bluuebunny/crossref_metadata_2025 huggingface dataset:
Pneumonitis in immunotherapy alone vs. chemoimmunotherapy: A systematic review and meta-analysis.
Authors: Barbaro Alexander Michael , Siskin Matthew , Grello Cassandra , Hernandez Adrian V , Dublin Jared , Breslin Sean , Punekar Salman Rafi , Velcheti Vamsidhar
Published: June 2022

e21120

Background: Immune checkpoint inhibitors (ICIs) are commonly used in the treatment of non-small cell lung cancer (NSCLC), and are given alone or in combination with cytotoxic chemotherapy. These agents are sometimes associated with immune related adverse events (irAEs). Pneumonitis in particular is a common and sometimes life-threatening complication of treatment with ICIs, especially in lung cancer patients. Chemotherapy is known to cause immune suppression and deplete T cell populations, and might be expected to attenuate the incidence or severity of irAEs when given with ICIs. To date, few studies explore this possibility. This meta-analysis compared the incidence of any grade and severe (grade ≥3) pneumonitis in patients who received ICIs alone vs. combination ICI + chemotherapy for the treatment of advanced NSCLC. Methods: Embase and PubMed databases were searched through May 2021 for clinical trials investigating the use of ICIs for treatment of advanced NSCLC alone and/or in combination with chemotherapy. Interventions were categorized into ICI alone vs. ICI + chemotherapy and rates of any grade and severe (grade ≥3) pneumonitis for patients in each category were collected. The incidence of these events across interventions was aggregated using inverse variance weighting, and rates among patients who received ICI alone and ICI + chemotherapy were compared. Results: 1929 studies were identified by the initial search, of which 36 met inclusion criteria. From these, 24 interventional arms using ICIs alone (total patients n = 11,163) and 12 using combination therapy (n = 4,129) were identified and analyzed. ICIs included agents targeting PD1 (n = 22), PD-L1 (n = 11), CTLA-4 (n = 1), and the combination of CTLA-4 with PD1 or PD-L1 (n = 2). Rates of any grade pneumonitis did not differ significantly between patients who received ICI alone vs combination therapy (0.03; 95% CI 0.02-0.04 vs 0.04; 95% CI 0.02-0.08; P = 0.5). Rates of severe pneumonitis also did not differ between groups (0.01; 95% CI 0.01-0.02 vs 0.01; 95% CI 0.00 – 0.02; P = 0.5). Conclusions: No difference was found in the rates of any grade or severe pneumonitis between patients who received ICI alone vs. ICI + chemotherapy.
A phase 1 study in patients with advanced non-small cell lung cancer treated with stereotactic radiotherapy to the primary tumor combined with durvalumab and tremelimumab.
Authors: Kievit Hanneke , Muntinghe-Wagenaar M Benthe , Ubbels Fred , Wijsman Robin , Hijmering-Kappelle Lucie , Hiddinga Birgitta , Groen Harry J.M. , Kerstjens Huib A.M. , van der Wekken Anthonie J. , Hiltermann T.Jeroen Jeroen Nicolaas
Published: June 2022

e21121

Background: Cancers can be recognized by the immune system and immunotherapy (ICI) has become an important treatment for lung cancer. Compared to chemotherapy, combining an anti-CTLA-4 and PD-L1 inhibitor increases response- and survival rates independent of PD-L1 status. We hypothesized that adding stereotactic radiotherapy (SBRT) to increase the release of cancer cell antigens might improve treatment results even further. Because of accumulating tumor heterogeneity it may be important to irradiate the primary tumor (addressing trunk mutations), rather than its metastases (branch mutations). We assessed toxicity of adding SBRT to (dual) ICI. Methods: In 3 sequential cohorts, ICI regimes combined with SBRT were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. All patients were irradiated on an FDG avid part of the primary tumor (1x20 Gy on 9cc) 1 week after the 1st dose of ICI; in case of dual ICI the 1st dose of the 2nd ICI was administered within 1 week following SBRT. Following treatments both ICI were combined. The 1st cohort (n = 3) received durvalumab (D) monotherapy for up to 1 year. The 2nd cohort starting with tremelimumab (T) and the 3rd cohort starting with D (both n = 6) received a combination of D and T (4 cycles) followed by D monotherapy for up to 1 year. The 2nd and 3rd cohort only proceeded when dose limiting toxicities (DLT) occurred in ≤33% of cases in the previous cohort. DLT was defined as any grade ≥3 toxicity that occurred during the first 8 weeks of therapy. Treatment related adverse events (TRAEs) were categorized using NCI CTCAE version 4.3. Descriptive statistics were used to summarize baseline characteristics and TRAEs. Results: Fifteen patients were included from June 2018 to November 2020. Last study visit was in September 2021. Baseline characteristics of the groups were comparable. The median irradiated tumor volume was 9.13 cc (8.98-9.60 cc) with a mean lung dose of 0.44 Gy (0.14-0.73 Gy). The V20 was nihil (0-0.1%) and the V5 1.8% (0-4%). There was 1 DLT in cohort 3 (colitis grade 3). There was 1 low grade TRAE (pneumonitis grade 2) in cohort 1. In cohort 2, 6 low grade TRAEs (CTC 1-2) were observed and 2 high grade (CTC 3) in 1 patient, who discontinued treatment. In cohort 3, 4 low grade and 1 high grade TRAE occurred. Median progression free survival was 2 months, median overall survival 10 months. Conclusions: No additional toxicity was observed by adding SBRT to the primary tumor to (dual) ICI. Clinical trial information: 2017-002797-39. [Table: see text]
Machine learning modeling of real-world primary resistance and hyperprogression in immune checkpoint inhibitor (ICI) treated advanced non-small cell lung cancer (aNSCLC) patients.
Authors: Das Rahul K , Hathi Deep K
Published: June 2022

