tbuckley/cabot-search huggingface dataset:
Potential role of botanical drug APG-157 as immune adjuvant in patients with oral squamous cell carcinoma.
Authors: Daniel Sanghoon Shin, Eri Srivatsan, Hassan Nasser, Anela Tosevska, Jonathan Jacobs, Matteo Pellegrini, Marilene Wang
Journal: Journal of Clinical Oncology (2019)

e17572 Background: Natural botanical drugs, such as curcumin, resveratrol and related flavonoids, are under clinical studies. Previous pilot study of curcumin, a polyphenol, for normal and patients with oral squamous cell carcinoma (OSCC) showed significant inhibition of inflammatory cytokines in saliva. Phase I investigation was performed on APG-157 to evaluate the potential utility an as oral drug for the treatment of OSCC. Methods: A double-blind, randomized, placebo-controlled phase I clinical trial was conducted with a botanical preparation containing a combination of curcumin related polyphenol molecules (pharmaceutical name APG-157). 12 Subjects with oral cancer and 13 normal control subjects were recruited. Two doses of the drug, 3x100 mg and 3x200 mg, were tested. The drug was administered orally each hour for 3 consecutive hours. Blood and saliva were collected pre-treatment and 1, 2, 3, and 24 hours post-treatment. Salivary cells and supernatants were analyzed for the expression of cytokines by multiplex ELISA and microbial content by 16S RNA sequence. Pre- and post-treatment tumor biopsies of one subject were studied for expression using the RNA seq and immunofluorescence (IF). Results: This study did not reveal any toxicity and there was a dose dependent inhibition of inflammatory cytokines, IL-1β, TNF-alpha and IL-8 in the salivary supernatant of cancer subjects treated with the drug. Tumor RNA-seq revealed down regulation of gene ontologies of cell adhesion, cell cycle and cell division and up regulation of generation of precursor metabolite/energy in the post-treatment tumor sample. Microbiome study showed significant decrease in Bacterioides after 24 hours of treatment. There was also a trend of decreasing Bacteroides among other cancer subjects treated with APG-157. IF showed a marked increase in the number of CD4, CD8 T cells in post-treatment tumor. PD-L1 expression was up-regulated in the post-treatment tumor sample. Conclusions: APG-157 is found to be safe and toxicity was not observed. The drug has shown a decrease in inflammatory cytokines. Moreover, there was a markedly increased CD4, CD8 T cells infiltration on a subject and decreased Bacteriodes microbial population after APG-157 treatment suggesting that it might have potential synergistic effect with immune checkpoint blockade immunotherapy. Decreased expression of cell growth related genes and increased expression of growth inhibitory genes pointed to a potential anti-tumor activity of APG-157.
Cost-effectiveness analysis of laparoscopic disease assessment in ovarian cancer.
Authors: Ross Harrison, Scott B. Cantor, Mariana Villanueva, Rudy Sam Suidan, Charlotte C. Sun, Jose Alejandro Rauh-Hain, Shannon Neville Westin, Nicole D. Fleming, Anil K Sood, Karen H. Lu, Larissa Meyer
Journal: Journal of Clinical Oncology (2019)

5556 Background: Laparoscopic assessment of disease resectability can be useful for treatment planning for patients [pts] with advanced ovarian cancer [OC] but may be associated with added cost. Methods: We performed a cost-effectiveness analysis from a payer perspective to compare (1) a conventional strategy, where standard new pt evaluation was used to assign pts to either primary cytoreduction [PCS] or neoadjuvant chemotherapy with interval cytoreduction [NACT], and (2) an alternative approach, where pts considered candidates for PCS would undergo laparoscopy to evaluate disease resectability using a validated scoring system, who were then triaged to either PCS or NACT based on this evaluation. Diagnostic work-up, surgical and adjuvant treatment, perioperative complications, and progression-free survival [PFS] were included in the model. We derived model parameters from the literature and our institution’s experience with laparoscopic triage. Utility estimates for health states related to primary treatment were assessed prospectively and taken from the literature. Costs were estimated using Medicare reimbursement. Effectiveness was defined in quality-adjusted progression-free life years [QPFLYs]. We performed multiple sensitivity analyses. Results: Under baseline model parameters, the expected cost of treating one pt under the conventional and alternative strategies was $26,539 and $26,653, respectively. The expected quality-adjusted progression-free survival for pts in the conventional and alternative strategies was 0.70 and 0.94 QPFLYs, respectively. The calculated incremental cost-effectiveness was $473.97 per QPFLY saved. The alternative strategy became cost saving if pts found to have resectable disease by laparoscopy underwent cytoreduction during the same procedure. The conventional strategy may be preferred if PCS increased PFS over NACT by ≥5 months. Conclusions: For newly-diagnosed advanced stage OC pts, laparoscopic assessment of disease resectability prior to PCS was a cost-effective strategy. A conventional strategy may be preferred if PCS produced substantially longer PFS. Sensitivity analysis suggests the benefit of utilizing laparoscopic triage is influenced by mitigation of serious perioperative morbidity and associated costs.
Understanding Limitations of the National Inpatient Sample to Facilitate its Proper Use
Authors: Makoto Mori, Kelly J. Brown, Arnar Geirsson
Journal: JAMA Surgery (2019)

