosed; therefore, clinicians must take great care to make the correct diagnosis based on a knowledge of the clinical and immunohistochemical findings of DLBCLLT.

CASE REPORT

A 74-year-old woman presented with a painful lesion on the left lower leg that was getting larger and more edematous and erythematous over the last 5 months. She experienced numbness and burning of the left lower leg 1 year prior to the development of the lesion. A review of her medical history revealed an otherwise healthy woman with no constitutional symptoms of fever, chills, nausea, vomiting, diarrhea, or chest pain. The patient did not exhibit mucosal, genital, or nail involvement. Physical examination revealed a group of four 1-cm, ill-defined, irregularly bordered, violaceous plaques on the left anterior tibial leg with faint surrounding erythematous to violaceous patches (Figure 1). The plaques were tender to palpation with no bleeding or drainage.

An 8.0-mm punch biopsy of the lesion was obtained. Hematoxylin and eosin staining on low-power magnification demonstrated a diffuse lymphocytic inflammatory infiltrate in the dermis and subcutis. Notable sparing of the subepidermal area (free grenz zone) was present (Figure 2A). On higher power, centroblasts and immunoblasts were visualized alongside extravasated red blood cells (Figure 2B). A diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCLLT) was made. Various immunohistochemical stains confirmed the diagnosis, including B-cell lymphoma 2 (BCL-2)(Figure 3A) and multiple myeloma oncogene 1 (MUM-1)(Figure 3B), which were highly positive in our patient. The patient had a negative bone marrow biopsy and positron emission tomography scan. She was started on rituximab infusions and multiple radiation treatments. At 2-year follow-up the lymphoma continued to recur despite radiation therapy.

COMMENT

Incidence and Clinical Characteristics

Primary cutaneous DLBCLLT is an intermediately aggressive form of primary cutaneous B-cell lymphoma (CBCL) that accounts for approximately 10% to 20% of all primary CBCLs and 1% to 3% of all cutaneous lymphomas.¹ Diffuse large B-cell lymphoma, leg type primarily affects elderly patients (median age, 70 years). Women are more commonly affected. Clinically, primary cutaneous DLBCLLT presents as red-brown to bluish nodules or tumors on one or both distal legs. Although referred to as leg-type diffuse large B-cell lymphoma, 10% to 15% of patients have lesions in anatomic areas other than the legs, most commonly the trunk.

Histopathology

The diagnosis of DLBCLLT is best made histologically. There is a dense inflammatory infiltrate present in the dermis and subcutis that may extend upward into the dermoepidermal junction. Often a subepidermal free grenz zone may be seen, and adnexal structures may be destroyed. This infiltrate is composed of confluent sheets of large round cells including centroblasts and immunoblasts.² Centroblasts are large cells that have nuclei with several small nucleoli adhering to the membrane, while immunoblasts are large round cells containing nuclei with large central nucleoli. Both centroblasts and immunoblasts stain positively for BCL-2. Centrocytes typically are absent. Staining for BCL-2 can be important in distinguishing DLBCLLT from other forms of CBCL. Diffuse large B-cell lymphoma, leg type also can demonstrate clusters of large atypical cells in the epidermis simulating epidermotropism and Pautrier microabscesses. Neoplastic cells in this condition may express monoclonal surface and cytoplasmic immunoglobulins. Primary cutaneous DLBCLLT typically is positive for B-cell markers CD20 and CD79a. Additionally, MUM-1/IRF4 (interferon regulatory factor 4) and forkhead box protein 1 (FOXP1) are strongly expressed by most patients, which helps distinguish it from other forms of CBCL.

Treatment

Diffuse large B-cell lymphoma, leg type is a relatively aggressive form of CBCL that requires more aggressive treatment than the conservative watchful waiting of some of the more indolent forms of primary CBCL. One regimen involves using cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Local chemotherapy or radiation with rituximab is another treatment option.^1,2 In patients with severe comorbidities, rituximab alone may be administered. The prognosis for DLBCLLT is not as favorable as other types of primary CBCL, with an estimated 5-year survival rate of approximately 50%.²

Differential Diagnosis

Lymphomas are malignancies of the lymphocytes that may be subdivided depending on the organ of origin. Both primary nodal lymphomas and primary cutaneous lymphomas exist. Primary nodal lymphomas arise from the lymph nodes and are divided into Hodgkin and non-Hodgkin lymphomas. There are 2 major types of primary cutaneous lymphomas: cutaneous T-cell lymphoma (CTCL) and CBCL. Most primary cutaneous lymphomas are CTCLs, accounting for 75% to 80%.³

Pseudolymphoma
Pseudolymphoma is an inflammatory condition that may histologically mimic cutaneous lymphoma but has a benign clinical course. Pseudolymphoma is not a specific disease but rather is a reactive lymphoproliferative response to a known or unknown stimulus.⁴ Pseudolymphoma can be broken down into 2 or 3 major categories: cutaneous B-cell pseudolymphoma; cutaneous T-cell pseudolymphoma; and debatably lymphomatoid papulosis, a chronic, self-remitting, papulonecrotic condition that resembles lymphoma histologically but clinically appears benign. It is unknown if lymphomatoid papulosis represents a pseudolymphoma or a true lymphoma. Lymphomatoid papulosis may represent an early indolent form of CTCL.⁴

Pseudolymphomas can be triggered by a variety of causes. Most cases are idiopathic, and a causative stimulus is never identified. Drugs are known to cause many cases of pseudolymphoma, either by a causing a hypersensitivity reaction or by depressing immunosurveillance.⁵ Pseudolymphomas may result from exogenous stimuli such as jewelry, tattoo dyes, injectable fillers (eg, silicone), insect bites, vaccines, and trauma.^6,7 Lastly, infections in the form of Borrelia, varicella, and molluscum contagiosum can potentially cause pseudolymphomas.⁴

Clinically, pseudolymphomas may demonstrate a B-cell or T-cell pattern. In cutaneous B-cell pseudolymphomas, asymptomatic solitary erythematous, violaceous, or flesh-colored nodules appear on the face, followed by the chest and arms. Cutaneous T-cell pseudolymphomas present with erythematous patches that are more likely to be symptomatic.⁴

Histologically, pseudolymphomas also are classified as demonstrating B-cell or T-cell patterns. The nodular inflammatory infiltrate of cutaneous B-cell pseudolymphoma corresponds with its clinically apparent nodules. It can be distinguished from lymphoma in that it is not solely a lymphocytic infiltrate but rather a mixed infiltrate including histiocytes, lymphocytes, eosinophils, and plasma cells. Additionally, cutaneous B-cell pseudolymphoma does not penetrate the dermis as deeply as CBCL.⁸ Cutaneous T-cell pseudolymphoma is more difficult to distinguish from CTCL because it also demonstrates a bandlike lymphocytic infiltrate in the papillary dermis with epidermotropism.⁹

Treatment must address the underlying cause of pseudolymphoma for resolution. Other treatment options include surgery, cryotherapy, local radiotherapy, topical steroids, and topical immunomodulators. Spontaneous resolution also can occur. The prognosis is better when a known trigger is eliminated, though idiopathic pseudolymphomas may be chronic in nature. It is important to rule out concurrent cutaneous lymphoma or rare transformation into cutaneous lymphoma.

Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas are a diverse group of neoplasms that account for most cutaneous lymphomas seen by dermatologists. In 1806, the first case of CTCL in the form of mycosis fungoides (MF) was described by Jean Louis Alibert. Mycosis fungoides represents the most common form of CTCL, accounting for approximately 50% of all primary cutaneous lymphomas.¹⁰ Mycosis fungoides was named after its morphological resemblance to mushrooms. Although not all cases exhibit a classic progression, MF is known for its stepwise progression from patch stage to tumor stage.

Clinically, lesions typically begin as patches that progress to plaques and finally tumors. This progression may not always occur and often can take years to decades to progress. Patches are characterized by erythematous, finely scaling lesions that may be easily confused with eczema or psoriasis. Lesions occur primarily in a swimming trunk distribution.

Mycosis fungoides histologically demonstrates a bandlike lymphocytic infiltrate with epidermotropism, which occurs when lymphocytes infiltrate the epidermis without spongiosis. These lymphocytes are larger, darker, and more angulated than normal lymphocytes. Intraepidermal nests of these atypical lymphocytes creating Pautrier microabscesses may be present. Tumor-stage lesions demonstrate diminished epidermotropism with dense sheets of lymphocytes in the dermis, and fat cells with cerebriform nuclei are present.

Therapies for MF may control the disease but may not prolong patients’ lives. Topical corticosteroids, phototherapy, and radiotherapy are options for skin-targeting therapies. Systemic chemotherapy and biological response modifiers also are viable treatment options. Prognosis for MF is poor.

There are a few notable variants of MF that are important to consider. Sézary syndrome is an erythrodermic variant of MF characterized by atypical Sézary cells. Clinically, it presents with generalized erythroderma with leonine facies, facial edema, and alopecia with associated symptoms of burning and pruritus. Histologically, Sézary syndrome is similar to MF with an increased CD4:CD8 ratio.¹⁰ Sézary syndrome may be treated with methotrexate or photopheresis, but the prognosis remains poor with an average survival of 5 years.

Cutaneous B-Cell Lymphoma
There are 5 types of primary CBCL: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, other; precursor B-cell lymphoblastic lymphoma; and primary cutaneous DLBCLLT, which was seen in our patient.¹¹

Primary cutaneous follicle center lymphoma is an indolent neoplastic proliferation in the skin. Clinically, it presents with solitary or grouped pinkish purple papules, plaques, or nodules on the trunk with surrounding patches of erythema.³ Lesions located on the back are referred to as Crosti lymphoma. Histopathology reveals a lymphocytic infiltrate with a diffuse follicular pattern and large round centroblasts, centrocytes, and immunoblasts with epidermal sparing. Tumor cells stain positively for κ or λ light chains, as well as CD20, CD79a, and B-cell lymphoma 6 (BCL-6); however, staining for the protein product of BCL-2 may be negative, which differentiates this form of CBCL from primary nodal B-cell lymphoma. Staining for MUM-1 may be negative, which contrasts with the strong expression seen in DLBCLLT. The follicular pattern of follicle center lymphoma stains positive for CD10, but the diffuse pattern may be CD10 negative. The prognosis for primary cutaneous follicle center lymphoma is favorable, but the recurrence rate is up to 50%.³ Treatment includes local radiotherapy or surgical excision.

Primary cutaneous marginal zone B-cell lymphoma is another indolent primary CBCL subtype that is closely related to mucosa-associated lymphoid tissue lymphomas and arises in areas of acrodermatitis chronica atrophicans and Borrelia infection. Clinically, it presents with recurrent, asymptomatic, red-brown papules, plaques, and nodules of the arms and legs. Histologically, there is a patchy infiltrate in the dermis and subcutis with sparing of the epidermis with pale-staining cells with indented nuclei, along with plasma cells and eosinophils. Primary cutaneous marginal zone B-cell lymphoma typically does not demonstrate epidermotropism. Centrocyte cells stain positively for CD20, CD79a, and BCL-2. The prognosis of primary cutaneous marginal zone B-cell lymphoma is favorable. Treatment is similar to primary cutaneous follicle center lymphoma with surgical excision, radiotherapy, and surveillance being the main modalities.

Primary cutaneous diffuse large B-cell lymphoma, other is an intermediately aggressive form of primary CBCL that is thought to be related to primary cutaneous DLBCLLT. Clinically, it presents with indurated erythematous to violaceous plaques on the trunk and thighs that may resemble a vascular tumor or panniculitis.^2,12 Histopathologically, this form of lymphoma presents with a round cell morphology without BCL-2 expression, which distinguishes it from DLBCLLT. If limited to skin, the prognosis is better than the systemic form but is still less favorable than other forms of CBCL.

Precursor B-cell lymphoblastic lymphoma is an extremely rare type of CBCL that potentially can occur in the skin. It primarily affects children and young adults. Clinically, it presents as a solitary large erythematous tumor of the head. Histologically, monomorphic proliferation of medium-sized cells with round nuclei that demonstrate a starry sky pattern with multiple mitotic cells can be observed.¹³ Immunohistochemical markers such as CD43, CD10, CD20, and CD79a may be positive. The disease is very aggressive with poor prognosis if left untreated.

CONCLUSION

We present a rare case of primary cutaneous DLBCLLT. Our case demonstrates the classic presentation of primary cutaneous DLBCLLT in a 74-year-old woman with a tumor on the lower left leg. Histologically, a dense dermal and subcutis infiltrate of centroblasts and immunoblasts with a grenz zone was present. Immunostaining in our patient was consistent with characteristic findings in the literature, staining highly positive for BCL-2 and MUM-1. Primary cutaneous DLBCLLT is an extremely rare and unique form of cutaneous lymphoma that can have potentially fatal consequences if undiagnosed; therefore, clinicians must take great care to make the correct diagnosis based on a knowledge of the clinical and immunohistochemical findings of DLBCLLT.

A 44-year-old woman presented to the ED complaining of crampy lower abdominal pain with nausea and vomiting. The patient described gradual onset 2 days prior, with symptoms worsening over the previous 12 hours. She denied diarrhea, constipation, or blood in her stool. She did admit to frequency of urination, but no dysuria or hematuria. She was gravida 2, para 2, aborta 0, with a last menstrual period 3 weeks prior. She denied vaginal bleeding or discharge. Her past medical history was unremarkable, she was on no medications, and denied alcohol use. She did admit to smoking one pack of cigarettes per day.

On physical examination, the patient’s vital signs were: blood pressure, 132/68 mm Hg; heart rate, 96 beats/min; respiratory rate, 18 breaths/min; and temperature, 99.8°F. Oxygen saturation was 99% on room air.

The head, ears, eyes, nose, and throat (HEENT) examination was completely normal, as was the heart and lung examination. The patient was tender to palpation in the lower abdomen, but without guarding or rebound. Bowel sounds were present and normoactive. A pelvic examination, including a bimanual examination, demonstrated mild left ovarian tenderness but without mass or cervical motion tenderness. The patient did not exhibit any costovertebral angle tenderness bilaterally. No rectal examination was performed.

The emergency physicians (EPs) ordered a complete blood count (CBC), basic metabolic profile (BMP), urinalysis, urine pregnancy test, and a vaginal wet preparation. In addition, the patient was administered 500 cc’s of normal saline intravenously (IV) and ondansetron (Zofran) 4 mg IV.

The urine pregnancy test result came back negative. The urinalysis was remarkable for positive leukocyte esterase, with five to 10 white cells and bacteria present. The CBC showed a mild leukocytosis, but with a normal hemoglobin and hematocrit. The BMP and vaginal wet preparation were completely normal.