e21127

Background: Many ICI-eligible patients display primary resistance (10-res), with some experiencing hyperprogressive disease (HPD). Machine learning (ML) on real-world data (RWD) can improve our clinical and mechanistic understanding related to ICI response. Methods: XGBoost models were built on ConcertAI’s oncology clinicogenomic database, comprising structured EMR, curated records from unstructured documents, and NGS reports, to predict 10-res and HPD in aNSCLC patients treated with ICI or chemotherapy (CT) within their 1st three lines between January 2015 and June 2021. HPD was defined as either tumor progression, treatment (Tx) discontinuation, or death within 49 days from Tx start (index date). 10-res was defined as any of these events after 49 days but within 180 days from Tx start. Models were trained on a clinical (N = 7647, ICI = 3265, 10-res = 3909, HPD = 2076), and a clinicogenomic (CG) (2304, 1271, 1084, 596) cohort. A 60:20:20 split was used for training, validation, and testing. Baseline period was defined as 180 days prior to the index date. Prognostic and predictive factors were identified from Shapley Additive Explanation (SHAP) values. Results: The clinical model was superior at predicting HPD; the CG model was better at predicting 10-res (AUROC = 0.67 for both). Total metastases (≥ 2) and lower levels of hemoglobin (HGB), and lymphocytes, higher ALP were risk factors for both HPD and 10-res. Elevated WBC and bilirubin, higher heart rate, lower body temperature, and history of anti-inflammatory medications were risk factors for HPD. Non-ICI-based regimens, low TMB, lower PD-L1 expression, and mutations in EGFR or KEAP1 were risk factors for 10-res. Mutation in KRAS was protective of 10-res. In addition to PD-L1 and TMB, the models identified prior lung radiation, smokers, higher baseline comorbidities, and positive MMR status as predictive of lower risk of 10-res from ICI but not in CT. STK11 mutation was predictive of higher risk of 10-res from ICI vs. CT. Non-adenocarcinoma histology was predictive of higher risk of HPD from ICI vs. CT. Conclusions: ML on RWD generated evidence to support both established and emerging prognostic and predictive markers for ICI response.[Table: see text]
Mutational profile, clinical characterization, and outcomes of lung cancer in solid organ transplant recipients.
Authors: Li Shenduo , Manochakian Rami , Zhao Yujie , Lou Yanyan
Published: June 2022

e21131

Background: Solid organ transplant recipients have increased risk for malignancies. Lung cancer is the second most common malignancy in this population. Those patients are usually on long-term immunosuppressive medications that may affect tumorigenesis, cancer characteristics, and treatment response. Previous studies have investigated the characteristics and outcomes of post-transplant patients with lung cancer in small-sized cohorts. However, the tumor mutational profile and detailed treatment response at different stages have not been reported. Methods: We conducted a retrospective study from a cohort of 52 solid organ transplant recipients who were diagnosed with lung cancer at Mayo Clinic from 2018 to 2021. We examined tumor molecular alteration using next generation sequencing (NGS), analyzed the treatment modalities, progression-free survival (PFS), and overall survival (OS) and compared those to the general population with lung cancer using historical data in previous large trials. Results: In our study, most transplanted solid organs are kidney (N = 28, 53.8%), followed by liver (N = 12, 23.1%) and heart (N = 9, 17.3%). The adenocarcinoma (N = 28, 53.8%) represented the most common histology, followed by squamous cell carcinoma (N = 19, 36.5%). It consisted of Stage I (30.8%), stage II (15.4%), stage III (25%), and stage IV (26.9%). The most common site of metastasis is bone (64.3%). Transplant recipients with lung cancer have a significantly high frequency of somatic BRCA 1/2 mutations (30.4%), compared to the general population with advanced lung cancer (2.1%, p < 0.001). The frequencies of TP53 mutations (52.2%) and EGFR mutations (30.4%) are also increased. For stage I patients who received surgery or radiation therapy, the disease-free survival (DFS) is 16.5 months. 9 of 14 stage IV patients received chemotherapy. The median number of cycles received is 4. The median PFS is 4.9 months, and the median OS of all stage IV patients is 6.1 months. 4 patients were found to have actionable EGFR mutations, and 3 of them were initially diagnosed with stage IIIA and received Osimertinib after progression. One stage IV patient who was post-liver transplant received pembrolizumab for up to 5 cycles before he developed aspiration pneumonia and then pursued hospice. The PFS is 3.7 months. No immune-related adverse event was reported. Conclusions: In our cohort of solid organ transplant recipients who developed lung cancer, we observed a much higher frequency of somatic BRCA 1/2 mutations, compared to the general population with lung cancer. In addition, our data suggested post-transplant patients with stage I lung cancer have a shorter disease-free survival, and patients with stage IV lung cancer have a shorter overall survival, compared to the general population with lung cancer. Further study containing a high number of solid transplant patients to validate these findings is warranted.
Efficacy and safety of IBI110 (anti-LAG-3 mAb) in combination with sintilimab (anti-PD-1 mAb) in first-line advanced squamous non-small cell lung cancer (sqNSCLC): Initial results from a phase Ib study.
Authors: Zhou Caicun , Xiong Anwen , Li Wei , Wang Lei , Wu Fengying , Yu Jia , Mao Chenyu , Qian Jiong , Zheng Yulong , Jiang Haiping , Gao Yuan , Xiao Cheng , Wang Wenxiang , Zhuang Wu , Yang Jun , Sun Jiya , Wang Hongli , Liu Ying , Xu Nong
Published: June 2022

