CD39 is expressed on functional effector and tissue resident memory CD8+ T cells.

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on antigen-specific CD8+ short-lived effector cells (SLECs), while it's co-ecto-enzyme, CD73, is found on memory precursor effector cells (MPEC) in vivo . Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory (T RM ) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine T RM across several non-lymphoid tissues and melanoma, while CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ T RM are fully functional when stimulated ex vivo with cognate antigen. This work further expands the identity of CD39 beyond a T cell exhaustion marker.

Rare immune-related adverse events in a patient with metastatic melanoma: a case report highlighting sarcoidosis-like reactions triggered by immune-checkpoint inhibitors.

Pembrolizumab and ipilimumab/nivolumab (ipi/nivo) combination are FDA-approved immune checkpoint inhibitor (ICI) therapies for metastatic melanoma. ICIs could result in various inflammation responses known as immune-related adverse events (IRAEs). We report a patient with metastatic melanoma who developed multiple IRAEs including sarcoidosis-like reaction (SLR), diabetic ketoacidosis (DKA), and worsening hypothyroidism on ICIs. A 71-year-old man with stage IIIC melanoma and lymph node metastasis began adjuvant therapy with pembrolizumab in May 2021. A surveillance positron emission tomography-computed tomography (PET-CT) scan four months later showed diffuse nodal uptake indicating potential metastases although the patient remained asymptomatic. His treatment was temporarily switched to ipi/nivo before biopsy was obtained for definitive diagnosis, which revealed non-caseating granulomas consistent with SLR. After resuming pembrolizumab, he developed DKA and worsening hypothyroidism in November 2021, both of which were attributed to IRAEs. His surveillance PET scan in March 2022 again revealed new hypermetabolic activity in several bones, subcutaneous tissue, and the left inguinal lymph node. Left inguinal node biopsy showed disease recurrence, while biopsies of hypermetabolic subcutaneous nodules and bone demonstrated non-caseating granulomas. Our case described a patient on ICIs who developed several IRAEs. SLR is often asymptomatic but remains a diagnostic challenge due to its indistinguishable appearance on imaging studies compared to metastasis. Better understanding of IRAEs and improved surveillance strategies are needed for optimal patient outcomes.

Oligometastatic Melanoma Treated by Metastasectomy in Combination with Immune Checkpoint and BRAF Inhibitors: A Case Series.

BACKGROUND Early therapies for metastatic melanoma improved patient quality of life; however, median survival remained unaffected. Studies are showing that surgical excision with the combination of immune checkpoint inhibitor (ICI) therapy has better outcomes than systemic therapy alone. This single-center case series describes 7 patients with oligometastatic melanoma treated by metastasectomy in combination with ICI and BRAF inhibitors. CASE REPORT One female and 6 male patients are included in our study, with ages ranging from 34 to 82 years. Oligometastatic melanoma is defined was having no more than 5 metastatic regions. Each patient had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients received either ICI therapy with ipilimumab, nivolumab, and/or pembrolizumab, or targeted therapy with encorafenib and binimetinib, or a combination. Patients underwent metastasectomies with curative intent. The main outcome and measurements obtained were the duration of disease-free survival, based on radiographic evidence. The range of disease-free survival in our population was 13 to 67 months, with the lower end limited by patient death and the upper limit being the present day. CONCLUSIONS This case series reiterates survival benefit for patients who received metastasectomy after exhibiting good response to ICI therapy. ICI and/or BRAF inhibitor therapy combined with metastasectomy provides a possible curative option for patients who may have previously been relegated to palliative-focused care. By using a multimodal approach with oncologists and surgeons, we can challenge our understanding of what constitutes a resectable cancer.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0.

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation. Other immunotherapy strategies, such as oncolytic virotherapy for injectable cutaneous melanoma and bispecific T-cell engager therapy for HLA-A*02:01 genotype-positive uveal melanoma, are also available to patients. Despite the remarkable efficacy of these regimens for many patients with cutaneous melanoma, traditional immunotherapy biomarkers (ie, programmed death-ligand 1 expression, tumor mutational burden, T-cell infiltrate and/or microsatellite stability) have failed to reliably predict response. Furthermore, ICIs are associated with unique toxicity profiles, particularly for the highly active combination of anti-PD-1 plus anti-CTLA-4 agents. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of melanoma, including rare subtypes of the disease (eg, uveal, mucosal), with the goal of improving patient care by providing guidance to the oncology community. Drawing from published data and clinical experience, the Expert Panel developed evidence- and consensus-based recommendations for healthcare professionals using immunotherapy to treat melanoma, with topics including therapy selection in the advanced and perioperative settings, intratumoral immunotherapy, when to use immunotherapy for patients with BRAFV600-mutated disease, management of patients with brain metastases, evaluation of treatment response, special patient populations, patient education, quality of life, and survivorship, among others.

Durable complete response to early immunotherapy discontinuation in a kidney transplant recipient with advanced cutaneous squamous cell carcinoma: A case report and review of literature.