The EP was concerned the patient might have something more serious than a simple urinary tract infection (UTI), so she ordered a computed tomography (CT) scan of the abdomen and pelvis with IV contrast.

The radiologist interpreted the CT scan as normal. The patient was discharged home with a prescription for an antibiotic for her UTI, encouraged to drink liquids, and instructed to follow-up with her primary care physician in 1 week.

The patient returned to the same ED approximately 48 hours later with worsening abdominal pain. On this presentation, she was tachycardic (110 beats/min) with a temperature of 101°F. The abdominal examination was remarkable for diffuse tenderness and voluntary guarding. The patient was administered IV fluids, morphine, and ondansetron. A repeat CT scan of the abdomen and pelvis with IV contrast showed a perforated sigmoid colon, with leakage of bowel contents into the peritoneum. The EP immediately started IV fluid resuscitation and administered IV antibiotics. The patient was taken emergently to the operating room by general surgery. The colon was repaired and a colostomy placed. The patient was able to be discharged home on day number 5.

The patient sued the hospital and the treating EP for failure to make the proper diagnosis on the initial ED visit, resulting in the patient having a long and difficult recovery, and the need for a colostomy. At trial, the jury returned a defense verdict.

Discussion

Diverticulitis, and its complications, account for a significant number of ED visits. It is the third most common inpatient gastrointestinal diagnosis in the United States, costing two billion dollars annually.¹It is defined as clinically evident microscopic inflammation of a diverticulum or diverticula, and occurs in approximately 4% of patients with diverticulosis.¹It is estimated that roughly 15% of these patients will experience a complication, defined as an abscess, perforation, fistula, or colonic obstruction; 15% to 30% will experience a recurrence.

The mean age of patients admitted to the hospital for diverticulitis is 63 years. While considered a disease of older patients, it should be included in the differential diagnosis for younger patients, as approximately 16% of admissions for acute diverticulitis are in patients less than 45 years.²Risk factors include poor diet (ie, low fiber, high fat, red meat), obesity, and smoking. The clinical presentation of diverticulitis has sometimes been referred to as “left-sided appendicitis” because of the similarities between the two entities. Patients will frequently complain of anorexia, change in bowel habits (either diarrhea or constipation), crampy abdominal pain (primarily in the left lower quadrant), low grade fever, and nausea with vomiting. Interestingly, 10% to 15% of patients with acute diverticulitis will complain of dysuria, urgency, or frequency (as in this patient) due to irritation of the bladder from an inflamed sigmoid colon.

Physical examination may reveal a low grade fever and tachycardia, if significant vomiting has been present. The abdomen is tender primarily in the left lower quadrant. The presence of severe tachycardia, hypotension, or a rigid abdomen with guarding and rebound suggests perforation. A pelvic examination should be performed on all women of child-bearing age. The rectal examination may reveal hemoccult positive stool; gross blood is rare.

Laboratory testing should include a CBC, BMP, urinalysis, and a urine pregnancy test (for women of child-bearing age). The CBC will usually reveal a mild leukocytosis. The urinalysis may reveal sterile pyuria for the reason previously described. Additional testing may be indicated by the history and physical examination.

A CT scan of the abdomen and pelvis is considered the gold standard with regards to imaging, with a reported sensitivity of 94% and specificity of 99%.³ Ideally, the CT scan should include both oral and IV contrast; however, IV alone is frequently used. In addition to identifying diverticulitis, CT can also visualize complications, including abscesses, perforation, and bowel obstruction. Ultrasound using high-resolution, graded compassion has a similar sensitivity and specificity as CT, with the advantage of less cost, can be performed at the bedside, and avoids radiation exposure.³ However, it is operator dependent and inferior to CT regarding visualizing complications.

Historically, antibiotics have been considered the treatment of choice for patients with acute uncomplicated diverticulitis, usually as an outpatient. Typically, this involves prescribing ciprofloxacin (or trimethoprim-sulfamethoxazole) plus metronidazole for 7 to 10 days. Monotherapy consisting of either moxifloxacin or amoxicillin/clavulanic acid is also acceptable. However, as our understanding of the important role of inflammation in this disease process, combined with the negative effects associated with antibiotic use, the role of antibiotics in uncomplicated diverticulitis has been called into question. In one recent study of 155 patients with acute uncomplicated diverticulitis, 97% were managed successfully as outpatients without antibiotics, admission, or complications.⁴ The American Gastroenterological Association (AGA) recommends that antibiotics should be used selectively, rather than routinely, in patients with acute uncomplicated diverticulitis. However, this is considered a “conditional recommendation with a low quality of evidence.”¹In other words, this recommendation could easily change based on newer studies. Similarly, other “conditional recommendations” by the AGA include suggesting a fiber-rich diet, or fiber supplementation, and no need to avoid the consumption of nuts and popcorn.¹ The majority of these patients begin to feel better in 2 to 3 days and have a good outcome.

Summary

For patients that appear ill, have significant comorbidities, are immunocompromised, or have a complication of acute diverticulitis, admission to the hospital with surgery consultation is recommended. For abscesses, interventional radiology has been used with success for CT-guided percutaneous drainage of diverticular abscesses. Intravenous antibiotics should be initiated; appropriate medications include metronidazole plus a third-generation cephalosporin (such as ceftriaxone or cefotaxime) or a fluoroquinolone (such as ciprofloxacin or levofloxacin). Monotherapy for the moderately ill patient includes piperacillin/tazobactam, ampicillin/sulbactam, ticarcillin/clavulanic acid, and imipenem. In addition, these patients should be placed at bowel rest (ie, nothing by mouth) with IV fluid resuscitation and hydration.

A 44-year-old woman presented to the ED complaining of crampy lower abdominal pain with nausea and vomiting. The patient described gradual onset 2 days prior, with symptoms worsening over the previous 12 hours. She denied diarrhea, constipation, or blood in her stool. She did admit to frequency of urination, but no dysuria or hematuria. She was gravida 2, para 2, aborta 0, with a last menstrual period 3 weeks prior. She denied vaginal bleeding or discharge. Her past medical history was unremarkable, she was on no medications, and denied alcohol use. She did admit to smoking one pack of cigarettes per day.

On physical examination, the patient’s vital signs were: blood pressure, 132/68 mm Hg; heart rate, 96 beats/min; respiratory rate, 18 breaths/min; and temperature, 99.8°F. Oxygen saturation was 99% on room air.

The head, ears, eyes, nose, and throat (HEENT) examination was completely normal, as was the heart and lung examination. The patient was tender to palpation in the lower abdomen, but without guarding or rebound. Bowel sounds were present and normoactive. A pelvic examination, including a bimanual examination, demonstrated mild left ovarian tenderness but without mass or cervical motion tenderness. The patient did not exhibit any costovertebral angle tenderness bilaterally. No rectal examination was performed.

The emergency physicians (EPs) ordered a complete blood count (CBC), basic metabolic profile (BMP), urinalysis, urine pregnancy test, and a vaginal wet preparation. In addition, the patient was administered 500 cc’s of normal saline intravenously (IV) and ondansetron (Zofran) 4 mg IV.

The urine pregnancy test result came back negative. The urinalysis was remarkable for positive leukocyte esterase, with five to 10 white cells and bacteria present. The CBC showed a mild leukocytosis, but with a normal hemoglobin and hematocrit. The BMP and vaginal wet preparation were completely normal.