e21145

Background: Although PD-1/L1 inhibitors have shown efficacy in advanced/metastatic sqNSCLC, many patients do not respond to this treatment. More effective combination therapies are needed. The efficacy and safety of IBI110 in combination with sintilimab as first-line therapy for advanced sqNSCLC was evaluated in a phase Ib study. Here, we report the initial results. Methods: Eligible patients with previously untreated, unresectable, locally advanced or metastatic NSCLC were enrolled in cohort D. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W until disease progression, unacceptable toxicity or death, in combination with chemo regimen (paclitaxel 175 mg/m2 plus carboplatin) IV Q3W for 4 cycles. The primary objective was to evaluate the safety, tolerability and efficacy of the combination therapy. Results: Totally, 20 patients were enrolled (median age: 63 [range: 52-74]; male: n = 19; ECOG 1: n = 16). As of data cutoff date, Jan 20, 2022, median follow up was 3.3 months (range: 2.6-7.0). The median exposure of combination therapy was 15.1 weeks (range: 6-52). The objective response rate was 80% (16/20, 9 patients with ≥2 efficacy assessments were confirmed PR and 7 needed further confirmation). The median progression-free survival and overall survival were not reached. The most common treatment-related adverse events (TRAEs) included white blood cell count decreased (50%), alopecia (50%), anaemia (45%), asthenia (40%), neutrophil count decreased (35%), rash (35%), and hyperglycaemia (30%); most common TRAEs ≥ grade 3 were neutrophil count decreased (30%), and white blood cell count decreased (20%). Immune-related AEs occurred in 11 patients (55%) and most were grade 1-2. The biomarker analysis including LAG-3 and PD-L1 expression in tumor specimen was ongoing. Conclusions: IBI110 in combination with sintilimab in first-line advanced sqNSCLC showed promising anti-tumor activity with acceptable safety. The study is still ongoing. Clinical trial information: NCT04085185.
Literature on target therapy of malignant melanoma.
Authors: Esmaeil Pour Mohammad Ali , Mohebtash Mahsa , Amin Ali , Khayyat Azadeh , Khalili-Toosi Amir-Reza , Guo Mengni , Mousavi Seyedreza , Liu Jieying
Published: June 2022

e21506

Background: Malignant melanoma (MM) of mucosal membranes (excluding anus and head and neck) is a rare but aggressive disease with poor outcome. There is little information available on the mechanism of development, risk factors and management of this tumor, mainly due to the low number of cases. Methods: We performed a literature review on MMM (between 1970-2020) with a focus on nonsurgical management and outcome. Results: We identified 9-papers discussing 1500-MM cases. Formerly, for the management of MMM, Dacarbazine, Interferon b, DAV-Feron, Carboplatin, Imatinib, and Paclitaxel were administered. More recently, novel immunotherapeutic and chemotherapeutic medications such as Immune Checkpoint Inhibitors (ICPI) and anti-VEGF agents have been administered in these patients. In 502 patients of metastatic MMM, adding ipilimumab to dacarbazine increased OS from 9.1-to-11.2 months with one year survival increasing from 36.3%-to-47.3 %. For nivolumab & ipilimumab combination therapy in 361 patients with MMM and CMM, MPSF in nivolumab monotherapy was 3-months and 6.2-months (for MMM and CMM, respectively); but in nivo-ipili combination, MPFS was 5.9-months and 11.7-months (for MMM and CMM, respectively). A benefit of bevacizumab addition to platinum-based chemotherapy in patients showing advanced disease on ICPI is unknown; however, combination-therapy may be reasonable if no access to ICPI or autoimmune diseases. Conclusions: MMM patients could benefit from combination of nivolumab to ipilimumab more than monotherapy with either medication alone.[Table: see text]
Characteristics of cytokine profiles of peripheral blood in patients with melanoma receiving checkpoint inhibitor therapy with disease progression.
Authors: Teplyakova Maria A. , Vladimirova Liubov Yu , Popova Irina L. , Lyanova Aza A. , Abramova Natalia A. , Storozhakova Anna E. , Ryadinskaya Ludmila A. , Tikhanovskaya Natalia M. , Udalenkova Irina A. , Kalabanova Elena A. , Kabanov Sergey N. , Sagakyants Aleksandr B. , Zlatnik Elena Yu , Shulgina Oksana G. , Zolotareva Ekaterina I. , Ulianova Elena P. , Pozdnyakova Viktoria V. , Przhedetskiy Yuriy V.
Published: June 2022

