tbuckley/cabot-search huggingface dataset:
Chemotherapy to reverse diminished immune responses (IRs) associated with a raised neutrophil lymphocyte ratio (NLR) in patients with advanced colorectal cancer (aCRC).
Authors: Samantha J. Turnbull, Emma West, Karen Scott, Emma Tidswell, Alan Melcher, Matthew T. Seymour, Christy Ralph, Jenny F. Seligmann
Journal: Journal of Clinical Oncology (2018)

e15635 Background: High peripheral blood NLR is a poor prognostic marker in cancer patients. We investigated the relationship between NLR and measured IRs in patients with chemo-naïve aCRC and the modulation of both by chemotherapy. Methods: We characterised functional IRs of peripheral blood mononuclear cells of 29 aCRC patients undergoing first-line chemotherapy. Samples were collected prior to and after 6 weeks of chemotherapy. NLR of ≥5 was defined as high; < 5 as low. Innate immune function was determined by NK cell degranulation and cytotoxicity against target tumour cells; adaptive T cell responses against immune stimuli by IFN-γ ELISpot. Secretion of immunomodulatory cytokines was determined by Luminex assay and immune cell activation by flow cytometry. Results: 41% of patients had NLR ≥5 at baseline. High baseline NLR was associated with reduced overall survival (6.6 vs 18.8 months, p = 0.0024), diminished NK cell activity and increased levels of immune inhibitory cytokines TGF-β and IL-10 (p = 0.0004 and p = 0.0014) compared to a low baseline NLR. After 6 weeks of chemotherapy NLR normalised in 83% of patients with high NLR at baseline. In these patients functional analysis demonstrated enhanced immune responses compared to the group with low baseline NLR: NK cell degranulation and cytotoxicity increased (p = 0.004 and p = 0.02, respectively) and levels of TGF-β fell. Differences between the high and low NLR groups remained despite enhancement of IRs in the high NLR group following chemotherapy. T cell responses increased in both groups but patients with a low NLR demonstrated increased tumour-specific responses against carcinoembryonic antigen (CEA) compared to those with a high baseline NLR. Similarly, levels of IL-10 remained increased in the high NLR group despite normalisation of NLR. PD-1 expression increased on NK cells (p = 0.01), B cells (p = p = 0.04) and monocytes (p = 0.02). Conclusions: High NLR is associated with decreased survival in patients with aCRC. This may be due to diminished IRs, which can be improved/reversed following chemotherapy and could identify a group of patients in whom immunotherapies may be of benefit.
Variability in Medicare utilization and payment among gynecologic oncologists.
Authors: Stephanie Lim, Allison Puechl, Gloria Broadwater, Jessie Ehrisman, Amelia Lorenzo, Jonathan Foote, Brittany Anne Davidson, Junzo P. Chino, Laura Jean Havrilesky
Journal: Journal of Clinical Oncology (2018)

5599 Background: The Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File (POSPUF) for 2015 is a publicly available file from the CMS that includes all direct payments to providers who care for fee-for-service Medicare recipients. The objective of this study was to analyze variability in gynecologic oncologists’ Medicare utilization and reimbursements, with attention to differences based on provider gender and time spent in practice. Methods: The POSPUF 2015 was analyzed with respect to Gynecologic Oncology specialty providers. We used publicly available data to confirm gynecologic oncology subspecialty and to determine each provider’s total number of years in gynecologic oncology practice. Evaluation, management, and procedure/surgery codes were analyzed; drug delivery codes were excluded due to variability in billing these by facility/hospital. Results: The POSPUF file included 824 gynecologic oncologist providers receiving a total of $28,772,739 in payments. The majority of providers practiced in large metropolitan areas (66%) or mid-sized metro areas (27%). While females composed 38.5% of gynecologic oncologists, they accounted for only 28.1% of Medicare reimbursements. The median Medicare reimbursement to a Gynecologic Oncologist was $24,828 (IQR $11,564, $45,412), but this was significantly different by gender; female $19,394 (IQR $10,913, $34,894) compared to male $29,395 (IQR $13,903, $52,941). Overall, female providers receive 30.4% of evaluation and management reimbursements and 22.5% of surgical reimbursements. During the first ten years in practice, women composed 47.0% of providers and accounted for 52.3% of the services reimbursed, compared to 36.25% of providers/26.6% of the reimbursed services (11-20 years in practice), and 18.11% of providers/16.4% of services ( > 20 years in practice). Conclusions: While male gynecologic oncologists receive higher median reimbursements than females, there is a trend toward equal services and reimbursements between genders among younger providers, suggesting a trend toward gender equity over time.