The EP was concerned the patient might have something more serious than a simple urinary tract infection (UTI), so she ordered a computed tomography (CT) scan of the abdomen and pelvis with IV contrast.

The radiologist interpreted the CT scan as normal. The patient was discharged home with a prescription for an antibiotic for her UTI, encouraged to drink liquids, and instructed to follow-up with her primary care physician in 1 week.

The patient returned to the same ED approximately 48 hours later with worsening abdominal pain. On this presentation, she was tachycardic (110 beats/min) with a temperature of 101°F. The abdominal examination was remarkable for diffuse tenderness and voluntary guarding. The patient was administered IV fluids, morphine, and ondansetron. A repeat CT scan of the abdomen and pelvis with IV contrast showed a perforated sigmoid colon, with leakage of bowel contents into the peritoneum. The EP immediately started IV fluid resuscitation and administered IV antibiotics. The patient was taken emergently to the operating room by general surgery. The colon was repaired and a colostomy placed. The patient was able to be discharged home on day number 5.

The patient sued the hospital and the treating EP for failure to make the proper diagnosis on the initial ED visit, resulting in the patient having a long and difficult recovery, and the need for a colostomy. At trial, the jury returned a defense verdict.

Discussion

Diverticulitis, and its complications, account for a significant number of ED visits. It is the third most common inpatient gastrointestinal diagnosis in the United States, costing two billion dollars annually.¹It is defined as clinically evident microscopic inflammation of a diverticulum or diverticula, and occurs in approximately 4% of patients with diverticulosis.¹It is estimated that roughly 15% of these patients will experience a complication, defined as an abscess, perforation, fistula, or colonic obstruction; 15% to 30% will experience a recurrence.

The mean age of patients admitted to the hospital for diverticulitis is 63 years. While considered a disease of older patients, it should be included in the differential diagnosis for younger patients, as approximately 16% of admissions for acute diverticulitis are in patients less than 45 years.²Risk factors include poor diet (ie, low fiber, high fat, red meat), obesity, and smoking. The clinical presentation of diverticulitis has sometimes been referred to as “left-sided appendicitis” because of the similarities between the two entities. Patients will frequently complain of anorexia, change in bowel habits (either diarrhea or constipation), crampy abdominal pain (primarily in the left lower quadrant), low grade fever, and nausea with vomiting. Interestingly, 10% to 15% of patients with acute diverticulitis will complain of dysuria, urgency, or frequency (as in this patient) due to irritation of the bladder from an inflamed sigmoid colon.

Physical examination may reveal a low grade fever and tachycardia, if significant vomiting has been present. The abdomen is tender primarily in the left lower quadrant. The presence of severe tachycardia, hypotension, or a rigid abdomen with guarding and rebound suggests perforation. A pelvic examination should be performed on all women of child-bearing age. The rectal examination may reveal hemoccult positive stool; gross blood is rare.

Laboratory testing should include a CBC, BMP, urinalysis, and a urine pregnancy test (for women of child-bearing age). The CBC will usually reveal a mild leukocytosis. The urinalysis may reveal sterile pyuria for the reason previously described. Additional testing may be indicated by the history and physical examination.

A CT scan of the abdomen and pelvis is considered the gold standard with regards to imaging, with a reported sensitivity of 94% and specificity of 99%.³ Ideally, the CT scan should include both oral and IV contrast; however, IV alone is frequently used. In addition to identifying diverticulitis, CT can also visualize complications, including abscesses, perforation, and bowel obstruction. Ultrasound using high-resolution, graded compassion has a similar sensitivity and specificity as CT, with the advantage of less cost, can be performed at the bedside, and avoids radiation exposure.³ However, it is operator dependent and inferior to CT regarding visualizing complications.

Historically, antibiotics have been considered the treatment of choice for patients with acute uncomplicated diverticulitis, usually as an outpatient. Typically, this involves prescribing ciprofloxacin (or trimethoprim-sulfamethoxazole) plus metronidazole for 7 to 10 days. Monotherapy consisting of either moxifloxacin or amoxicillin/clavulanic acid is also acceptable. However, as our understanding of the important role of inflammation in this disease process, combined with the negative effects associated with antibiotic use, the role of antibiotics in uncomplicated diverticulitis has been called into question. In one recent study of 155 patients with acute uncomplicated diverticulitis, 97% were managed successfully as outpatients without antibiotics, admission, or complications.⁴ The American Gastroenterological Association (AGA) recommends that antibiotics should be used selectively, rather than routinely, in patients with acute uncomplicated diverticulitis. However, this is considered a “conditional recommendation with a low quality of evidence.”¹In other words, this recommendation could easily change based on newer studies. Similarly, other “conditional recommendations” by the AGA include suggesting a fiber-rich diet, or fiber supplementation, and no need to avoid the consumption of nuts and popcorn.¹ The majority of these patients begin to feel better in 2 to 3 days and have a good outcome.

Summary

For patients that appear ill, have significant comorbidities, are immunocompromised, or have a complication of acute diverticulitis, admission to the hospital with surgery consultation is recommended. For abscesses, interventional radiology has been used with success for CT-guided percutaneous drainage of diverticular abscesses. Intravenous antibiotics should be initiated; appropriate medications include metronidazole plus a third-generation cephalosporin (such as ceftriaxone or cefotaxime) or a fluoroquinolone (such as ciprofloxacin or levofloxacin). Monotherapy for the moderately ill patient includes piperacillin/tazobactam, ampicillin/sulbactam, ticarcillin/clavulanic acid, and imipenem. In addition, these patients should be placed at bowel rest (ie, nothing by mouth) with IV fluid resuscitation and hydration.

A 44-year-old woman presented to the ED complaining of crampy lower abdominal pain with nausea and vomiting. The patient described gradual onset 2 days prior, with symptoms worsening over the previous 12 hours. She denied diarrhea, constipation, or blood in her stool. She did admit to frequency of urination, but no dysuria or hematuria. She was gravida 2, para 2, aborta 0, with a last menstrual period 3 weeks prior. She denied vaginal bleeding or discharge. Her past medical history was unremarkable, she was on no medications, and denied alcohol use. She did admit to smoking one pack of cigarettes per day.

On physical examination, the patient’s vital signs were: blood pressure, 132/68 mm Hg; heart rate, 96 beats/min; respiratory rate, 18 breaths/min; and temperature, 99.8°F. Oxygen saturation was 99% on room air.

The head, ears, eyes, nose, and throat (HEENT) examination was completely normal, as was the heart and lung examination. The patient was tender to palpation in the lower abdomen, but without guarding or rebound. Bowel sounds were present and normoactive. A pelvic examination, including a bimanual examination, demonstrated mild left ovarian tenderness but without mass or cervical motion tenderness. The patient did not exhibit any costovertebral angle tenderness bilaterally. No rectal examination was performed.

The emergency physicians (EPs) ordered a complete blood count (CBC), basic metabolic profile (BMP), urinalysis, urine pregnancy test, and a vaginal wet preparation. In addition, the patient was administered 500 cc’s of normal saline intravenously (IV) and ondansetron (Zofran) 4 mg IV.

The urine pregnancy test result came back negative. The urinalysis was remarkable for positive leukocyte esterase, with five to 10 white cells and bacteria present. The CBC showed a mild leukocytosis, but with a normal hemoglobin and hematocrit. The BMP and vaginal wet preparation were completely normal.

The EP was concerned the patient might have something more serious than a simple urinary tract infection (UTI), so she ordered a computed tomography (CT) scan of the abdomen and pelvis with IV contrast.

