Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in ...multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.
We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours.
We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.
As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.
PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five ...monoclonal anti-PD-L1 antibodies used in recent landmark publications.
PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/
-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies.
Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (
= 0.81-0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/
-scores strongly correlated with percentage of PD-L1(+) cells (
> 0.78, all clones).
The 5H1, SP142, 28-8, 22C3, and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/
-score in chromogenic PD-L1 IHC assays.
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Melanoma currently lacks a reliable blood‐based biomarker of disease activity, although circulating tumor DNA (ctDNA) may fill this role. We investigated the clinical utility (i.e., impact on ...clinical outcomes and interpretation of radiographic data) of measuring ctDNA in patients with metastatic or high‐risk resected melanoma. Patients were prospectively accrued into ≥ 1 of three cohorts, as follows. Cohort A: patients with radiographically measurable metastatic melanoma who underwent comparison of ctDNA measured by a BEAMing digital PCR assay to tissue mutational status and total tumor burden; when appropriate, determinations about initiation of targeted therapy were based on ctDNA data. Cohorts B and C: patients with BRAF‐ or NRAS‐mutant melanoma who had either undergone surgical resection of high‐risk disease (cohort B) or were receiving or had received medical therapy for advanced disease (cohort C). Patients were followed longitudinally with serial ctDNA measurements with contemporaneous radiographic imaging to ascertain times to detection of disease activity and progressive disease, respectively. The sensitivity and specificity of the ctDNA assay were 86.8% and 100%, respectively. Higher tumor burden and visceral metastases were found to be associated with detectable ctDNA. In two patients in cohort A, ctDNA test results revealed a targetable mutation where tumor testing had not; both patients experienced a partial response to targeted therapy. In four of 30 patients with advanced melanoma, ctDNA assessments indicated evidence of melanoma activity that predicted radiographic evidence of disease progression by 8, 14, 25, and 38 weeks, respectively. CtDNA was detectable in three of these four patients coincident with radiographic evaluations that alone were interpreted as showing no evidence of neoplastic disease. Our findings provide evidence for the clinical utility of integrating ctDNA data in managing patients with melanoma in a real‐world setting.
We investigated the clinical utility (i.e, impact on outcomes) of measuring circulating tumor DNA (ctDNA) in patients with metastatic or high‐risk resected melanoma. CtDNA interrogation revealed targetable mutations where tumor testing did not, allowing for treatment with (and anti‐tumor response to) targeted therapy. Additionally, ctDNA revealed evidence of melanoma activity in patients with no radiographic evidence of tumor. Image is of a 5cm hypermetabolic metastasis (arrowhead) within a fibroid uterus representing progressive melanoma, presaged months earlier by ctDNA.
Cutaneous eruptions are among the most common immune-related adverse events (irAEs) associated with anti-programmed cell death protein 1/programmed cell death ligand 1 therapy, and are often ...clinically and histologically characterized as lichenoid. Nonlichenoid patterns may also occur and are likely to be encountered by surgical pathologists, given the increasing clinical use of these agents. The purpose of this study is to describe the histopathologic features of nonlichenoid cutaneous irAEs from patients receiving anti-programmed cell death protein 1/programmed cell death ligand 1 therapies for a variety of underlying advanced malignancies. Sixteen patients with 17 biopsied eruptions were included from 2 academic institutions with extensive experience administering and monitoring responses to immune checkpoint blockade as well as treating the potential side effects. Eruptions occurred a median of 10 days (range, 1 d to 11.4 mo) after treatment initiation. Nearly half of specimens demonstrated either a psoriasiform/spongiotic or an urticarial-type reaction pattern on histologic review. Patterns consistent with Grover disease, bullous pemphigoid, and granulomatous dermatitis were also observed. Nearly two-thirds of patients required systemic corticosteroids for treatment of the cutaneous irAE, and 19% of patients discontinued immunotherapy due to their skin eruptions. 75% of patients showed an objective antitumor response. The diverse array of nonlichenoid cutaneous irAE presented here should reflect and inform the scope of histologic patterns encountered by the practicing surgical pathologist. Such eruptions are seen in patients with a variety of underlying tumor types, many of whom ultimately demonstrate a favorable response to immune checkpoint blockade.
The aim of this study was to evaluate the ability of computed tomography (CT) in differentiating between intrapancreatic accessory spleen (IPAS) from pancreatic neuroendocrine tumor (PanNET).
Eight ...IPASs and 12 PanNETs in the pancreatic tail were retrospectively evaluated by 2 radiologists. Readers assigned a diagnosis to each examination and evaluated for the presence or absence of 9 CT findings that may aid in the diagnosis.
Reader 1 had a sensitivity of 0.83 and a specificity of 1; reader 2 had a sensitivity of 0.78 and a specificity of 0.86. Three of the 9 CT findings were found to be statistically significant in IPASs: the lesion present along the pancreatic dorsal surface, the lesion demonstrating the same enhancement as the spleen on venous phase, and heterogeneous enhancement during arterial phase.