Compassionate use program with FDT-TPI (trifluridine-tipiracil) in pre-treated metastatic colorectal cancer patients: Spanish real world data.
Authors: Pilar Garcia-Alfonso, Ana Ruiz, Alfredo Carrato, Jose M Vieitez, Cristina Gravalos, Carles Pericay, Manuel Benavides, Mayte Delgado, Guillem Argiles, Rocio Garcia-Carbonero
Journal: Journal of Clinical Oncology (2017)

e15019 Background: Trifluridine/tipiracil (FTD-TPI) is comprised of an antineoplastic nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Compassionate use programs (CUPs) provide a treatment option for patients with unmet medical needs and an early opportunity to obtain data on efficacy, safety and use in a real-world setting. Methods: Patients were registered and approved to receive 2 cycles of trifluridine/tipiracil treatment, which could be renewed as necessary, we analysed baseline characteristics, safety results and exposure to the treatment with trifluridine/tipiracil (FTD-TPI) in the Spanish CUP. Results: A total 636 were registered in Spain and 538 received treatment with trifluridine/tipiracil. Median age was 64 years, of which 25% were older than 70 years old and 60% were male, 67% of pts were ECOG PS 1. Oral trifluridine/tipiracil was initiated at 35 mg/m 2 bid. Most pts had received 2, 3, or ≥4 lines of prior treatment for metastatic disease (27%, 28%, and 38%, respectively); and 4% unknown. 275 (47%) patients had KRAS mutated and 209 (36%) had KRAS wild type. 35% received adjuvant chemotherapy and 20% of the patients were treated with regorafenib in previous lines. The main reasons for not initiating treatment included cancellation of request due to worsening condition and progressive disease. Treatment was generally well tolerated. A total of 173 AEs were reported in the Spanish CUP, the majority were myelosuppressive AEs; febrile neutropenia (grade ≥3) was reported in 6 pts (1.3%), grade _ &gt; 3 neutropenia was reported in 56 (33%), grade 4 neutropenia in 16 (9%). Grade 3 anemia was reported in 8 (15% of the total AEs reported).The majority of pts 306 (56%) were allocated 3-4 cycle of treatment, 95(17.3%) 5-6 cycles, and 30(5. 5%) between 7-8 cycles. Conclusions: Thisreal-world data analysis is consistent with those reported in phase 3 trials of trifluridine/tipiracil (FDT-TP)in pretreated mCRC. The efficacy analyses of this population is planned.
Biologic and clinical relevance of an IFNG mRNA signature (IFNGS) and PD-L1 protein expression in tumor and immune cells in urothelial cancer (UC) patients (pts) treated with durvalumab (D).