The radiologist interpreted the CT scan as normal. The patient was discharged home with a prescription for an antibiotic for her UTI, encouraged to drink liquids, and instructed to follow-up with her primary care physician in 1 week.

The patient returned to the same ED approximately 48 hours later with worsening abdominal pain. On this presentation, she was tachycardic (110 beats/min) with a temperature of 101°F. The abdominal examination was remarkable for diffuse tenderness and voluntary guarding. The patient was administered IV fluids, morphine, and ondansetron. A repeat CT scan of the abdomen and pelvis with IV contrast showed a perforated sigmoid colon, with leakage of bowel contents into the peritoneum. The EP immediately started IV fluid resuscitation and administered IV antibiotics. The patient was taken emergently to the operating room by general surgery. The colon was repaired and a colostomy placed. The patient was able to be discharged home on day number 5.

The patient sued the hospital and the treating EP for failure to make the proper diagnosis on the initial ED visit, resulting in the patient having a long and difficult recovery, and the need for a colostomy. At trial, the jury returned a defense verdict.

Discussion

Diverticulitis, and its complications, account for a significant number of ED visits. It is the third most common inpatient gastrointestinal diagnosis in the United States, costing two billion dollars annually.¹It is defined as clinically evident microscopic inflammation of a diverticulum or diverticula, and occurs in approximately 4% of patients with diverticulosis.¹It is estimated that roughly 15% of these patients will experience a complication, defined as an abscess, perforation, fistula, or colonic obstruction; 15% to 30% will experience a recurrence.

The mean age of patients admitted to the hospital for diverticulitis is 63 years. While considered a disease of older patients, it should be included in the differential diagnosis for younger patients, as approximately 16% of admissions for acute diverticulitis are in patients less than 45 years.²Risk factors include poor diet (ie, low fiber, high fat, red meat), obesity, and smoking. The clinical presentation of diverticulitis has sometimes been referred to as “left-sided appendicitis” because of the similarities between the two entities. Patients will frequently complain of anorexia, change in bowel habits (either diarrhea or constipation), crampy abdominal pain (primarily in the left lower quadrant), low grade fever, and nausea with vomiting. Interestingly, 10% to 15% of patients with acute diverticulitis will complain of dysuria, urgency, or frequency (as in this patient) due to irritation of the bladder from an inflamed sigmoid colon.

Physical examination may reveal a low grade fever and tachycardia, if significant vomiting has been present. The abdomen is tender primarily in the left lower quadrant. The presence of severe tachycardia, hypotension, or a rigid abdomen with guarding and rebound suggests perforation. A pelvic examination should be performed on all women of child-bearing age. The rectal examination may reveal hemoccult positive stool; gross blood is rare.

Laboratory testing should include a CBC, BMP, urinalysis, and a urine pregnancy test (for women of child-bearing age). The CBC will usually reveal a mild leukocytosis. The urinalysis may reveal sterile pyuria for the reason previously described. Additional testing may be indicated by the history and physical examination.

A CT scan of the abdomen and pelvis is considered the gold standard with regards to imaging, with a reported sensitivity of 94% and specificity of 99%.³ Ideally, the CT scan should include both oral and IV contrast; however, IV alone is frequently used. In addition to identifying diverticulitis, CT can also visualize complications, including abscesses, perforation, and bowel obstruction. Ultrasound using high-resolution, graded compassion has a similar sensitivity and specificity as CT, with the advantage of less cost, can be performed at the bedside, and avoids radiation exposure.³ However, it is operator dependent and inferior to CT regarding visualizing complications.

Historically, antibiotics have been considered the treatment of choice for patients with acute uncomplicated diverticulitis, usually as an outpatient. Typically, this involves prescribing ciprofloxacin (or trimethoprim-sulfamethoxazole) plus metronidazole for 7 to 10 days. Monotherapy consisting of either moxifloxacin or amoxicillin/clavulanic acid is also acceptable. However, as our understanding of the important role of inflammation in this disease process, combined with the negative effects associated with antibiotic use, the role of antibiotics in uncomplicated diverticulitis has been called into question. In one recent study of 155 patients with acute uncomplicated diverticulitis, 97% were managed successfully as outpatients without antibiotics, admission, or complications.⁴ The American Gastroenterological Association (AGA) recommends that antibiotics should be used selectively, rather than routinely, in patients with acute uncomplicated diverticulitis. However, this is considered a “conditional recommendation with a low quality of evidence.”¹In other words, this recommendation could easily change based on newer studies. Similarly, other “conditional recommendations” by the AGA include suggesting a fiber-rich diet, or fiber supplementation, and no need to avoid the consumption of nuts and popcorn.¹ The majority of these patients begin to feel better in 2 to 3 days and have a good outcome.

Summary

For patients that appear ill, have significant comorbidities, are immunocompromised, or have a complication of acute diverticulitis, admission to the hospital with surgery consultation is recommended. For abscesses, interventional radiology has been used with success for CT-guided percutaneous drainage of diverticular abscesses. Intravenous antibiotics should be initiated; appropriate medications include metronidazole plus a third-generation cephalosporin (such as ceftriaxone or cefotaxime) or a fluoroquinolone (such as ciprofloxacin or levofloxacin). Monotherapy for the moderately ill patient includes piperacillin/tazobactam, ampicillin/sulbactam, ticarcillin/clavulanic acid, and imipenem. In addition, these patients should be placed at bowel rest (ie, nothing by mouth) with IV fluid resuscitation and hydration.

A new definition in myocardial infarction. Also today, aspirin and fish oil flop in patients with diabetes, CT angiography cuts MI in patients with stable chest pain, and rivaroxaban is no help for heart failure outcomes.

A new definition in myocardial infarction. Also today, aspirin and fish oil flop in patients with diabetes, CT angiography cuts MI in patients with stable chest pain, and rivaroxaban is no help for heart failure outcomes.

A new definition in myocardial infarction. Also today, aspirin and fish oil flop in patients with diabetes, CT angiography cuts MI in patients with stable chest pain, and rivaroxaban is no help for heart failure outcomes.

WASHINGTON – Current guidelines recommend a minimum of annual screening for gonorrhea and chlamydia in all sexually active individuals with HIV infection. However, this goal, which is frequently not attained in HIV clinics, may be excessive in certain populations with HIV infection.

Courtesy CDC

In particular, women as well as men who have sex exclusively with women (MSW) may best be served by targeted, age-based screening rather than universal screening, according to a presentation by Susan A. Tuddenham, MD, an assistant professor of medicine at Johns Hopkins University, Baltimore.

“Detection and treatment of gonorrhea and chlamydia in HIV-positive patients in the United States is a priority both because of patient morbidity and because of the potential for these infections to enhance transmission of HIV,” said Dr. Tuddenham.

She and her colleagues assessed data from 16,864 gonorrhea and chlamydia tests of all adults in care at three HIV Research Network sites during 2011-2014. She presented the data at a conference on STD prevention sponsored by the Centers for Disease Control and Prevention.

They assessed the number needed to screen (NNS) in order to identify a single infection across three risk populations of individuals with HIV infection: 1,123 women, 1,236 men who have sex only with women (MSW), and 3,501 men who have sex with men (MSM). NNS was defined as the number of persons tested divided by the number who tested positive and was calculated for the three risk groups for urogenital and extragenital (rectal and pharyngeal) sampling and by age.