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MPs call for action to tackle variable access to sexual health services
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The latest statistics on sexual health appear positive but are masking a number of concerning underlying trends and inequalities in access, the Commons Health and Social Care Committee has warned.1

In a new report, the MPs warned that while the overall number of sexually transmitted infections (STIs) and teenage pregnancies is falling, diagnoses of syphilis and gonorrhoea are still rising, …
Phase 2 study of camrelizumab (anti-PD-1 antibody) combined with apatinib and chemotherapy for the first-line treatment of advanced esophageal squamous cell carcinoma.
Authors: Bo Zhang, Ling Qi, Xi Wang, Jun Jiang, Xin Zhang, Yun Liu, Lan Mu, Jing Huang
Journal: Journal of Clinical Oncology (2019)

4033 Background: Both anti-PD-1 antibodies and molecular antiangiogenic agents have shown promising anti-tumor activities in patients with advanced esophageal cancer. We conducted this single-center phase 2 study to evaluate the efficacy and safety of camrelizumab (anti-PD-1 antibody) plus apatinib (VEGFR2-TKI) in combination with liposomal paclitaxel and nedaplatin in the first-line treatment of patients with esophageal squamous cell carcinoma (ESCC). Methods: Patients with unresectable locally advanced or metastatic ESCC received camrelizumab 200mg d1, liposomal paclitaxel 150mg/m 2 d1, nedaplatin 50mg/m 2 d1 and apatinib 250mg d1-14. Treatments were repeated every 14 days for up to 6-9 cycles, followed by maintenance therapy with camrelizumab, apatinib, or both. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. PD-L1 positivity, defined as a combined positive score (CPS) ≥1, was evaluated by immunohistochemistry (IHC). Results: Between Aug 6 th 2018 and Feb 6 th 2019, a total of 29 patients were enrolled. The median age was 62 years (43-70). Most patients were male (22/29, 75.9%) with metastatic disease (25/29, 86.2%). Response evaluation by independent central review was available in 26 patients, with 19 achieving a best response of PR, 6 with SD, and 1 with PD. The ORR and DCR were 73.1% (19/26) and 96.2% (25/26), respectively. Data for PFS and OS were not matured. The most common grade 3/4 adverse events were leucopenia (21/29, 72.4%) and neutropenia (15/29, 51.7%). Two cases of treatment-related SAEs occurred, both led to hospitalization: one patient developed grade 3 febrile neutropenia, grade 4 leucopenia and grade 3 anorexia; another patient developed grade 4 toxic epidermal necrolysis. Conclusions: Camrelizumab plus apatinib in combination with liposomal paclitaxel and nedaplatin could be a new treatment option for patients with unresectable locally advanced or metastatic ESCC. Clinical trial information: NCT03603756.
Genetic variability of tramadol pharmacokinetic genes and pain treatment outcome after breast cancer surgery.
Authors: Nikola Besic, Katja Goricar, Jakob Jeriha, Vita Dolzan, Branka Strazisar
Journal: Journal of Clinical Oncology (2019)

e23133 Background: Tramadol is a treatment of choice for pain management after axillary lymph node dissection in breast cancer patients. Tramadol is metabolized via CYP2D6 and UGT2B7, while ABCB1, ABCC2 and SLC22A1 are involved in transport of tramadol metabolites. Genetic variability of metabolizing enzymes or drug transporters may therefore affect efficacy and adverse effects of tramadol. The aim of this study was to evaluate the association of genetic variability in tramadol pharmacokinetics pathway on long-term outcome of tramadol pain treatment after breast cancer surgery. Methods: The study included 102 breast cancer patients treated with either 75 or 37.5 mg of tramadol for pain relief after breast cancer surgery including axillary lymph node dissection as part of a randomized clinical trial KCT 04/2015-DORETAonko/si at Institute of Oncology Ljubljana. All patients were genotyped for 14 polymorphisms in ABCB1, ABCC2, CYP2D6, SLC22A1 and UGT2B7 genes, as well as for CYP2D6 duplication and deletion. CYP2D6 phenotype was predicted from the genotype data and patients were categorized as poor (PM), intermediate, extensive or ultrarapid metabolizers. The association of genetic factors with pain one year after treatment was evaluated using logistic regression and Mann-Whitney test. Results: One year after treatment, 21 (20.8%) patients were still experiencing chronic and 25 (24.8%) neuropathic pain. CYP2D6 PMs were significantly more likely to experience chronic and neuropathic pain after tramadol treatment (OR = 5.96, 95% CI = 1.22-29.13, p = 0.027 and OR = 9.31, 95% CI = 1.65-50.59, p = 0.011, respectively), even after adjustment for tramadol dose (p = 0.032 and p = 0.016, respectively). PMs also had higher average pain intensity compared to others regardless of tramadol dose (p = 0.042). In patients receiving lower tramadol dose, ABCB1 rs1128503, rs2032582 and rs1045642 were associated with more chronic pain in the dominant model (p = 0.004, p = 0.004 and p = 0.047, respectively). Conclusions: Genetic variability in tramadol pharmacokinetics pathway may be associated with pain treatment outcome in breast cancer patients, therefore pharmacogenetic testing could enable more effective tramadol treatment. Clinical trial information: EudraCT 2015-000992-28.
Characterization of a novel entity of high-grade well-differentiated colorectal neuroendocrine tumors.
Authors: Salman Rafi Punekar, Lena Masri-Lavine, Cristina Hajdu, Elliot Newman, Daniel Jacob Becker
Journal: Journal of Clinical Oncology (2019)