BACKGROUND: The usage of immunotherapy to treat skin malignancies in transplant patients requires weighing the risk of acute organ transplant rejection with the potential reduction of antitumor efficacy by transplant immunosuppression. Reducing the duration of immune checkpoint inhibitor treatment may help prevent acute transplant rejection and late immune-related adverse events. CASE PRESENTATION: An allogenic kidney transplant patient who developed regionally metastatic cutaneous squamous cell carcinoma received four cycles of pembrolizumab with complete response to therapy. Therapy was discontinued due to fatigue, significant cancer response, and to reduce the risk of acute graft rejection. His renal function remained stable, and he achieved subsequent durable response after treatment discontinuation. CONCLUSION: Organ transplant recipients with complete response to immunotherapy for cutaneous squamous cell carcinoma may continue to respond despite early treatment cessation. This may reduce the risks of late immune-related adverse events and acute graft rejection.

Complete response of a large basosquamous carcinoma following treatment with cemiplimab and vismodegib.

The anti-PD-1 antibody cemiplimab has demonstrated effectiveness in the setting of locally advanced basal cell carcinoma (BCC) and squamous cell carcinoma. We describe a case of a large, locally invasive basosquamous carcinoma, an aggressive type of BCC, invading the left sternocleidomastoid muscle with near compression of the left internal jugular vein producing a severe anaemia secondary to ulceration and chronic blood loss. The patient was initially started on vismodegib monotherapy but failed to respond. He was then started on cemiplimab in addition to vismodegib. Improvement was noted after one cycle. After 21 cycles of cemiplimab, the left shoulder ulcerated lesion was completely re-epithelialised. He remains in complete remission after 31 cycles of cemiplimab in addition to vismodegib.

Clinical influence of multiplex polymerase chain reaction routine uses in urgent pediatric admissions.

BACKGROUND: The coronavirus disease 2019 outbreak has prompted some hospitals to implement screening tests upon admission since 2020. FilmArray® Respiratory 2.1 Panel (FilmArray) is a multiplex polymerase chain reaction (PCR) test with high sensitivity and specificity for detecting respiratory pathogens. We aimed to assess the clinical influence of the routine use of FilmArray for pediatric patients, including those without symptoms suggestive of an infection. METHODS: We conducted a single-center retrospective observational study, which investigated patients aged ≤15 years who underwent FilmArray on admission in 2021. We collected the patients' epidemiological information, symptoms, and FilmArray results from their electronic health records. RESULTS: A positive result was observed in 58.6% of patients admitted to the general ward or intensive care unit (ICU) but only in 1.5% of patients in the neonatal ward. Among the patients admitted to the general ward or ICU who tested positive, 93.3% had symptoms suggestive of infections, 44.6% had a sick contact before admission, and 70.5% had siblings. However, 62 (28.2%) out of 220 patients without the four (fever, respiratory, gastrointestinal, and dermal) symptoms also had positive results. Among them, 18 patients with adenovirus and three with respiratory syncytial virus were isolated to private rooms. However, 12 (57.1%) patients were discharged without symptoms suggestive of viral infection. CONCLUSION: Multiplex PCR routine use for all inpatients may lead to excessive management of positive cases because FilmArray cannot quantify microorganisms. Thus, targets for testing should be considered carefully based on patients' symptoms and histories of sick contacts.

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment. METHODS: We conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0. RESULTS: A total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate. CONCLUSIONS: The clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease.

Does denosumab offer survival benefits? -Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs. METHODS: This observational study used retrospective data from a tertiary cancer center from 2015-2020. Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Kaplan-Meier curves were obtained for survival analysis. RESULTS: We identified 69 patients and all had skeletal metastases, and 37.7% had brain metastases. Median OS was 6.3 months and median PFS was 2.8 months, with overall response rate (ORR) of 18.8% and disease control rate (DCR) of 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with <3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases. However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Most of the patients tolerated denosumab well, and hypocalcemia was the most commonly reported side effect. CONCLUSIONS: Patients receiving combination therapy did not perform poorly comparing to published studies despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.

Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma.

The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ T cells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer.

Ipilimumab and nivolumab induced immune-related adverse events in metastatic mucosal melanoma.

Mucosal melanoma is a rare subtype of melanoma and represents a unique diagnosis and treatment challenge. Immune-checkpoint inhibitors (ICIs) have revolutionised metastatic melanoma treatment, and one of the leading regimens is the combination of ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4: CTLA4) and nivolumab (anti-programmed cell death protein 1: PD1). We report a case of a patient with metastatic mucosal melanoma treated with ipilimumab and nivolumab who developed multiple immune-related adverse events (irAEs) including uveitis, type I diabetes complicated by diabetic ketoacidosis, destructive thyroiditis, hepatitis and vitiligo. Endocrinopathies including type 1 diabetes and hypothyroidism were treated with insulin and levothyroxine. Hepatitis was responsive to steroids. She had sustained complete response 12 months after discontinuation of the combination therapy. With the wide usage of ICIs in multiple types of malignancies, it is important for general practioners to recognise common and serious irAEs due to ICIs.

Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy.

While T-cell responses to cancer immunotherapy have been avidly studied, long-lived memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8+ T-cell responses across tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident memory T (TRM) cells shared between tumors and distant vitiligo-affected skin. Paired T-cell receptor sequencing further identified clonotypes in tumors that co-existed as TRM in skin and as effector memory T (TEM) cells in blood. Clonotypes that dispersed throughout tumor, skin, and blood preferentially expressed a IFNG / TNF-high signature, which had a strong prognostic value for melanoma patients. Remarkably, clonotypes from tumors were found in patient skin and blood up to nine years later, with skin maintaining the most focused tumor-associated clonal repertoire. These studies reveal that cancer survivors can maintain durable memory as functional, broadly-distributed TRM and TEM compartments.

Clinicopathologic and Genomic Characterization of Inflammatory Myofibroblastic Tumors of the Head and Neck: Highlighting a Novel Fusion and Potential Diagnostic Pitfall.

Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.

Advances in Oncology in US and Japan: Focusing on Cancer and Infectious Diseases.

This is a review article based on the international symposium report of the "US-Japan Conference on Advances in Oncology: Cancer and Infectious Diseases" held online on June 25, 2021, which provided an update on the association between oncology and infectious disease research from cutting-edge basic science to high-impact clinical trials.

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients.

Background: Biomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice. Methods: Tumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome. Results: For 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant (p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved (p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%). Conclusions: Cell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings.

Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial.

INTRODUCTION: Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy. METHODS: This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated. RESULTS: A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42-63) and 92% (95% CI: 84-96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5-not reached) months. CONCLUSIONS: Almonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.

A Phase II Study of Glembatumumab Vedotin for Metastatic Uveal Melanoma.

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5-5.6), and the median overall survival was 11.9 months (95% CI 9.0-16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

Molecular matching and treatment strategies for advanced stage lung cancer at Dartmouth-Hitchcock Medical Center: A three-year review of a Molecular Tumor Board.

Matching of actionable tumor mutations with targeted therapy increases response rates and prolongs survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population. Tumor DNA was sequenced using a 50-gene targeted next-generation sequencing panel. Cases were evaluated by a multidisciplinary MTB who suggested a course of treatment based on each patient's molecular findings. During a three-year period, 21 lung cancer patients were presented at the MTB. All patients lacked common activating EGFR mutations and ALK rearrangements. One patient had Stage IIIb disease; all others were Stage IV; 18 patients had received ≥1 prior line of therapy (range 0-5). Suggestions for treatment with a targeted therapy were made for 19/21 (90.5%) patients, and four patients (21%) underwent treatment with a targeted agent, two as part of a clinical trial. Identified barriers to treatment with targeted therapy included: ineligibility for clinical trials (n â€‹= â€‹2), lack of interest in study/distance to travel (n â€‹= â€‹2), lack of disease progression (n â€‹= â€‹2), poor performance status (n â€‹= â€‹5), decision to treat next with immunotherapy (n â€‹= â€‹3), and unknown (n â€‹= â€‹1). For the majority of lung cancer patients, the MTB provided recommendations based on tumor genetic profiles. Identified barriers to treatment suggest that presentation to the MTB at earlier stages of disease may increase the number of patients eligible for treatment with a genetically informed targeted agent.

Rapid EGFR mutation testing in lung cancer tissue samples using a fully automated system and single-use cartridge.

INTRODUCTION: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) patients predicts response to EGFR tyrosine kinase inhibitors (TKIs). The Idylla™ system (Biocartis, Mechelen, Belgium) is a fully integrated, cartridge-based platform that provides automated sample processing and real-time PCR-based mutation detection in a single-use cartridge. This study evaluated the Idylla™ EGFR Mutation Assay cartridges against next-generation sequencing (NGS) using formalin fixed, paraffin embedded (FFPE) lung cancer tissue samples. METHODS: Thirty-four FFPE lung adenocarcinoma tissue samples were tested on the Idylla™ system. 21 had at least one mutation in EGFR and 13 had no EGFR mutation as determined by NGS analysis using the Ion AmpliSeq 50-gene Cancer Hotspot Panel v2 (Thermo Fisher Scientific). One 10 â€‹µm FFPE tissue section was used for each Idylla™ test and all cases met the Idylla™ minimum tumor content requirement (≥10%). RESULTS: Idylla™ results were in complete agreement with those obtained by NGS for EGFR mutations targeted by the Idylla™. NGS identified two additional EGFR mutations that are not targeted by the Idylla™ in two samples (E709V and V774M). No EGFR mutations were detected by the Idylla™ in samples determined by NGS as having wild-type EGFR. CONCLUSION: The fully automated Idylla™ system offers rapid and reliable testing for clinically actionable mutations in EGFR directly from FFPE tissue sections. Its simplicity and ease of use compared to other available molecular techniques make it suitable for routine clinical use in a variety of settings.