e21509

Background: The limited range of patients clinically responding to checkpoint inhibitor therapy (CIT) is of interest and requires studying the immunological mechanisms underlying this phenomenon. It also remains to be decided or better clarified which biomarkers should be considered when selecting patients for immunotherapy. The purpose of this study was to evaluate some parameters of the cytokine profiles of peripheral blood in melanoma patients receiving CIT with the disease progression. Methods: The study included 11 patients aged 47-82 years with advanced melanoma. CIT (nivolumab 3 mg/kg once every 14 days or 240 mg once every 14 days) continued until the appearance of reliable signs of the disease progression (in combination with symptomatic deterioration of the patient's condition). The levels of cytokines (TNF-α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ) in the blood serum of patients were determined by ELISA before treatment, after 4 and after 8 injections. The results were expressed as specific content (units/mg). Results: All patients developed disease progression after immunotherapy. CIT was accompanied by different changes most pronounce after the 8th CIT cycle. Levels of IL-1β, IFN-γ, IL-10 and α-TNF exceeded the values before CIT by 118%, 131%, 84% and 20%, respectively (5.2 [4.37; 6.1] versus 2.0 [0.44;4], p≤0.041, 3.9 [3.7;4.5] vs. 1.7 [0.5;3.5], p≤0.021, 6.5 [5.8 ;8.2] vs. 3.5 [3.2;5.4], p≤0.04; 4.1 [3.9;4.9] vs. 3.4 [3.2;3.9] pg/ml, p≤0.047). Levels of IL-6, on the contrary, decreased by the 8th CIT cycle by 32%: 5.1 [3.5; 6.1] versus 7.5 [6.2; 22.3] pg/ml, p≤ 0.045. Levels of IL-2 and IL-8 did not change. Conclusions: The revealed significant increase in levels of IL-1β, IFN-γ, IL-10 and α-TNF, as well as the IL-6 decrease, may indicate certain features of the cytokine profile of melanoma patients during the treatment, which may affect the imbalance of regulatory molecules and contribute to the disease progression.
Survival outcomes following immune checkpoint inhibitor therapy of advanced cutaneous melanoma by age and tumor infiltrating lymphocytes in the primary cutaneous site.
Authors: Kane Mallory , Holmes Aaron N. , Kerr Phil , Hegde Upendra P.
Published: June 2022

e21514

Background: Tumor infiltrating lymphocytes (TILs) in the tumor microenvironment generate anti-tumor immunity and are associated with response to immune checkpoint inhibitor (ICI) therapy of melanoma. However, likelihood of response to ICI therapy depends upon intensity of TILs, proportion of effector and regulatory T cells and age. Methods: In a research study approved by the Institutional Review Board of University of Connecticut, we retrospectively analyzed outcome of patients diagnosed with cutaneous melanoma between 2009 and 2019 and developed unresectable stage III or stage IV disease requiring ICI treatment. Patients were stratified by age (< 75 and > 75 years old) and TILs at the primary cutaneous melanoma site categorized as brisk (present throughout vertical phase), non-brisk (present in one of more foci of vertical phase) or absent. Patient’s age at the time of metastases, as well as 12-month and 24-month overall survival (OS) following ICI treatment was recorded. Results: A total of 93 patients were screened, and 68 were included for analysis of survival outcome. Patients had to receive at least one dose of ICI treatment at UConn Health and had available data on TILs of primary cutaneous melanoma. In patients over 75 years of age, those with brisk TILs had an increased 24-month survival compared to those with non-brisk or absent TILs (100% vs. 45%, p = 0.04). In patients < 75 years of age, the 24 month survival was similar in those with brisk and non-brisk or absent TILs (67% vs. 69%, p = .91). There was no significant difference in overall survival between patients < 75 or > 75 years with brisk TILs (67% vs. 100%, p = .19). Additionally, in patients with non-brisk or absent TILs, there was a not quite significant difference in survival between those > 75 vs < 75 years (45% vs. 69%, p = .09). Conclusions: Our findings suggest that intensity of TILs in primary cutaneous melanoma is predictive of outcome following ICI treatment of advanced melanoma in patients over 75 years of age. These findings support possible interaction between qualitative differences of TILs and patient age. Our findings may help identify older melanoma patients who may benefit from ICI treatment.
Survival outcomes of pulmonary metastasectomy in advanced melanoma patients: An inverse probability weighted analysis.
Authors: Syaj Sebawe , Akhdar Marah , Alser Osaid , Elshami Mohamedraed , Hamouri Shadi
Published: June 2022

e21518

Background: Pulmonary metastasectomy (PM) is a commonly performed procedure for certain patients with lung metastasis. We aimed to estimate the effect of PM on the survival outcomes of advanced melanoma patients with lung metastasis. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) database for all adult patients with advanced melanoma (AYA site recode) with lung metastasis (Stage M1b according to AJCC 7th edition) who were diagnosed from 2010 to 2015. Patients with known liver, brain, or bone metastasis were excluded. Our primary outcomes were overall survival (OS) and cancer-specific survival (CSS) in months. We used Kaplan-Meier plots to compare survival outcomes between treatment groups. We adjusted for potential confounders including age, sex, marital status, primary tumor surgery, chemotherapy, and radiotherapy in a multivariate analysis. We carried out an inverse probability (IP)-weighted Cox regression in an attempt to eliminate the effect of nonrandomization when estimating the treatment effect of PM on OS and CSS. Results: We included 520 patients; 98 (18.8%) underwent PM and 422 (81.2%) did not. The sample median age was 71 (IQR: 61-80). T0 stage was prevalent in 179 (34.4%) and N0-1 in 302 (58.1%). Primary surgical resection was performed for 217 (41.7%) patients, 136 (26.2%) patients had undergone chemotherapy, and radiotherapy was administered in 64 (12.3%) patients. Patients who underwent PM had a higher median OS than patients who did not (43.0 months, 95% CI: 25.0-not reached vs. 13 months, 95% CI: 11-16). The median CSS in PM group patients was not reached (95% CI: 43.0-not reached), while it was 16 months (95% CI: 13-21) in non-PM patients. After multivariate adjustment, older age, being single, and not undergoing primary surgical resection, were all significant independent prognostic factors for worse OS and CSS. In contrast, sex and receipt of chemotherapy and/or radiotherapy did not affect either OS or CSS. PM group patients had a significant survival advantage than non-PM patients, in terms of OS and CSS (HR = 0.50, 95% CI: 0.37-0.67 and HR = 0.45, 95% CI: 0.32-0.63, respectively). On the IP-weighted Cox analysis, the survival benefits of PM were still significantly favorable for OS (IP-weighted HR = 0.42, 95% CI: 0.30-0.59) and CSS (IP-weighted HR = 0.38, 95% CI: 0.26-0.57). Conclusions: PM in a multimodality treatment setting resulted in a marked survival advantage for patients with advanced melanoma who had lung metastasis only. The management of such patients should be delicately individualized to optimize their survival outcomes.
Safety and effectiveness of avelumab in patients with curatively unresectable merkel cell carcinoma (MCC) in a real-world setting: A post-marketing surveillance in Japan.
Authors: Uhara Hisashi , Kiyohara Yoshio , Sato Masashi , Endo Shehla , Song Bingbing , Sato Yoshinori , Tanaka Yutaro , Kambe Anzu , Yamazaki Naoya
Published: June 2022

