tbuckley/cabot-search huggingface dataset:
Pembrolizumab as first-line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC): Phase 2 results from CARSKIN.
Authors: Eve Maubec, Marouane Boubaya, Peter Petrow, Nicole Basset-Seguin, Jean Jacques Grob, Brigitte Dréno, Marie Beylot-Barry, Isabelle Scheer-Senyarich, Sabine Helfen, Marie Thérèse Leccia, Andreea Raluca Stefan, Philippe Saiag, Julie De Quatrebarbes, Nicolas Meyer, Lydia Deschamps, Céline Alloux, Isabelle Lopez, Soufian Cherbal, Annick Tibi, Vincent Lévy
Journal: Journal of Clinical Oncology (2019)

9547 Background: Cemiplimab, a PD-1-axis blocking agent, has recently been approved for unresectable cSCCs. We report results of the CARSKIN study evaluating pembrolizumab in the first-line setting. Methods: Chemotherapy naive patients (pts) with unresectable cSCCs, either locally or regionally advanced or metastatic, and ECOG PS ≤1 were accrued to this multi-institutional phase II trial to assess tumor response rate (RR) and safety of pembrolizumab administered IV (200 mg Q3W) for a period up to 24 months (mo). Baseline PD-L1 expression was centrally assessed on tumor. The primary endpoint was the RR at 15 weeks (wks) per RECIST v1.1 (independent review). A Simon two-stage design was used. Results: From 03/2017 to 01/2018, 39 pts (79% males, median age 79 years) were enrolled. Disease was local (18%), regional (62%) or metastatic (21%); 38% of pts were PS 0. The median number of infusions was 8. The median follow-up was 10.2 mo; 15 pts are still on pembrolizumab. Thirty-four pts were evaluable for tumor response, and 39 for toxicity. The RR at 15 wks was 38.5 % (95% CI: 24–55%) in the ITT population corresponding to 2 CR and 13 PR. The best responses were 3 CR and 12 PR. The DCR was 51% (20/39 including 5 SD) at 15 wks. The median PFS was 8.4 mo and the median OS was not reached. No responder has progressed to date including 2 pts who discontinued pembrolizumab for 6 to 12 mo. Treatment-related AEs (TRAEs) occurred in 67% of pts, including 8% with severe TRAEs (1 gr 3 cholestasis, 1 gr 3 colitis and 1 death due to recurrence of a non-related head and neck cancer) and 10% who discontinued because of a TRAE. Centrally assessed baseline PD-L1 expression was positive in 77% of patients (1% tumor staining threshold), but it failed to predict response at 15 wks with a median PD-L1 expression of 10% in responders and non-responders at 15 wks (P = .55). Conclusions: In this series of 39 elderly pts with unresectable cSCCs, the safety profile was consistent with previous pembrolizumab studies. First-line pembrolizumab provided robust antitumor activity regardless of PD-L1 expression levels. Clinical trial information: NCT02883556.
Clinical heterogeneity of elderly melanoma patients in the real-world setting: Potential implications for treatment outcomes following immune based therapy.