Authors: Carlos Bais, Michael Kuziora, Chris Morehouse, Brandon W. Higgs, Rajiv Raja, Young Lee, Melissa de Los Reyes, Marlon Rebelatto, Keith Steele, Xiaoping Jin, Li Shi, Fernanda Pilataxi, Yong Ben, Joyce Antal, Ashok Kumar Gupta, Koustubh Ranade
Journal: Journal of Clinical Oncology (2017)

3037 Background: PD-L1 can be induced by IFNG in tumor cells (TC) and immune cells (IC). TC PD-L1 expression prevalence in UC is low and the relevance of scoring TC (in addition to IC) is not fully understood. We recently reported a positive correlation between high levels of an IFNGS and outcome in a cohort of 30 UC pts treated with D. Here, we assessed the potential predictive value of the IFNGS in an additional 32 pts (total N = 62) and further explored the relationship between the IFNGS and TC and/or IC PD-L1 IHC expression patterns. Methods: Study CP1108 was a phase 1/2 trial evaluating D in pts with solid tumors; 191 UC pts received 10 mg/kg D with median follow up of 8.4 mo. 144 of these pts have available ORR and PD-L1 data and 62 pts have ORR, PD-L1 and IFNGS data. Pts with ≥25% TC or IC were scored as PD-L1 high (TC+ or IC+). Pts within the top tertile of IFNGS ( LAG3, PDL1, CXCL9, and IFNG mRNAs) tumor expression were scored positive. Cox proportional hazards models were used adjusting for age, gender, ECOG, smoking status, line of therapy, and liver metastasis at baseline. ORR was evaluated using RECIST v1.1. Results: IFNGS+ pts had increased ORR (45 vs 16%) and improved PFS (adj HR 0.3; p = 0.005) and OS (adj HR 0.18; p = 0.016) over IFNGS- pts. IFNGS expression was significantly higher in pts who were PD-L1 high (TC+/IC+) compared with TC-/IC- (low/negative) pts (mean IFNGS expression 3.5 vs 1.1; p = 0.0155) and also in TC+ or IC+ vs TC-/IC- (mean IFNGS 2.2 vs 1.1; p = 0.000127). TC-/IC+ and TC+/IC- groups had a mean IFNGS expression of 2 and 2.2 respectively. ORR in all 1108 UC pts with available IHC and ORR data (N = 144) was 29% for TC+/- pts, 36% in TC-/IC+ pts, and 7% in the TC-/IC- pts. Conclusions: IFNGS predicted improved outcomes in a cohort of 62 2L+ UC pts treated with D. TC-/IC- PD-L1 pts had lowest levels of IFNGS expression. Observations that TC+ (and IC+) pts contribute to IFNGS enrichment and that TC+/IC-, and TC-/IC+ pts have increased response vs TC-/IC-pts provides rationale for TC+ inclusion (in addition to IC+) in the SP263 PD-L1 scoring algorithm for UC. IFNGS is an additional potential predictive biomarker in UC pts that warrants further investigation.
The association of comorbid conditions and BMI on overall survival in geriatric breast cancer patients.
Authors: Meghna R. Desai, Muhammad Iqbal, Sukesh Manthri, Kathy Robinson, Robert S. Mocharnuk
Journal: Journal of Clinical Oncology (2017)

e21525 Background: Breast cancer is the most common cancer and the second leading cause of cancer death in women. More than one-half of all women diagnosed with breast cancer are older than 65 years, and the incidence increases with age. Geriatric cancer patients also have higher comorbidity than the general cancer population. Patients with 3 or more comorbid conditions had a 20-fold higher rate of mortality from causes other than breast cancer. The purpose of this study was to determine whether specific comorbidities associated with specific organ systems, in addition to increased BMI, resulted in decreased survival. Methods: In this retrospective analysis, 269 patients with histologically confirmed invasive or in-situ breast cancer and above 65 years of age at the time of diagnosis were eligible. Patient comorbidities were recorded by system, including cardiovascular, renal, pulmonary, endocrine, neurologic, psychiatric and other systems. Patient BMI was also recorded. The primary outcome was overall survival (OS). Survival analysis was conducted by Kaplan Meier estimation and Cox proportional hazards regression analysis. Results: Patients with renal comorbidities were found to have decreased OS, disease free and progression free survival compared with rest of the population (HR 2.65, p = 0.023; HR 2.71, p = 0.021; HR 27.5, p = 0.019). For patients with cardiovascular (HR 1.46, p = 0.479), pulmonary (HR 1.63, p = 0.176), endocrine (HR 0.99, p = 0.991), neurologic (HR 1.92, p = 0.15) and psychiatric (HR 1.68, p = 0.187) comorbidities, there was no significant difference in OS compared with their counterparts. Patients with 4 or more systemic comorbidities had decreased OS compared with patients with either 1 or 2 systemic comorbidities (HR 0.178, p = 0.012; HR 0.404, p = 0.038). There was no significant change in OS with increased BMI (HR 0.998, p = 0.871). Conclusions: In patients with newly diagnosed breast cancer age 65 or older, those with renal comorbidities were found to have decreased OS, DFS and PFS. Patients with 4 or more systemic comorbidities also had decreased OS compared with those who had 1 or 2 comorbidities. Other comorbidities and BMI did not affect OS in these patients.