e21528

Background: Avelumab is an anti–PD-L1 monoclonal antibody that was approved in Japan for the treatment of patients with curatively unresectable MCC in Sept 2017. Because the number of Japanese patients with MCC participating in the global Phase II JAVELIN Merkel 200 study was limited (3 patients), Japan was mandated to conduct an all-case surveillance as a post-marketing surveillance (PMS) study. In the all-case surveillance, safety and efficacy information is accumulated with respect to a defined period of time or a defined number of post-approval prescription cases and is provided as real-world data. This report summarizes the results of the final analysis of this MCC PMS. Methods: This PMS is a multicenter, non-comparative, prospective, observational study. Since Nov 2017 (following approval in Japan), all patients with MCC who received at least one dose of avelumab in Japan were enrolled, and case report forms (CRF) were collected for all patients who started treatment through Oct 2019. Results: As of Sept 22, 2021, 152 patients from 86 sites were enrolled, and CRFs were collected from 77 patients. Of the 75 patients (53 sites) who met the analysis adequacy criteria, 48% were female, and the median age at the start of avelumab treatment was 77.0 years (42-95 years). Of the treatment lines in which avelumab was administered, 93.3% (70/75) were prescribed as first-line therapy. The incidence of adverse reactions was 61.3% (46/75), and 9.3% (7/75) discontinued treatment due to adverse reactions. Grade 3 and 4 adverse reactions occurred in 12.0% (9/75) and 4.0% (3/75), respectively; no grade 5 adverse reactions were reported. Infusion reactions were reported in 28.0% (21/75). The objective response rate (proportion of patients whose best response was assessed by the investigator as a complete or partial response) up to 1 year after the start of avelumab treatment was 45.3% (95% CI: 33.8, 57.3). The 1-year overall survival rate was 59.6% (95% CI: 47.0, 70.1). Conclusions: This study report is the first real-world evidence collected and analyzed from actual clinical use of avelumab in patients with curatively unresectable MCC in the East Asia region. Despite the different baseline patient characteristics, avelumab therapy in clinical practice had a manageable safety profile with no new safety concerns and has shown similar efficacy to that observed in the JAVELIN Merkel 200 trial.
Predictors of complication after groin dissection: A contemporary experience.
Authors: Jamjoum Ghader , Araji Thea , Nguyen Diana , Meguerditchian Ari N.
Published: June 2022

e21531

Background: Inguinal lymphadenectomy (ILND) has historically been associated with significant morbidity. The advent of sentinel node biopsy and selective dissection protocols have significantly decreased the frequency with which ILND is performed, reserving it for complex, recurrent disease. The study objective is to obtain contemporary morbidity rates for this complex procedure and to identify potentially preventable risk factors. Methods: Retrospective review of medical charts for all superficial, deep, and combination groin dissections performed for melanoma, sarcoma, and other rare cancers at a single, high-volume academic center between 01/2007 and 12/2020. Data points collected: patient, disease, surgery characteristics, and cancer outcomes. Outcome of interest: any complication within 30 days of surgery. Complications: wound infection, wound necrosis/disruption, seroma, drainage procedure, hematoma, lymphedema, and other. Multivariate logistic regression performed using SAS Enterprise 9.4. Results: : 139 cases were identified; type of dissection was 89, 12, and 38 for superficial, deep, and combined respectively. Melanoma accounted for 84.9% of cases, sarcoma for 8.6%. 56.1% of patients had an adverse postoperative event within 30 days. The majority of patients did not have a history of smoking, diabetes, cardiovascular disease, hypothyroidism, or radiation therapy. 61.2% were recurrent cancer cases with 56.8%, 19.4%, and 23.7% being clinically evident, radiological-only, and sentinel node positive disease respectively. Type and frequency of complications is reported in Table. Increasing age (OR: 1.04, 95CI: 1.01-1.07, P < 0.01) and number of positive lymph nodes harvested (OR: 1.22, 95CI: 1.00-1.50, P = 0.05) were associated with more complications. Deep dissection showed lower likelihood of complications than those with superficial (OR: 0.15, 95CI: 0.03-0.84, P < 0.05). Conclusions: A number of risk factors for complications were identified opening up opportunities for preventative intervention such as prehabilitation, use of frailty score, and neo-adjuvant therapy. Deep vein thrombosis, abscess, general deterioration, neuropathic pain, numbness. Frequency by occurrence, not patient. [Table: see text]
Attacking effect of diabetes mellitus and chronic neurogenic pain on malignant process:Are mitochondria of the heart damaged?
Authors: Neskubina Irina V. , Frantsiyants Elena M. , Kaplieva Irina V. , Cheryarina Natalia D. , Surikova Ekaterina I. , Shikhlyarova Alla I. , Bandovkina Valeria A. , Pogorelova Yulia A. , Nemashkalova Ludmila A. , Trepitaki Lidia K. , Kachesova Polina S. , Kotieva Inga Movlievna , Morozova Maria I. , Przhedetskiy Yuriy V. , Zhukova Galina V. , Goroshinskaya Irina A. , Kit Oleg I.
Published: June 2022