Authors: Upendra P. Hegde, Harsh V Parmar, Christina Elizabeth Stevenson
Journal: Journal of Clinical Oncology (2019)

e21026 Background: Recent studies have indicated that immune checkpoint inhibitor treatment of metastatic melanoma is effective irrespective of older age. However, in the real world setting, not all older patients (pts.) diagnosed with high-risk cutaneous melanoma have same levels of immune function due to wide variation of older age and aging associated diseases that adversely influence it. Frailty associated with co-morbidities, autoimmunity, cancer, and their treatments are three such conditions that influence treatment outcomes following immune based treatment of melanoma in older subjects. To better understand this interaction between melanoma, aging-associated diseases and potential outcomes following immune checkpoint inhibitor treatment in the real world, we reviewed clinical data of elderly melanoma pts. from the University of Connecticut's Neag Cancer Center following an IRB approval. Methods: We retrospectively reviewed clinical characteristics of elderly pts. diagnosed with high-risk cutaneous melanoma (Stage IIC, III, IV) at the University of Connecticut from 2012-2019. Pts. over the age of 60 years were divided into two main groups: Group I ("Fit elderly") and Group II ("Elderly with immune suppressive conditions"). Group II pts. were further divided into three subgroups: A ("Co-morbidities and frailty"), B ("Autoimmunity and its treatment") and C ("Cancer and its treatment"). Results: From 2012-2019, a total of 56 elderly pts. diagnosed with high-risk cutaneous melanoma were stratified as the following: Group I - 31 pts. (55%) and Group II - 25 pts. (45%); among the Group II pts., Group A contained 14 pts. (56%), Group B 5 pts. (20%), and Group C 6 pts. (24%). The median age for all 56 elderly pts. was 77 yrs. (range 61 to 99). In Group I, the median age was 73 yrs. (range 61-91). In Group II, the median age was 82 years (range 66-99); A median age 85 yrs (range 66-99), B median age 78 yrs (range 66-86), and C 80.5 yrs. (range 66-86). 9 out of 56 pts. (16%) did not receive immune checkpoint inhibitor treatment, of which 7 pts. (56%) were frail and 2 pts. (22%) were non-frail. Conclusions: Our data indicate that the existence of significant clinical heterogeneity among high-risk elderly melanoma pts. encountered in the community setting reflects a wide spectrum of immune function. Larger studies stratifying elderly subjects by co-morbidities and immune suppressive conditions will help shed accurate light on clinical relevance of immune based treatment of melanoma in older subjects.
Preclinical development of combination therapy targeting the dominant cytokine interleukin-1β for renal cell carcinoma.
Authors: David Henry Aggen, Ali Ghasemzadeh, Wendy Mao, Nivi Chowdhury, Matthew Chaimowitz, Jessica Hawley, Vinson Wang, Matthew Dallos, Cheng Zhang, Hu Li, Xinzheng Victor Guo, Charles G. Drake
Journal: Journal of Clinical Oncology (2019)

e14237 Background: Targeting myeloid-derived suppressor cells (MDSCs), key mediators of intrinsic and adaptive immune resistance, remains a significant challenge in kidney cancer immunotherapy. One potential driver of MDSC mediated tumor immunosuppression is the cytokine interleukin-1 beta (IL-1β). Although large cancer prevention studies show that targeting IL1 decreases cancer risk, the exact mechanism of anti-IL-1 mediated anti-tumor efficacy is not yet defined. To understand the immunogenic effects of IL-1β blockade and effects on MDSCs, we used the RENCA model of RCC. Methods: We inoculated BALB/c mice with 1x10 6 RENCA cells. On Day +10 we treated mice (n = 8/group) with vehicle, αPD1, αIL1β, cabozantinib, combination αPD1/αIL1β, or cabozantinib/αIL1β. We harvested day +18 tumors to quantify tumor size and immune cells by flow cytometry. We then isolated immune cells for differential gene expression profiling by RNAseq. Results: Treatment with αIL1β significantly decreased tumor size compared to vehicle or αPD1 monotherapy. Combining αPD1/αIL1β or cabozantinib/αIL1β potentiated the anti-tumor effects of αPD1 or cabozantinib monotherapy respectively. Anti-IL1β therapy decreased polymorphonuclear (PMN)-MDSC infiltration (αIL1β: 0.76% +/- 0.21 vs. vehicle: 1.89% +/- 0.37, P = 0.014). Relative to PD1 monotherapy, combining αPD1 and αIL1β decreased PMN-MDSCs (αPD1: 2.14% +/- 0.56 vs αPD1/αIL1β: 0.91% +/- 0.15, P = 0.033) and increased M1-like tumor associated macrophages (TAM) (αPD1: 0.798% +/- 0.21 vs. αPD1/αIL1β: 12.04% +/- 2.9, P = 0.0008). Gene expression profiling from sorted immune cells from αIL1β treated tumors revealed multiple differentially regulated cytokines including interleukin-6, IFN-γ, and IL-10. Conclusions: Blockade of IL-1β depletes intratumoral PMN-MDSCs and increases M1-like TAM with minimal effects observed on the T cell compartment. Treatment with cabozantinib or αPD1 in combination with αIL1β led to sustained control of tumor growth. IL-1β represents a promising target for kidney cancer immunotherapy. Based on the preclinical data, a clinical trial of neoadjuvant αPD1 and αIL1β therapy is planned for patients with high risk RCC.