Dr. Tuddenham and her colleagues found that NNS based on urogenital screening was similar in all three groups for those individuals aged younger than or equal to 25 years: 15 for women (95% confidence interval, 9-71); 21 for MSW (95% CI, 6-171); and 20 for MSM (95% CI, 12-36). However at ages greater than 25 years, the picture changed, with urogenital NNS increasing to 363 for women (95% CI, 167-1000); 160 for MSW (95% CI, 100-333). For MSM over the age of 25 years, however, the NNS only increased to 46 (95% CI, 38-56).

There were insufficient numbers of extragenital screenings of women and MSW for analysis. But for MSM, rectal NNS was 5 and 10 for those men aged 25 years and younger and those aged over age 25 years, respectively, and pharyngeal NNS was 8 and 20 for the two groups, respectively.

“Our results provide some support for age-based screening cutoffs for women and MSW, with universal screening appropriate for those less than or equal to 25 years of age, and targeted screening for those over 25,” said Dr. Tuddenham. She emphasized the importance of continued universal screening of MSM of all ages for gonorrhea/chlamydia, in particular using extragenital screening as well in order to capture those missed by urogenital screening alone.

Dr. Tuddenham reported that she had no disclosures.

[email protected]

WASHINGTON – Current guidelines recommend a minimum of annual screening for gonorrhea and chlamydia in all sexually active individuals with HIV infection. However, this goal, which is frequently not attained in HIV clinics, may be excessive in certain populations with HIV infection.

Courtesy CDC

In particular, women as well as men who have sex exclusively with women (MSW) may best be served by targeted, age-based screening rather than universal screening, according to a presentation by Susan A. Tuddenham, MD, an assistant professor of medicine at Johns Hopkins University, Baltimore.

“Detection and treatment of gonorrhea and chlamydia in HIV-positive patients in the United States is a priority both because of patient morbidity and because of the potential for these infections to enhance transmission of HIV,” said Dr. Tuddenham.

She and her colleagues assessed data from 16,864 gonorrhea and chlamydia tests of all adults in care at three HIV Research Network sites during 2011-2014. She presented the data at a conference on STD prevention sponsored by the Centers for Disease Control and Prevention.

They assessed the number needed to screen (NNS) in order to identify a single infection across three risk populations of individuals with HIV infection: 1,123 women, 1,236 men who have sex only with women (MSW), and 3,501 men who have sex with men (MSM). NNS was defined as the number of persons tested divided by the number who tested positive and was calculated for the three risk groups for urogenital and extragenital (rectal and pharyngeal) sampling and by age.

Dr. Tuddenham and her colleagues found that NNS based on urogenital screening was similar in all three groups for those individuals aged younger than or equal to 25 years: 15 for women (95% confidence interval, 9-71); 21 for MSW (95% CI, 6-171); and 20 for MSM (95% CI, 12-36). However at ages greater than 25 years, the picture changed, with urogenital NNS increasing to 363 for women (95% CI, 167-1000); 160 for MSW (95% CI, 100-333). For MSM over the age of 25 years, however, the NNS only increased to 46 (95% CI, 38-56).

There were insufficient numbers of extragenital screenings of women and MSW for analysis. But for MSM, rectal NNS was 5 and 10 for those men aged 25 years and younger and those aged over age 25 years, respectively, and pharyngeal NNS was 8 and 20 for the two groups, respectively.

“Our results provide some support for age-based screening cutoffs for women and MSW, with universal screening appropriate for those less than or equal to 25 years of age, and targeted screening for those over 25,” said Dr. Tuddenham. She emphasized the importance of continued universal screening of MSM of all ages for gonorrhea/chlamydia, in particular using extragenital screening as well in order to capture those missed by urogenital screening alone.

Dr. Tuddenham reported that she had no disclosures.

[email protected]

WASHINGTON – Current guidelines recommend a minimum of annual screening for gonorrhea and chlamydia in all sexually active individuals with HIV infection. However, this goal, which is frequently not attained in HIV clinics, may be excessive in certain populations with HIV infection.

Courtesy CDC

In particular, women as well as men who have sex exclusively with women (MSW) may best be served by targeted, age-based screening rather than universal screening, according to a presentation by Susan A. Tuddenham, MD, an assistant professor of medicine at Johns Hopkins University, Baltimore.

“Detection and treatment of gonorrhea and chlamydia in HIV-positive patients in the United States is a priority both because of patient morbidity and because of the potential for these infections to enhance transmission of HIV,” said Dr. Tuddenham.

She and her colleagues assessed data from 16,864 gonorrhea and chlamydia tests of all adults in care at three HIV Research Network sites during 2011-2014. She presented the data at a conference on STD prevention sponsored by the Centers for Disease Control and Prevention.

They assessed the number needed to screen (NNS) in order to identify a single infection across three risk populations of individuals with HIV infection: 1,123 women, 1,236 men who have sex only with women (MSW), and 3,501 men who have sex with men (MSM). NNS was defined as the number of persons tested divided by the number who tested positive and was calculated for the three risk groups for urogenital and extragenital (rectal and pharyngeal) sampling and by age.

Dr. Tuddenham and her colleagues found that NNS based on urogenital screening was similar in all three groups for those individuals aged younger than or equal to 25 years: 15 for women (95% confidence interval, 9-71); 21 for MSW (95% CI, 6-171); and 20 for MSM (95% CI, 12-36). However at ages greater than 25 years, the picture changed, with urogenital NNS increasing to 363 for women (95% CI, 167-1000); 160 for MSW (95% CI, 100-333). For MSM over the age of 25 years, however, the NNS only increased to 46 (95% CI, 38-56).

There were insufficient numbers of extragenital screenings of women and MSW for analysis. But for MSM, rectal NNS was 5 and 10 for those men aged 25 years and younger and those aged over age 25 years, respectively, and pharyngeal NNS was 8 and 20 for the two groups, respectively.

“Our results provide some support for age-based screening cutoffs for women and MSW, with universal screening appropriate for those less than or equal to 25 years of age, and targeted screening for those over 25,” said Dr. Tuddenham. She emphasized the importance of continued universal screening of MSM of all ages for gonorrhea/chlamydia, in particular using extragenital screening as well in order to capture those missed by urogenital screening alone.

Dr. Tuddenham reported that she had no disclosures.

[email protected]

The baseline physical component score of the Medical Outcomes Short Form 36 (SF-36) was an independent predictor of mortality for patients with systemic lupus erythematosus (SLE), according to recent analysis of data from the University of California, San Francisco, (UCSF) Lupus Outcomes Study.

wildpixel/Thinkstock

Desiree R. Azizoddin, PsyD, of Stanford Health Care in Palo Alto, Calif., and her colleagues analyzed patient-reported outcomes (PROs) of 728 patients with SLE from the UCSF study, which included measures such as self-rated health, the Center for Epidemiologic Studies Depression scale (CESD), and SF-36 mental and physical component scores between 2007 and 2015. Patients had a mean age of 50.6 years and consisted of mostly whites (68.5%) and women (92.2%), with a mean SLE disease duration of 16.7 years.

“As PROs can be measured easily, quickly, reliably in a systematic manner, without use of many resources (including cost) and experts, PROs can serve as an important tool in community settings that provide care for individuals with SLE,” Dr. Azizoddin and her colleagues wrote in Arthritis Care & Research. “Implementation and integration of PROs may potentially help decrease mortality among patients with SLE in the long run.”