Different small leucine-rich proteoglycans expression pattern by tumor location in colorectal cancer.
Authors: Maria Del Pilar Solis Hernandez, Ivan Fernandez-Vega, Olivia García-Suárez, Natalia Perez Lopez, Luis M Quirós, Beatriz García
Journal: Journal of Clinical Oncology (2017)

e15138 Background: Colorectal cancer (CRC) is a heterogeneous disease defined by anatomic, functional and molecular differences depending on the primary tumor location (PTL). Several molecular phenotypes have been associated with aggressive behavior, and some of these markers are related with proteoglycans, which in turn show alterations in CRC. Small leucine-rich proteoglycans (SLRPs) are a family of molecules encoded by18 genes that may appear coupled to different glycosaminoglycan chains ––including chondroitin/dermatan or keratan sulphate–– or not, depending on the specific species. They are ubiquitously expressed in extracellular matrices, and it’s been described their role in organ size and shape regulation during embryonic development. This study aims to investigate the expression patterns of SLRPs in CRC depending on the PTL. Methods: A transcriptomic approach was carried out by using qPCR to analyze SLRP core protein transcriptions in 32 tumor specimens and their respective healthy tissue: 12 right-sided &amp; 20 left-sided. When significant differences were detected, immunohistochemical techniques were used to enhance the test. Results: While right-sided (R) CRC displayed significant alterations in 2 genes (biglycan BGN overexpression p = 0.015, osteoglycin OGN underexpression p = 0.048), left-sided (L) showed differences in 5 genes (BGN overexpression p = 0.0019 and underexpression of OGN p = 0.0016, prolargin PRELP p = 0.0049, chondroadherin CHAD p = 0.0180 and podocan PODN p = 0.0061). In L tumors CHAD was the most affected gen underexpressed by 16 times, while in R it was present in only 50% of healthy tissue. Transcripts for opticin and nyctalopin were not detected in most patients regardless of PTL. Lumican, decorin, keratocan, asporin, ECM2, fibromodulin, tsukushi, osteoadherin, osteomodulin, epiphycan and PODN-like 1 were detected with no significant differences compared to healthy tissue. Conclusions: Normal mucosa of the large bowel expresses most SLRP. BGN and OGN seem to be dysregulated in both L and R CRC, but CHAD, PRELP and PODN appear to show differences only in L CRC. These alterations could be related to the interaction with different ligands and modulation of homeostasis.
BTC1.06 Calmodulin(CaM) as a potential cancer prognostic marker promotes cell invasion and migration, associated with the induction of EMT in Glioblastoma
Authors: F Yuan, X Yang
Journal: Neuro-Oncology (2018)

Numerous studies have shown that calmodulin (CaM) is considered to be the major regulator of Ca2+-dependent signaling, which involves the regulation of cell proliferation, programmed cell death and autophagy in cancer. However, little is known about underlying mechanism of CaM in glioblastoma multiforme (GBM) invasion and migration. Calmodulin (CaM) expression levels were examined in glioma tissues and normal brain (NB) tissues. The molecular mechanisms of calmodulin expression and its effects on cell invasion, migration and associated with the induction of EMT were also explored by Western blot, Immunofluorescence staining, Transwell chamber assay and Wound healing assay as well as in vivo tumorigenesis in nude mice. Compared with normal tissue and lower grade glioma (LGG) specimens, CaM expression level was elevated in GBM specimens. Knocking down CaM expression could significantly decreased glioma cell migration and invasion abilities in vitro and in vivo. Simultaneously, knockdown of CaM resulted in restoration of E-cadherin expression and suppression of mesenchymal cell markers, such as Vimentin, ZEB1 and N-Cadherin. which indicted that CaM promoted EMT-like process in glioma in vitro. These findings suggested that CaM maybe provides novel therapeutic strategy targeting the invasive of GBM.