Results from a phase Ib/II study of enzalutamide and metformin in men with castration resistant prostate cancer (CRPC).
Authors: Mamta Parikh, Daniel Robles, Chong-xian Pan, Primo Lara, Joy C Yang, Allen Gao, Christopher P. Evans
Journal: Journal of Clinical Oncology (2019)

5054 Background: Preclinical models have shown that autophagy is a cell survival mechanism to overcome treatment-induced stress and facilitate progression and resistance in CRPC. Metformin (met) demonstrates autophagy inhibition and resensitizes CRPC tumors to enzalutamide (enza) as a combination in in vitro models. A Phase Ib/II trial was conducted to evaluate the combination. Methods: Eligible patients (pts) had established CRPC, ECOG 0-2, adequate hematologic and organ function, and ≤ 2 prior treatments for CRPC. Major exclusion criteria included prior enza or met treatment, presence of brain metastases, history of DM2 or seizures. An initial cohort of 3 pts were treated with enza 160 mg PO daily and met 500 mg PO bid (DL1), with met dose escalated to 1000 mg PO bid (DL2) in subsequent 3 pts if dose-limiting toxicity (DLT) was observed in ≤1 pt in DL 1, and cycles of 28 days. Once primary objective of maximum tolerated dose (MTD) was established, additional pts were enrolled at MTD for a total of 24 evaluable pts. Secondary objectives of the study included PSA response and safety. Results: From 8/24/16-12/31/18, a total of 3 pts were enrolled to DL1, with no DLTs observed in that cohort, with an additional 21 enrolled to DL2; 12 remain on trial. Median age was 71, with 8/24 (33%) and 3/24 (12.5%) with prior docetaxel and abiraterone treatment, respectively. One DLT due to Grade 3 abdominal pain was observed at DL2 prior to establishing MTD. Grade 3 AEs observed in 1/24 (4%) of pts were diarrhea, fatigue, hypertension, lower GI bleed, myalgia; 2/24 (8%) had abdominal pain. One pt had Grade 4 hallucinations. Among pts who discontinued, 8 were discontinued for progression, 3 withdrew consent, and 1 experienced an SAE (seizure). Pts received median of 11 cycles (1-31) of treatment. PSA response ≥ 50% was observed in 19/24 (79%) pts. Conclusions: The combination of enzalutamide 160 mg PO daily and metformin 1000 mg PO bid is well-tolerated, and clinically active. Clinical trial information: NCT02339168.
Proteome analysis of human mesenchymal stem cells undergoing chondrogenesis when exposed to the products of various magnesium-based materials degradation
Authors: Adela Helvia Martínez Sánchez, Maryam Omidi, Marcus Wurlitzer, Marceline Manka Fuh, Frank Feyerabend, Hartmut Schlüter, Regine Willumeit-Römer, Bérengère J.C. Luthringer
Journal: Bioactive Materials (2019)

Treatment of physeal fractures (15%-30% of all paediatric fractures) remains a challenge as in approximately 10% of the cases, significant growth disturbance may occur. Bioresorbable Magnesium-based implants represent a strategy to minimize damage (i.e., load support until bone healing without second surgery). Nevertheless, the absence of harmful effects of magnesium-implants and their degradation products on the growth plate should be confirmed. Here, the proteome of human mesenchymal stem cells undergoing chondrogenesis was evaluated when exposed to the products of various Magnesium-based materials degradation. The results of this study indicate that the materials induced regulation of proteins associated with cell chondrogenesis and cartilage formation, which should be beneficial for cartilage regeneration.