The researchers reported 71 deaths (9.8%) in the study. A univariate analysis showed that self-rated health as fair or poor and all SF-36 subscale scores, except for mental health and role emotional subscales, were predictors of mortality. After the investigators performed a multivariate analysis, they found that baseline SF-36 physical component scores alone were associated with an increased mortality risk (hazard ratio, 0.97; 95% confidence interval, 0.94-0.99; P less than .01), with a 3.5% lower risk for each point-rating increase in the score.

“Insight to predictors of mortality, above and beyond those that require physician resources such as assessments of renal involvement and traditional physician-completed measures of disease activity and damage in this complex disease, affords rheumatologists and SLE providers with additional tools to assess potential patient health trajectories,” Dr. Azizoddin and her colleagues wrote in their study. “Identification of such predictors will expand opportunities for early interventions aimed at the reduction of such risk, including allocation of appropriate medical resources in areas with large numbers of patients with compromised health.”

The researchers noted that bias in self-reporting, a lack of prospective evaluations at each visit, and clinical applicability to only similar cohorts were limitations in the study.

This study was funded by the Robert Wood Johnson Foundation Investigator Awards in Health Policy Research and individually was awarded grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

SOURCE: Azizoddin DR et al. Arthritis Care Res. 2018 Aug 24. doi: 10.1002/acr.23734.

The baseline physical component score of the Medical Outcomes Short Form 36 (SF-36) was an independent predictor of mortality for patients with systemic lupus erythematosus (SLE), according to recent analysis of data from the University of California, San Francisco, (UCSF) Lupus Outcomes Study.

wildpixel/Thinkstock

Desiree R. Azizoddin, PsyD, of Stanford Health Care in Palo Alto, Calif., and her colleagues analyzed patient-reported outcomes (PROs) of 728 patients with SLE from the UCSF study, which included measures such as self-rated health, the Center for Epidemiologic Studies Depression scale (CESD), and SF-36 mental and physical component scores between 2007 and 2015. Patients had a mean age of 50.6 years and consisted of mostly whites (68.5%) and women (92.2%), with a mean SLE disease duration of 16.7 years.

“As PROs can be measured easily, quickly, reliably in a systematic manner, without use of many resources (including cost) and experts, PROs can serve as an important tool in community settings that provide care for individuals with SLE,” Dr. Azizoddin and her colleagues wrote in Arthritis Care & Research. “Implementation and integration of PROs may potentially help decrease mortality among patients with SLE in the long run.”

The researchers reported 71 deaths (9.8%) in the study. A univariate analysis showed that self-rated health as fair or poor and all SF-36 subscale scores, except for mental health and role emotional subscales, were predictors of mortality. After the investigators performed a multivariate analysis, they found that baseline SF-36 physical component scores alone were associated with an increased mortality risk (hazard ratio, 0.97; 95% confidence interval, 0.94-0.99; P less than .01), with a 3.5% lower risk for each point-rating increase in the score.

“Insight to predictors of mortality, above and beyond those that require physician resources such as assessments of renal involvement and traditional physician-completed measures of disease activity and damage in this complex disease, affords rheumatologists and SLE providers with additional tools to assess potential patient health trajectories,” Dr. Azizoddin and her colleagues wrote in their study. “Identification of such predictors will expand opportunities for early interventions aimed at the reduction of such risk, including allocation of appropriate medical resources in areas with large numbers of patients with compromised health.”

The researchers noted that bias in self-reporting, a lack of prospective evaluations at each visit, and clinical applicability to only similar cohorts were limitations in the study.

This study was funded by the Robert Wood Johnson Foundation Investigator Awards in Health Policy Research and individually was awarded grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

SOURCE: Azizoddin DR et al. Arthritis Care Res. 2018 Aug 24. doi: 10.1002/acr.23734.

The baseline physical component score of the Medical Outcomes Short Form 36 (SF-36) was an independent predictor of mortality for patients with systemic lupus erythematosus (SLE), according to recent analysis of data from the University of California, San Francisco, (UCSF) Lupus Outcomes Study.

wildpixel/Thinkstock

Desiree R. Azizoddin, PsyD, of Stanford Health Care in Palo Alto, Calif., and her colleagues analyzed patient-reported outcomes (PROs) of 728 patients with SLE from the UCSF study, which included measures such as self-rated health, the Center for Epidemiologic Studies Depression scale (CESD), and SF-36 mental and physical component scores between 2007 and 2015. Patients had a mean age of 50.6 years and consisted of mostly whites (68.5%) and women (92.2%), with a mean SLE disease duration of 16.7 years.

“As PROs can be measured easily, quickly, reliably in a systematic manner, without use of many resources (including cost) and experts, PROs can serve as an important tool in community settings that provide care for individuals with SLE,” Dr. Azizoddin and her colleagues wrote in Arthritis Care & Research. “Implementation and integration of PROs may potentially help decrease mortality among patients with SLE in the long run.”

The researchers reported 71 deaths (9.8%) in the study. A univariate analysis showed that self-rated health as fair or poor and all SF-36 subscale scores, except for mental health and role emotional subscales, were predictors of mortality. After the investigators performed a multivariate analysis, they found that baseline SF-36 physical component scores alone were associated with an increased mortality risk (hazard ratio, 0.97; 95% confidence interval, 0.94-0.99; P less than .01), with a 3.5% lower risk for each point-rating increase in the score.

“Insight to predictors of mortality, above and beyond those that require physician resources such as assessments of renal involvement and traditional physician-completed measures of disease activity and damage in this complex disease, affords rheumatologists and SLE providers with additional tools to assess potential patient health trajectories,” Dr. Azizoddin and her colleagues wrote in their study. “Identification of such predictors will expand opportunities for early interventions aimed at the reduction of such risk, including allocation of appropriate medical resources in areas with large numbers of patients with compromised health.”

The researchers noted that bias in self-reporting, a lack of prospective evaluations at each visit, and clinical applicability to only similar cohorts were limitations in the study.

This study was funded by the Robert Wood Johnson Foundation Investigator Awards in Health Policy Research and individually was awarded grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

SOURCE: Azizoddin DR et al. Arthritis Care Res. 2018 Aug 24. doi: 10.1002/acr.23734.

The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.

Courtesy Novartis

Tisagenlecleucel will be available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.

NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.

Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.

The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

However, tisagenlecleucel will be available only for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.

“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.

The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.

Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta), has not fared as well as in England. The National Institute for Health and Care Excellence (NICE) recently issued draft guidance recommending against the use of axicabtagene ciloleucel in England.

Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy. However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and the therapy does not meet the criteria for inclusion in the Cancer Drugs Fund.

[email protected]

The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.

Courtesy Novartis

Tisagenlecleucel will be available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.

NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.

Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.

The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

However, tisagenlecleucel will be available only for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.

“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.

The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.

Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta), has not fared as well as in England. The National Institute for Health and Care Excellence (NICE) recently issued draft guidance recommending against the use of axicabtagene ciloleucel in England.

Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy. However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and the therapy does not meet the criteria for inclusion in the Cancer Drugs Fund.

[email protected]

The National Health Service (NHS) of England has announced that tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR) T-cell therapy, will soon be available for certain leukemia patients.

Courtesy Novartis

Tisagenlecleucel will be available through the Cancer Drugs Fund, and patients could potentially begin receiving the treatment within weeks.

NHS England struck a deal with Novartis to lower the price of tisagenlecleucel, which costs around £282,000 per patient at its full list price. The discount offered to the NHS is confidential.