e21557

Background: Mitochondrial dysfunction is one of the mechanisms for the development of heart disease that requires close study. Diabetic cardiomyopathy is the leading cause of death in such patients due to the development of heart failure. Chronic pain may be associated with higher prevalence of cardiovascular disease, and little is known about its potential biological consequences. The purpose of this study was to analyze parameters of free radical oxidation and mitochondrial respiration in heart cells in experimental animals with malignant tumors growing in presence of diabetes mellitus (DM) and chronic neurogenic pain. Methods: The study included outbred female rats (n = 32) weighing 180-220 g and C57BL/6 female mice (n = 84) weighing 21-22 g. Experimental groups of rats were: intact animals (n = 8), controls (n = 8) with DM, comparison group (n = 8) with subcutaneously inoculated Guerin’s carcinoma, and main group (n = 8) with Guerin’s carcinoma subcutaneously inoculated after 1 week of persistent hypothyroidism. Experimental groups of mice were: intact animals (n = 21), controls (n = 21) with a model of chronic neurogenic pain (CNP) created by bilateral sciatic nerve ligation, comparison group (n = 21) with subcutaneously inoculated melanoma (B16/F10), and main group (n = 21) with melanoma subcutaneously inoculated 3 weeks after the CNP model was created (CNP+B16/F10). Heart mitochondria were isolated by differential centrifugation. Levels of cytochrome C (ng/g of protein), 8-hydroxy-2'-deoxyguanosine (8-OHdG) (ng/g of protein), and malondialdehyde (MDA) (nM/g of protein) were measured in mitochondrial samples by ELISA. Statistical analysis was performed using the Statistica 10.0 program. Results: DM in rats upregulated 8-OHdG by 6.3 times and MDA by 1.9 times (p < 0.05) and downregulated cytochrome C by 1.5 times (p < 0.05) in heart cell mitochondria, compared to intact values. DM+Guerin’s carcinoma in rats increased 8-OHdG by 14.0 times and MDA by 1.7 times (p < 0.05) and decreased cytochrome C by 1.5 times (p < 0.05), compared to intact values. CNP in mice did not affect the studied parameters in mitochondria of the heart. CNP+B16/F10 in mice increased 8-OHdG by 7.1 times and MDA by 1.6 times (p < 0.05) and decreased cytochrome C by 1.6 times (p < 0.05) in heart cell mitochondria. Conclusions: Comorbidity (diabetes mellitus, chronic neurogenic pain) together with malignant pathology aggravates mitochondrial dysfunction of heart cells which results in DNA damage and destabilization of the respiratory chain mediated by free radical oxidation processes.
Prognostic factors for recurrence and mortality in patients with localized malignant melanoma: Analysis of the Epidemiological Registry of Malignant Melanoma in Colombia REMMEC ACHO.
Authors: Ospina Serrano Aylen Vanessa , Contreras Fernando , Triana Ivan , Ortiz Diaz Juan David , Ramos Pedro , Vargas Claudia , Arango Natalia , Idrobo Henry , Munevar Isabel , Yepes Andres , Mantilla William , Jimenez Paola , Rivas Tafurt Giovanna Patricia , Lema-Medina Mauricio , Alcala Marcela , Gomez Diego , Chinchia Isabel , Barrero Angela , Sanchez-Vanegas Guillermo
Published: June 2022

e21572

Background: Malignant melanoma is the skin cancer with the highest mortality rate. In early stages, it may have a better prognosis and some possibility of cure. In Colombia, given the increase in cases, a national registry of the disease has been initiated with the aim of characterizing the population and establishing the prognostic factors in the local context. Methods: Cohort study based on data from the Epidemiological Registry of Malignant Melanoma in Colombia (REMMEC). For this first phase,data from January 2011 to December 2021 were analyzed. Patients were older than 18 years, with confirmed diagnosis of localized melanoma. Mortality and recurrence incidence rates were calculated using the Kaplan-Meier method, overall survival was estimated at 5 years of follow-up for each stage. Finally, a prognostic model was made for the mortality outcome, using the Cox proportional hazards method. Results: 759 patients were included, the mean age was 66 years (SD: 15.6), 57% women (n = 431), 29% phototype I or II (n = 219), and the most frequent histological subtype was acral lentiginous (n = 211; 36%). In relation to the stage, 13.9% with stage 0 (n = 106), 24.2% in stage I (n = 184), 30% in stage II (n = 228), and 31.7% in stage III (n = 241). ECOG-3-4 in 1.05% (n = 8). Regarding the health regimen, the subsidized patients were 199 (26%), and the contributive 560 (73.8%), of which 35 and 30.6% had stage III, respectively. 92% of all patients underwent local surgery (n = 699) and 30% (n = 226) local lymphadenectomy. The median follow-up time was 36 months (IQR: 17-72). The mortality incidence rate was 3.6 cases per 100 person-years (95% CI: 2.9-4.3), and the recurrence rate was 6.8 cases per 100 person-years (95% CI: 5.9 -7.8). Overall survival at five years for patients in stage 0 and I was 97% (95% CI: 89-99), for stage II it was 80% (95% CI: 72.6-86.6); for stage III 65% (95% CI: 57-72). 22.4% (n = 170) received adjuvant treatment . 26.2% (n = 199) had metastatic recurrence. The prognostic factors for mortality are presented in Table. Conclusions: In the Colombian context, in patients with localized melanoma, ECOG 3 or 4, stage III at the time of diagnosis, receiving radiotherapy, the presence of ulceration, chronic sun exposure, and the subsidized health regimen are poor prognostic factors.[Table: see text]
An 11-gene expression signature related to tumorigenesis and immunosuppression in primary cutaneous melanoma predicts sentinel lymph node metastatic status.
Authors: Tarhini Ahmad A. , Hobbs Brian , Khunger Arjun , Yassine Ibrahim , Kobeissi Iyad , Hwu Patrick , Sondak Vernon K. , LaFramboise William , Kirkwood John M.
Published: June 2022