A novel nutritional supplement prevents muscle loss and accelerates muscle mass recovery in caloric-restricted mice
Authors: Anita M. van den Hoek, Gerben C.M. Zondag, Lars Verschuren, Christa de Ruiter, Joline Attema, Elly C. de Wit, Anne M.K. Schwerk, Bruno Guigas, Serene Lek, Annemarie Rietman, Rein Strijker, Robert Kleemann
Journal: Metabolism (2019)

Muscle atrophy is defined as decreased muscle mass, associated with aging as well as with various chronic diseases and is a fundamental cause of frailty, functional decline and disability. Frailty represents a huge potential public health issue worldwide with high impact on healthcare costs. A major clinical issue is therefore to devise new strategies preventing muscle atrophy. In this study, we tested the efficacy of Vital01, a novel oral nutritional supplement (ONS), on body weight and muscle mass using a caloric restriction-induced mouse model for muscle atrophy.Mice were calorically restricted for 2 weeks to induce muscle atrophy: one control group received 60% kcal of the normal chow diet and one intervention group received 30% kcal chow and 30 kcal% Vital01. The effects on body weight, lean body mass, muscle histology and transcriptome were assessed. In addition, the effects of Vital01, in mice with established muscle atrophy, were assessed and compared to a standard ONS. To this end, mice were first calorically restricted on a 60% kcal chow diet and then refed with either 100 kcal% chow, a mix of Vital01 (receiving 60% kcal chow and 40 kcal% Vital01) or with a mix of standard, widely prescribed ONS (receiving 60 kcal% chow and 40 kcal% Fortisip Compact).Vital01 attenuated weight loss (-15% weight loss for Vital01 vs. -25% for control group, p < 0.01) and loss of muscle mass (Vital01 with -13%, -12% and -18%, respectively, for gastrocnemius, quadriceps and tibialis vs. 25%, -23% and -28%, respectively, for control group, all p < 0.05) and also restored body weight, fat and muscle mass more efficiently when compared to Fortisip Compact. As assessed by transcriptome analysis and Western blotting of key proteins (e.g. phospoAKT, mTOR and S6K), Vital01 attenuated the catabolic and anabolic signaling pathways induced by caloric restriction and modulated inflammatory and mitochondrial pathways. In addition, Vital01 affected pathways related to matrix proteins/collagens homeostasis and tended to reduce caloric restriction-induced collagen fiber density in the quadriceps (with -27%, p = 0.051).We demonstrate that Vital01 preserves muscle mass in a calorically restricted mouse model for muscle atrophy. Vital01 had preventive effects when administered during development of muscle atrophy. Furthermore, when administered in a therapeutic setting to mice with established muscle atrophy, Vital01 rapidly restored body weight and accelerated the recurrence of fat and lean body mass more efficiently than Fortisip Compact. Bioinformatics analysis of gene expression data identified regulatory pathways that were specifically influenced by Vital01 in muscle.
Prognostic value of systemic immune-inflammation index in elderly patients with esophageal squamous cell cancer.
Authors: Shengjun Ji, Qingqing Chen
Journal: Journal of Clinical Oncology (2019)

e15500 Background: The aim is to assess the value of systemic immune-infflammation index (SII) in elderly patients with esophageal squamous cell cancer after radiotherapy. Methods: Total 128 patients larger than 65 years were included. The optimal threshold of SII was determined by establishing a receiver operating characteristic (ROC) curve, and the relationship between SII and prognosis was analyzed. Results: The ROC curve showed that the optimal threshold of the pretherapeutic SII for predicting the efficacy of radiotherapy was 700.97. Univariate analysis showed that SII was significantly associated with radiotherapy (P&lt;0.001). The OS of the low SII group was 83.5%, 62.0%, 48.1% for 1 year, 2 years, and 3 years, respectively. The OS of the high SII group was 75.5%, 30.6%, 24.5% for 1 year, 2 years, and 3 years, respectively. The differences were statistically significant (all P&lt;0.001). Univariate analysis showed that SII, N stage, and TNM stage were all related to the OS (all P &lt; 0.01). Cox multivariate analysis showed that SII were independent prognostic factors. Conclusions: SII is a predictive index for elderly patients with esophageal squamous cell cancer after radiotherapy.
Outcomes and patterns of failures after hypofractionated radiation therapy for intrahepatic cholangiocarcinoma.