Tisagenlecleucel was recently approved by the European Commission (EC) to treat patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.

The EC also approved tisagenlecleucel to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.

However, tisagenlecleucel will be available only for ALL patients in England, at least initially. A decision has not been made regarding funding for tisagenlecleucel in DLBCL, and Novartis previously decided to launch tisagenlecleucel in ALL first.

“It’s fantastic news for children and young people with this form of leukemia that CAR T-cell therapy will be made available on the NHS, making them the first in Europe to have routine access to this exciting new type of immunotherapy,” said Charles Swanton, Cancer Research UK’s chief clinician.

The first three NHS hospitals to go through the international accreditation process for the provision of tisagenlecleucel are in London, Manchester, and Newcastle. Subject to passing accreditation requirements, the first treatments could begin in a matter of weeks.

Another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta), has not fared as well as in England. The National Institute for Health and Care Excellence (NICE) recently issued draft guidance recommending against the use of axicabtagene ciloleucel in England.

Axicabtagene ciloleucel was approved by the EC to treat patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy. However, NICE said it isn’t clear how much of a benefit axicabtagene ciloleucel may provide over salvage chemotherapy. NICE also said the price of axicabtagene ciloleucel is too high for the therapy to be considered a cost-effective use of NHS resources, and the therapy does not meet the criteria for inclusion in the Cancer Drugs Fund.

[email protected]

Preclinical research indicates that TYK2 inhibitors could be effective in treating anaplastic large-cell lymphoma (ALCL).

Courtesy M.Bernkopf/Vetmeduni Vienna

Researchers found evidence to suggest that TYK2 “is highly expressed in all cases of human ALCL.”

The team also discovered that TYK2 inhibition induces apoptosis in human ALCL cells, and it delays tumor onset, and prolongs survival in a mouse model of ALCL.

Olaf Merkel, PhD, of the Medical University of Vienna in Austria, and his colleagues detailed these findings in Leukemia.

The researchers said their analyses suggest TYK2 is expressed in all types of ALCL, regardless of ALK status, and TYK2 mediates the same anti-apoptotic response across ALCLs.

“Therefore, we could consider TYK2 signaling as the Achilles’ heel of ALCL, as, in all patients we have analyzed, the tumor cells relied on this activity to support the essential survival signal,” Dr. Merkel said in a statement.

He and his colleagues found that disrupting TYK2 – either via gene knockdown or with small-molecule TYK2 inhibitors – induced apoptosis in human ALCL cells in vitro.

In a mouse model of NPM-ALK-induced lymphoma, Tyk2 deletion slowed the rate of tumor growth and significantly prolonged survival. The median survival was 53.3 weeks in mice with Tyk2 deletion and 16.0 weeks in control mice (P less than .0001).

Additional experiments in human ALCL cell lines showed that “TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells,” the researchers said.

They also found that “activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1, and aberrant ALCL cell survival.”

Taking these findings together, the researchers concluded that TYK2 inhibitors could be effective for treating ALCL.

“We are looking forward to TYK2 inhibitors becoming available,” said study coauthor Lukas Kenner, MD, of the Medical University of Vienna. “[I]n the more rare lymphomas, we urgently need better therapies.”

The researchers received grant funding from various organizations but reported having no conflicts of interest.

[email protected]

SOURCE: Prutsch N et al. Leukemia. 2018 Aug 21. doi: 10.1038/s41375-018-0239-1.

Preclinical research indicates that TYK2 inhibitors could be effective in treating anaplastic large-cell lymphoma (ALCL).

Courtesy M.Bernkopf/Vetmeduni Vienna

Researchers found evidence to suggest that TYK2 “is highly expressed in all cases of human ALCL.”

The team also discovered that TYK2 inhibition induces apoptosis in human ALCL cells, and it delays tumor onset, and prolongs survival in a mouse model of ALCL.

Olaf Merkel, PhD, of the Medical University of Vienna in Austria, and his colleagues detailed these findings in Leukemia.

The researchers said their analyses suggest TYK2 is expressed in all types of ALCL, regardless of ALK status, and TYK2 mediates the same anti-apoptotic response across ALCLs.

“Therefore, we could consider TYK2 signaling as the Achilles’ heel of ALCL, as, in all patients we have analyzed, the tumor cells relied on this activity to support the essential survival signal,” Dr. Merkel said in a statement.

He and his colleagues found that disrupting TYK2 – either via gene knockdown or with small-molecule TYK2 inhibitors – induced apoptosis in human ALCL cells in vitro.

In a mouse model of NPM-ALK-induced lymphoma, Tyk2 deletion slowed the rate of tumor growth and significantly prolonged survival. The median survival was 53.3 weeks in mice with Tyk2 deletion and 16.0 weeks in control mice (P less than .0001).

Additional experiments in human ALCL cell lines showed that “TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells,” the researchers said.

They also found that “activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1, and aberrant ALCL cell survival.”

Taking these findings together, the researchers concluded that TYK2 inhibitors could be effective for treating ALCL.

“We are looking forward to TYK2 inhibitors becoming available,” said study coauthor Lukas Kenner, MD, of the Medical University of Vienna. “[I]n the more rare lymphomas, we urgently need better therapies.”

The researchers received grant funding from various organizations but reported having no conflicts of interest.

[email protected]

SOURCE: Prutsch N et al. Leukemia. 2018 Aug 21. doi: 10.1038/s41375-018-0239-1.

Preclinical research indicates that TYK2 inhibitors could be effective in treating anaplastic large-cell lymphoma (ALCL).

Courtesy M.Bernkopf/Vetmeduni Vienna

Researchers found evidence to suggest that TYK2 “is highly expressed in all cases of human ALCL.”

The team also discovered that TYK2 inhibition induces apoptosis in human ALCL cells, and it delays tumor onset, and prolongs survival in a mouse model of ALCL.

Olaf Merkel, PhD, of the Medical University of Vienna in Austria, and his colleagues detailed these findings in Leukemia.

The researchers said their analyses suggest TYK2 is expressed in all types of ALCL, regardless of ALK status, and TYK2 mediates the same anti-apoptotic response across ALCLs.

“Therefore, we could consider TYK2 signaling as the Achilles’ heel of ALCL, as, in all patients we have analyzed, the tumor cells relied on this activity to support the essential survival signal,” Dr. Merkel said in a statement.

He and his colleagues found that disrupting TYK2 – either via gene knockdown or with small-molecule TYK2 inhibitors – induced apoptosis in human ALCL cells in vitro.

In a mouse model of NPM-ALK-induced lymphoma, Tyk2 deletion slowed the rate of tumor growth and significantly prolonged survival. The median survival was 53.3 weeks in mice with Tyk2 deletion and 16.0 weeks in control mice (P less than .0001).

Additional experiments in human ALCL cell lines showed that “TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells,” the researchers said.

They also found that “activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1, and aberrant ALCL cell survival.”

Taking these findings together, the researchers concluded that TYK2 inhibitors could be effective for treating ALCL.

“We are looking forward to TYK2 inhibitors becoming available,” said study coauthor Lukas Kenner, MD, of the Medical University of Vienna. “[I]n the more rare lymphomas, we urgently need better therapies.”

The researchers received grant funding from various organizations but reported having no conflicts of interest.

[email protected]

SOURCE: Prutsch N et al. Leukemia. 2018 Aug 21. doi: 10.1038/s41375-018-0239-1.