CT can be used to differentiate between IPAS and PanNET with good specificity and sensitivity. The IPAS mirrors the spleen's enhancement and is usually located along the dorsal surface of the pancreas.
Isolated celiac or superior mesenteric artery (SMA) dissection is a rare entity in the absence of aortic dissection. Our objective was to detail imaging and clinical course of celiac and or SMA ...dissections.
We conducted a retrospective search from 2004 to 2010 using "celiac and/or SMA dissection" keywords. Analysis of medical record and imaging at diagnosis and follow-up was performed. Dissections for any reason without aortic dissection were included.
Twenty-four celiac and 18 SMA dissections were detected in 38 patients. One third of the dissections diagnosed with interactive multiplanar reconstruction/maximum intensity projection (MIP)/3-dimensional (3D) rendering were missed on standard imaging planes. No patients had bowel ischemia or died. Eighty-four percent of the patients were observed, 2 patients received anticoagulation, 2 patients received surgical repair, and 3 patients received stenting. Twenty-three of 25 cases treated with observation exhibited no change or improvement/resolution (2/25) with 20.9-month mean follow-up.
Most isolated celiac and SMA dissections were asymptomatic/incidental, supporting observation and surveillance with intervention reserved for vascular compromise. Interactive multiplanar reconstruction/maximum intensity projection/3D rendering can increase diagnostic sensitivity.
Cutaneous eruptions are among the most common immune-related adverse events (irAEs) associated with anti-PD-1/PD-L1 therapy, and are often clinically and histologically characterized as lichenoid. ...Non-lichenoid patterns may also occur and are likely to be encountered by surgical pathologists, given the increasing clinical use of these agents. The purpose of this study is to describe the histopathologic features of non-lichenoid cutaneous irAEs from patients receiving anti-PD-1/PD-L1 therapies for a variety of underlying advanced malignancies. Sixteen patients with 17 biopsied eruptions were included from two academic institutions with extensive experience administering and monitoring responses to immune checkpoint blockade as well as treating the potential side effects. Eruptions occurred a median of 10 days (range 1 day to 11.4 months) after treatment initiation. Nearly half of specimens demonstrated either a psoriasiform/spongiotic or an urticarial-type reaction pattern on histologic review. Patterns consistent with Grover’s disease, bullous pemphigoid, and granulomatous dermatitis were also observed. Nearly two-thirds of patients required systemic corticosteroids for treatment of the cutaneous irAE, and 19% of patients discontinued immunotherapy due to their skin eruptions. 75% of patients showed an objective antitumor response. The diverse array of non-lichenoid cutaneous irAE presented here should reflect and inform the scope of histologic patterns encountered by the practicing surgical pathologist. Such eruptions are seen in patients with a variety of underlying tumor types, many of whom ultimately demonstrate a favorable response to immune checkpoint blockade.
The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight ...treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.
To use combined proton (1H) and sodium 23 (23Na) magnetic resonance (MR) imaging to noninvasively quantify total tissue sodium concentration and to determine if concentration is altered in malignant ...human brain tumors.
Absolute tissue sodium concentration in malignant gliomas was measured on quantitative three-dimensional 23Na MR images with tissue identification from registered 1H MR images. Concentration was determined in gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and vitreous humor in 20 patients with pathologically proven malignant brain tumors (astrocytoma, n = 17; oligodendroglioma, n = 3) and in nine healthy volunteers. Sodium concentration in tumors and edema was determined from 23Na image signal intensities in regions that were contrast material enhanced on T1-weighted 1H images (tumors) or regions that were only hyperintense on fluid-attenuated inversion recovery (FLAIR) 1H images (edema). Sodium concentrations were measured noninvasively from 23Na images obtained with short echo times (0.4 msec) by using external saline solution phantoms for reference. Differences in mean sodium concentration of all healthy tissue and lesions in patients were tested with a paired t test. Concentration in uninvolved tissues in patients was compared with that in the same tissue types in the volunteers with an independent samples two-tailed t test.
Mean concentration (in millimoles per kilogram wet weight) was 61 +/- 8 (SD) for GM, 69 +/- 10 for WM, 135 +/- 10 for CSF, 113 +/- 14 for vitreous humor, 103 +/- 36 for tumor, 68 +/- 11 for unaffected contralateral tissue, and 98 +/- 12 for FLAIR hyperintense regions surrounding tumors. Significant differences (P <.002) in sodium concentration were demonstrated by using a t test for both tumors and surrounding FLAIR hyperintense tissues versus GM, WM, CSF, and contralateral brain tissue.
23Na MR imaging with short echo times can be used to quantify absolute tissue sodium concentration in patients with brain tumors and shows increased sodium concentration in tumors relative to that in normal brain structures.
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