Authors: Ibrahim Abu-Gheida, Aashini Patel, Mohamed Zaid, Dalia Elganainy, Milind M. Javle, Kanwal Pratap Singh Raghav, Jean-Nicolas Vauthey, Thomas A. Aloia, Ching-Wei David Tzeng, Bruce D. Minsky, Grace L. Smith, Emma B Holliday, Cullen M. Taniguchi, Albert Koong, Sunil Krishnan, Joseph M. Herman, Prajnan Das, Christopher H. Crane, Eugene Jon Koay
Journal: Journal of Clinical Oncology (2019)

e15609 Background: Locally advanced unresectable intrahepatic cholangiocarcinoma (IHCC) remains incurable. Prior data has shown the effectiveness of hypofractionated radiation therapy (HRT) with biological equivalent doses (BED) greater than 80.5 Gy in improving local control and survival for this patient population. This is an updated report of our IHCC experience with HRT in 15 or 25 fractions using a simultaneous integrated boost technique. Methods: A retrospective analysis of 63 patients (median age 64, range 29-87) diagnosed between 2007-2016 who received HRT was performed. RT dose ranged from 58-90 Gy in 15 fractions and 62.5-100 Gy in 25 fractions, translating to a median BED of 97.5 (range 78.1-144 Gy). Median primary tumor size at diagnosis was 7.8 cm (2.4-17cm). Forty-eight (76%) patients received gemcitabine-based therapy prior to HRT. Results: Median follow up was 31 months (4-110). The 2 year overall-survival (OS), local-progression-free-survival (LPFS), intrahepatic-distant-metastasis-free-survival (IH-DMFS) and extraheptic-distant-metastasis-free-survival (EH-DMFS) were 71% (95% CI 58-82), 67% (95% CI 50-80), 40% (95% CI 28-54) and 40% (95% CI 27-54) respectively. Pattern of failure analysis revealed 16 patients with local failure after HRT, of which only 5 (8% of total) progressed within the high iso-dose field line (BED &gt; 80.5). After HRT, 41 (65%) patients had intrahepatic metastasis that occurred outside the radiation field, and 34 (54%) patients developed extrahepatic metastasis. On multi-variate analysis, T-stage was an independent predictor of OS, LPFS, IH-DMFS, and EH-DMFS. Larger normal liver volume and 15 fraction treatments were independently associated with better LPFS and IH-MFS respectively. There were no significant HRT-related toxicities. Conclusions: HRT demonstrates safety and efficacy for durable local control and prolonged overall survival in patients with unresectable IHCC. Dominant modes of failure are outside the HRT field. Improvements in systemic therapies could further improve outcomes for this patient population.
CMLVAX100 Peptide Vaccinations induce Peptide Specific “cytotoxic” CD4+ T Cells (CD4+CTLs) in Chronic Myeloid Leukemia Patients: New Insights about Peptide Vaccine-Mediated Antitumor Response
Authors: Monica Bocchia, Maristella Tassi, Micaela Ippoliti, Marzia Defina, Elisabetta Abruzzese, Malgorzata Monika Trawinska, Alessandro Gozzetti, Donatella Raspadori, Francesco Lauria
Journal: Blood (2008)
TAKTIC: A prospective, multicenter, uncontrolled, phase IB/II study of LY2780301 (LY) in combination with weekly paclitaxel (wP) in HER2-negative locally advanced (LA) or metastatic breast cancer (MBC) patients.