Incidence of ototoxicity in head and neck cancer (HNSCC) patients (pts) receiving concomitant chemo-radiation (CRT) with weekly or triweekly cisplatin (Cis).
Authors: Jishu Das, Amy Custer, Dukagjin Blakaj, Matthew O. Old, Songzhu Zhao, Aashish D Bhatt, Stephan Y Kang, Amit Agrawal, Enver Ozer, Jessica Wobb, Robert Rupert, Darrion L Mitchell, Guy Brock, Claire F. Verschraegen, James William Rocco, Marcelo R Bonomi
Journal: Journal of Clinical Oncology (2018)

6046 Background: Cisplatin ( Cis) is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Little is known about the incidence of hearing loss when using different cisplatin schedules in patients receiving concomitant CRT. We, therefore, assessed prospectively the incidence of ototoxicity in patients receiving weekly or triweekly Cis concomitantly with radiation. Methods: Head and Neck Squamous Cell Cancer patients receiving definitive or adjuvant cisplatin-based CRT were included. Cisplatin was administered weekly (40 mg/m2 weekly, 7 cycles) or triweekly (100 mg/m2 every three weeks, 3 cycles). Radiation was administered to a total dose of 70 Gy as definitive treatment or 66 Gy as adjuvant treatment (2 Gy/fraction). Intensity-modulated radiation therapy was used in all cases. Pure-tone air-conduction audiometry was performed in all pts before starting and after completion of CRT. The primary endpoint of the analysis was Common Terminology Criteria for Adverse Event (CTCAE v4.0) hearing change ≥3 at the end of CRT. Results: A total of 96 pts (M:77/F:19) were included (oropharynx 56 pts, other 40). Age: 55y (26-78). 68 pts received weekly cis and 28 triweekly regimen. 58 pts received definitive treatment and 38 adjuvant treatment. Nine pts receiving weekly cis (13%) experience G3 ototoxicity vs 14 pts (50%) receiving triweekly cis (P < 0.001, OR = 6.4, 95% CI 2.1-20.7). Risk of ototoxicity was not associated with age, cis cumulative dose, sex, tumor primary site, or CRT modality (definitive vs. adjuvant). After adjusting for these factors in a multivariable model cis schedule remained significant (OR = 8.7, 95% CI 2.31-32.75, p = 0.001). With a minimum follow-up of three months, the complete response rate after treatment was 84% for weekly CRT and 86% for triweekly CRT. Conclusions: Triweekly Cis-based CRT increases the risk of irreversible severe ototoxicity. This risk should be discussed with patients that are candidates for cis-based CRT.
Randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients with relapsed or refractory multiple myeloma (RRMM): COLUMBA.
Authors: Saad Zafar Usmani, Maria-Victoria Mateos, Nizar J. Bahlis, Sebastian Grosicki, Andrew Spencer, Rajesh Bandekar, Tara J. Masterson, Pamela L. Clemens, Christoph Johann Heuck, Ming Qi, Hareth Nahi
Journal: Journal of Clinical Oncology (2018)

TPS8058 Background: DARA, a human IgG1κ monoclonal antibody that targets CD38, induces deep and durable responses in patients with RRMM. In a phase 1b RRMM study, a SC co-formulation of DARA with recombinant human hyaluronidase (rHuPH20; DARA SC) was found to be well tolerated with low infusion-related reaction (IRR) rates. Moreover, response rates were similar to those observed historically with DARA IV. The phase 3 COLUMBA study will compare the efficacy, pharmacokinetics, and IRRs of DARA SC versus DARA IV in patients with RRMM. Methods: This is an ongoing phase 3, randomized, open-label, multicenter, non-inferiority study of DARA SC (1,800 mg DARA in combination with rHuPH20 [2,000 U/mL] administered by manual push [15 mL] over 3-5 minutes at alternating left/right abdominal sites) versus DARA IV (16 mg/kg IV infusion) weekly for Cycles 1-2 (28-day cycles), every 2 weeks for Cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. Pre- and/or post-infusion medications include paracetamol, diphenhydramine, methylprednisolone, and an optional leukotriene inhibitor. Eligible patients (≥18 years) with RRMM must have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI; ≥2 cycles or 2 months of treatment) and an immunomodulatory drug (IMiD; ≥2 cycles or 2 months of treatment), or must be double refractory to both a PI and an IMiD. The co-primary endpoints are overall response rate and maximum Ctrough concentration of DARA on Cycle 3 Day 1. Secondary endpoints include IRR rates, progression-free survival, ≥very good partial response and ≥complete response rates, time to next therapy, overall survival, time to response, and duration of response. Approximately 480 patients will be enrolled and randomly assigned (1:1) to the 2 treatment groups. Randomization will be stratified by body weight at baseline (≤65 kg, 66 kg to 85 kg, > 85 kg), number of prior lines of therapy (≤4 prior lines versus > 4 prior lines), and type of myeloma (IgG versus non-IgG). Clinical trial information: NCT03277105.