e21579

Background: A biomarker derived from the primary melanoma tumor to predict regional sentinel lymph node (SLN) metastatic status can be valuable in guiding the decision making in planning the SLN surgical procedure for candidate patients. Methods: Gene expression profiling was performed on primary cutaneous melanoma tumor biopsies of 49 (24 known SLN+, 25 SLN-) patients (T3a/b, T4a/b) who underwent SLN for staging using transcriptome profiling analysis. U133A 2.0 Affymetrix gene chips were used. Significance Analysis of Microarrays (SAM) was used to test the association between gene expression level of the primary tumor and SLN status. Genes with fold change > 1.5 and q value < 0.05 were considered differentially expressed. Pathway analysis was performed using Ingenuity Pathway Analysis. Benjamini and Hochberg method was used to adjust for multiple testing in pathway analysis. All statistical analyses were implemented in R. Results: A total of 49 patients with primary cutaneous melanoma were studied, of which, 24 were diagnosed as SLN positive and 25 as SLN negative by routine H&E and immunohistochemistry. Using SLN metastatic status as the outcome, a univariate logistic regression model was fitted with individual probe sets. A total of 251 probe sets were filtered and 11 probe sets were considered as differentially expressed (DE) between SLN-ve and SLN+ve groups, with the selection criterion set at Benjamini- Hochberg method -adjusted p -value below 0.05 and the absolute log fold change above 0.5. As each of the 11 probe sets was matched to a unique known gene, an 11 gene signature was derived and among them, the expression level of 7 genes was significantly reduced in the SLN+ve group compared to the SLN-ve group, while 4 genes were overexpressed in the SLN+ve group. Integrative and interactive heatmaps were produced from hierarchical cluster analysis to show the 11 differentially expressed genes. Selected genes were found to be uniformly related to tumorigenesis, malignant progression, DNA repair, cell cycle regulation, chemoresistance, immunosuppression and/or involvement in multiple cancer-related pathways. Several of the selected genes were previously shown to be prognostic in various malignancies. Conclusions: We present a unique 11-gene expression signature derived from primary melanoma tumor biopsy samples and related to tumorigenesis and immunosuppression that may be useful for the prognostic stratification of melanoma patients. This may allow the optimal selection of patients for SLN biopsy.
Whole-slide multispectral imaging reveals the immune subtypes of melanoma associated with the tumor microenvironment: An automated 7-color mIF assay.
Authors: Patel Bhavika , Allen Stephanie , Boldt Brittney , Ramirez Noah , Mammadova Najiba , Haggerty Agnes , Mehra Navi
Published: June 2022

e21591

Background: Immunotherapy and precision medicine are rapidly developing approaches to cancer therapy. Biomarkers that detect the tumor and tumor microenvironment allow for the development of strategies that accelerate the advancement of treatments to enhance a patient’s immune system. Akoya’s MOTiF PD-1/PD-L1 Auto Melanoma Kit is a validated, multiplex immunoassay enabling detection of the 6 most clinically relevant immuno-oncology and spatial biomarkers: FoxP3, PD-L1, Sox10/S100, PD-1, CD8 and CD68. Methods: In this study, the MOTiF PD-1/PD-L1 panel was used to analyze the tumor microenvironment and specifically assess immune phenotypes within melanoma samples from 3 patients. This study demonstrates a fully optimized and end-to-end workflow solution for biomarker discovery in melanoma. Results: We demonstrate the utility of Akoya’s MOTiF PD-1/PD-L1 Melanoma panel kit in studying the cellular diversity while retaining spatial context. Stained slides were analyzed using the InForm and Phenoptr Reports image analysis platforms to identify phenotypes and better understand spatial relationships between cell phenotypes. The MOTiF PD-1/PD-L1 panel kit provides reproducibility across different patient samples. Conclusions: This data provides insight into the innate and adaptive immune landscape for targeted design of new immunotherapies as well as improved efficacy and reduced toxicity in the treatment of melanoma.
NOTCH4 mutation as a potential predictive biomarker for immunotherapy in NRAS wildtype melanoma.
Authors: Li Hongxia , Zhang Qin , Duan Qianqian , Tan Yuan , Sun Tingting , Qi Chuang , Ren Yong
Published: June 2022