Authors: Cecile Vicier, Nicolas Isambert, Florence Dalenc, Mario Campone, Christelle Levy, Keyvan Rezai, Magali Provansal, José Adelaide, Séverine Garnier, Arnaud Guille, Max Chaffanet, Cornel Popovici, Emmanuelle Charafe-Jauffret, Jihane Pakradouni, Aurelie Autret, Anthony Goncalves
Journal: Journal of Clinical Oncology (2019)

1091 Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane-resistance. LY is a dual inhibitor of p70 S6 kinase and AKT. TAKTIC study aimed to determine the recommended phase II dose (RP2D) of the combination of LY with wP (phase Ib) and to estimate overall response rate (ORR) of this regimen (phase II) in HER2-negative LA or MBC patients, both in the overall patient population and in patients with activation of PI3K/AKT pathway (PI3KAKT+). Methods: HER2-negative inoperable LA or MBC patients (pts), with (phase Ib) or without (phase II) previous cytotoxic treatment for advanced disease were eligible. Oral LY (400 or 500mg) was administered daily in combination with intravenous wP (70 or 80mg/m 2 ). A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PI3KAKT+ was defined as activating mutation of PIK3CA and/or AKT by targeted NGS or homozygous loss of PTEN by array comparative genomic hybridization (aCGH) or loss of PTEN by immunohistochemistry, as evaluated on available fresh tumor tissue. Results: A total of 12 and 35 patients (pts) were included in the phase Ib and II, respectively. In phase Ib, only 1 dose-limiting toxicity (confusion) was observed at the last dose level (LY, 500 + wP, 80), which was determined as RP2D. Main drug-related adverse events (AE) in phase Ib were skin toxicity (92% of pts, G3-4 in 33%), and paresthesia (50% of pts, G3-4 in 8%). In the phase II study, ORR was 62.9 % [44.9,78.5] including 1 CR and 21 PR in the overall population and 55.6 % [30.8,78.5] in PI3KAKT+ pts (10 PR in 18 pts). Median progression-free survival was 12.4 months [7.9,17.9] and 6-month clinical benefit rate was 82.9% [66.4,93.4]. AEs in phase II were similar to phase I part, except that 17% of pts experienced pneumonia (G3-4 in 9%). Conclusions: Combining LY and wP in HER2-negative LA or MBC was feasible with preliminary evidences of efficacy, independently of PI3K/AKT activation. Clinical trial information: NCT01980277.
Mixed invasive ductal-lobular carcinoma: Clinicopathological characterization and clinical outcomes.
Authors: Azadeh Nasrazadani, Yujia Li, George Tseng, Jennifer Xavier, Sarah Hugar, Adrian V. Lee, Peter C. Lucas, Rachel Catherine Jankowitz, Steffi Oesterreich, Priscilla F. McAuliffe
Journal: Journal of Clinical Oncology (2019)

e12531 Background: Mixed Invasive Ductal-Lobular Carcinoma (IDC-L) is a histological subtype of invasive breast carcinoma comprised of both ductal and lobular morphologies. There is limited information on the relative proportions of the individual components in IDC-L and on outcomes compared to invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). Methods: Clinical information was abstracted from 16,308 patients with invasive breast cancer seen at UPMC Magee Women’s Hospital from 1990-2017 using the UPMC Network Cancer Registry. A systematic chart review was performed on a subset of patients annotated with IDC-L (n=806); however, a thorough review of pathology reports led to the exclusion of all but 408 patients for further analysis, due to the lack of a standardized definition of IDC-L. Of the 408 cases, 92% were estrogen receptor (ER)+. Survival of patients with ER+ IDC-L (n=376) was compared to ER+ IDC (n=9,716) and ER+ ILC (1,465). For a subset of IDC-L cases (n=54), distributions of individual subtype components were abstracted from pathology reports. Results: IDC-L made up 2.5% of the total cases (408/16,308). IDC-L tumors were on average 31% ductal and 69% lobular (p =0.001). Survival analysis showed worse disease free survival (DFS) (p=0.05) and overall survival (OS) (p=0.002) in patients with ER+ ILC compared to ER+ IDC, with ER+ IDC-L patients showing a median OS superior to ILC yet inferior to IDC counterparts (ns). Conclusions: Identification of patients with IDC-L through cancer registry protocols representative of standard practices by national cancer registries revealed a lack of a standardized definition of mixed IDC-L. Reliance on accuracy of these diagnoses calls in to question the reliability of prior clinico-pathologic analyses reported on this topic. DFS and OS of IDC-L patients falls between that of IDC and ILC patients while ILC patients showed significantly worse outcome. The predominant distribution of lobular morphology in IDC-L tumors suggests this subtype may have additional characteristics similar to lobular rather than ductal carcinomas. Comprehensive clinical and molecular characterization of a carefully identified IDC-L cohort is underway.