Phase I/II study of the PI3Kβ inhibitor GSK2636771 in combination with pembrolizumab (P) in patients (pts) with PD-1 refractory metastatic melanoma (MM) and PTEN loss.
Authors: Hussein Abdul-Hassan Tawbi, Weiyi Peng, Denai Milton, Rodabe Navroze Amaria, Isabella Claudia Glitza, Wen-Jen Hwu, Sapna Pradyuman Patel, Michael K.K. Wong, Scott Eric Woodman, Cassian Yee, Jennifer Leigh McQuade, Michael T. Tetzlaff, Alexander J. Lazar, Suzanne Cain, Elizabeth M. Burton, Jan Hendrik Beumer, Patrick Hwu, Michael A. Davies
Journal: Journal of Clinical Oncology (2018)

TPS9596 Background: Immune checkpoint blockade (ICB) improves overall survival and provides long-term disease control in 35-40% of pts with MM. However, more than a third of pts experience no clinical benefit (de novo resistance) and many progress even after achieving an initial response (acquired resistance). Our group has demonstrated that increased activation of phosphatidylinositol 3-kinase (PI3K) pathway, most commonly through loss of the tumor suppressor gene PTEN, plays a critical role in resistance to ICB. PTEN loss occurs in up to 30% of MM pts and correlates with decreased T cell infiltration and inferior outcomes to ICB. In preclinical models, we showed that loss of PTEN inhibits T cell mediated tumor killing and decreases T cell trafficking into tumors, and that selective inhibition of the PI3Kβ-subunit with GSK2636771 was superior to pan-PI3K inhibitors and significantly increased the activity of ICB, and the number of infiltrating CD4+ and CD8+ T cells. We therefore hypothesized that PI3Kβi will reverse resistance to ICB in MM with PTEN-loss. To test this hypothesis, we are conducting a Phase I/II study of the PI3Kβ inhibitor GSK2636771 in combination with P in pts with PD-1 refractory MM and PTEN loss. Methods: The primary objective of the Phase I portion is to determine the safety and Maximum-Tolerated Dose (MTD) and/or the Recommended Phase II Dose (RP2D) of GSK2636771 in combination with P in pts with PD-1 refractory disease and PTEN loss. Pts will be treated with P given at 200 mg IV q 3-wk cycle. GSK2636771 will be given orally starting at a dose level of 300 mg PO qd for 21 days and escalated to a maximum dose of 400 mg PO qd using a "3+3" design. The Phase II portion will enroll a total of 35 pts at the MTD/RP2D. Continuous monitoring for both toxicity and futility will be assessed. The primary objective of the Phase II portion is to determine the safety, tolerability, and efficacy of the combination as defined by Objective Response Rate (ORR) by RECIST 1.1 in MM with PTEN loss. Secondary Objectives include the PKs of GSK2636771 and correlation with ORR and pharmacodynamic effects in tumor tissue as measured by pathway inhibition and T cell trafficking into tumors. Clinical trial information: NCT03131908.