e21594

Background: NRAS wildtype melanoma account for 80-85% melanoma patients and have been reported had a better response for immunotherapy. Although PD-L1 expression and tumor mutation burden (TMB) have been considered as important biomarkers for immunotherapy in many types of tumors, the predictive efficacy of them in melanoma is controversial. Since evidences showed NOTCH pathway mutation was a potential predictive biomarker for immune checkpoint inhibitors in some types of tumors. Here we explored the relationship between NOTCH family genes mutations and efficacy of NRAS wildtype melanoma immunotherapy. Methods: 265 NRAS wildtype ICI-pretreatment melanomas from cBioPortal (https://www.cbioportal.org), which is divided to discovery (N = 76) and validation (N = 189) cohort to analyze the association between NOTCH family genes (NOTCH1-4) mutation and efficacy of ICIs therapy. All nonsynonymous somatic mutations, including nonsense, missense, nonstop, frameshift deletion and insertion, in-frame deletion and insertion, and splice site mutations were considered for inclusion in our study. The potential mechanism was subsequently explored through RNA expression in immunotherapy treated population. Results: Patients with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in discovery (HR: 0.30, 95%CI: 0.11-0.83, P = 0.01) and validation cohort (HR: 0.21, 95%CI: 0.07-0.68, P = 0.003). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P < 0.05). RNA data revealed that enhanced anti-tumor immunity was observed in NOTCH4-Mut tumors. Activated CD4 memory T cell, CD8 T cell, follicular helper T cell (Tfh) and Neutrophils were more abundant in NOTCH4-Mut tumors. In addition, the results of enrichment analysis showed that several immune-related pathways varied significantly between NOTCH4-Mut and NOTCH4-Wt tumors, including Interferon γ response, DNA repair, epithelial mesenchymal transition (EMT), angiogenesis. Conclusions: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guiding immunotherapeutic responsiveness.
The GERMELATOX-A (Dermatologic Cooperative Oncology Group): Study attitude of German melanoma patients towards toxicity during adjuvant treatment.
Authors: Kähler Katharina C. , Hüning Svea , Nashan Dorothée , Meiss Frank , Rafei-Shamsabadi David A , Rißmann Hannes , Colapietro Chiara , Livingstone Elisabeth , Maul Lara Valeska , Heppt Markus V , Hassel Jessica Cecile , Gutzmer Ralf , Loquai Carmen , Heinzerling Lucie , Sachse Michael Max , Bohne Ann-Sophie , Moysig Laura , Peters Wienke , Rusch Judith , Blome Christine
Published: June 2022

e21597

Background: Trials of adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in recurrence-free survival (RFS) with a very similar relative risk reduction. Both treatment modalities are characterized by specific side effects. Therefore the decision for or against a treatment modality is very often driven by the risk for toxicity. This study addressed for the first time the attitudes and preferences of German and Swiss patients and physicians for adjuvant treatment with ICI and TT. Methods: In this multicenter study („GERMELATOX-A“) patients with low-risk melanoma (pT1a, AJCC stage I, familiar with cancer diagnosis but no adjuvant treatment planned), and dermatooncologists from 11 German and 1 Swiss skin cancer centers were asked to fill out a questionnaire. Here, side effect scenarios typical for each ICI and TT with mild-to-moderate or severe toxicity and also melanoma recurrence leading to cancer death were described. We asked patients and physicians about the reduction in melanoma relapse (relapse-free survival, RFS) and the survival increase (overall survival, OS) at 5 yrs they would expect to tolerate defined side-effects. Results: Data were obtained from 136/107 patients/physicians, respectively (median age: 59 yrs/32 yrs, 56.2%/67.6% female).Overall, by visual analog scale, patients valued a melanoma relapse worse than all scenarios of side-effects during adjuvant treatment with ICI or TT. In general patients required higher risk reductions for DFS and OS for both ICI and TT and their drug related side effects compared to physicians to accept this treatment. In case of severe side effects, patients needed a 20% higher reduction of relapse rate at 5 yrs for ICI compared to TT (71.4%/50.0%). Physicians required identical relapse reduction rates for ICI and TT in case of severe side effects (42.9%). Conclusions: This study demonstrated a pronounced variation of German and Swiss patient preferences on adjuvant treatment related to drug class specific side effects and outcomes and a clear difference between patients' and physicians' attitudes. This difference might influence decision making for adjuvant treatment options and should therefore also be investigated in further trials for current adjuvant treatment modalities. As adjuvant melanoma treatment with ICI and TT will possibly be implemented in earlier stages soon, precise knowledge of the patient perspective can be helpful for the process of decision making.
MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients: A retrospective study.
Authors: Saint-Ghislain Mathilde , Geoffrois Lionnel , Gastaud Lauris , Lesimple Thierry , Negrier Sylvie , Penel Nicolas , Kurtz Jean Emmanuel , Le Corre Yannick , Dutriaux Caroline , Gardrat Sophie , Barnhill Raymond , Matet Alexandre , Cassoux Nathalie , Ramtohul Toulsie , Servois Vincent , Mariani Pascale , Piperno-Neumann Sophie , Rodrigues Manuel
Published: June 2022

e21601

Background: MBD4 encodes a glycosylase implicated in repair of lesions induced by DNA deamination and its inactivation in tumors is associated with a hypermutated phenotype. Uveal melanoma (UM) is a rare but aggressive form of melanoma carrying an extremely low mutation burden. Although metastatic UM (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI. Since then, other MBD4-inactivated UMs, acute myeloid leukemias, colorectal adenocarcinomas, gliomas and spiradenocarcinoma cases have been reported. Methods: Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients. Results: Three hundred mUM patients were analyzed. Median follow-up was 17.3 months. Ten objective responses and 20 stable disease for > 12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (CB; i.e. responder patients and stable disease) rate of 10%. Median progression-free survivals (PFS) in patients without and with CB were 3.1 and 16.3 months, respectively (p < 0.0001). Of the 134 tumors sequenced for MBD4, five (3.7%) were mutated. MBD4 inactivation was associated with higher mutation burden (179 to 643 variants versus a median of 16 in MBD4 wild-type), better objective response rate as 60% of MBD4m versus 4% of MBD4-wild type patients responded (Fisher’s exact p-test = 0.0009). Median PFS was 4.0 months in MBD4-wild type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median overall survival was 16.6 months in MBD4-wild type and unreached in MBD4m patients (HR = 0.11; p = 0.004). Conclusions: In mUM patients, MBD4 mutation is highly predictive for response to ICI, PFS and overall survival benefit. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM and other tumor types where MBD4 mutations are reported.