e15696 Background: Small studies suggest that a new pathologic entity of high-grade (by Ki-67 or mitotic index) well-differentiated (by histologic features) neuroendocrine tumors (NETs) exist throughout the GI tract, but the prognosis and characteristics of affected patients are unknown. We sought to further characterize the prognosis and demographics of patients with high-grade (HG) well-differentiated (WD) colorectal NET. Materials and Methods: We used the Surveillance Epidemiology and End Results (SEER) database to study patients with NETs of the colon and rectum diagnosed from 2000 to 2015. We identified patient demographics, clinical and tumor characteristics, and studied associations with tumor grade. We compared overall survival (OS) between patients with low-grade (LG)(grade 1-2) well-differentiated (ICD-0-3 = carcinoid), high-grade (grade 3-4) well-differentiated, and high-grade poorly-differentiated NETs (ICD-0-3 = small cell neuroendocrine). We used logistic regression to detect associations with grade and Cox proportional hazards models to examine predictors of survival. Results: We identified 5,894 cases with colorectal carcinoid tumor (5780 [98.1%] LG and 114 [1.9%] HG); the cohort was 68% white, 48% male, and had a median age of 54. Patients diagnosed with HG carcinoid tumors were more likely to be of older age (OR 2.23; 95% CI 1.19-4.19 for age 60-69 vs &lt; 50) and unmarried (OR 1.56; 95% CI 1.02-2.38), and less likely to be diagnosed after 2010 (OR 0.09; 95% CI 0.06-0.15). OS for patients with HG carcinoids (median 36 m; 95% CI 13-92) fell in between OS for those with HG small cell NETs (median 7 m; 95% CI 6-8), and LG carcinoid tumor (median not reached, &gt; 120 m). Among patients with carcinoid tumors, black patients (HR 1.31; 95% CI 1.03-1.67, older patients (HR 3.60; 95% CI 2.50-5.19 for age 60-69 vs &lt; 50), unmarried patients (HR 1.52; 95% CI 1.24-1.87), and those with HG features (HR 3.85; 95% CI 2.88-5.15) had worse survival. Conclusions: We defined a subset of high-grade well-differentiated NETs, more commonly diagnosed in older, unmarried patients, with a prognosis between that of high grade small cell NETs and low grade carcinoid tumors. Our analysis adds the first national registry study to the literature in support of a new classification of non-pancreatic high-grade well differentiated NETs.
Prognostic and predictive biomarkers for clear cell renal cell carcinoma utilizing next generation sequencing.
Authors: Jamal Zekri, Abdelrazak Meliti, Mohammed Abhas Baghdadi, Turki Sobahy, Saba Imtiaz
Journal: Journal of Clinical Oncology (2019)

e16070 Background: The management of the clear cell renal cell carcinoma (cc-RCC) has evolved over the past decade. Clinical patients’ and tumor characteristics have a limited role in predicting the outcome of these patients. The search for reliable prognostic and predictive biomarkers should be pursued in particular during the current era of next generation sequencing (NGS) technology. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens of cc-RCC were sequenced using NGS and a customized gene panel testing for 72 tumor-related genes. High potential variants were defined by mutation effect (stop-loss, stop-gain, frame-shift substitutions or non-synonymous SNV) and class (pathogenic or likely pathogenic). Cases with identical variants were identified. Results: In total, all 47 cases had 69,052 variants, of which 20,453 were classified as high potential variants. Identical alterations in 15 genes were present in all samples. These genes are: MUC3A, MUC12, MUC7, SRRT, MUC2, MUC5AC, MUC5B, MUC22, MUC6, CR1, MUC4, MUC16, MUC19, MUC17 and MERTK. The numbers of identical and non-identical variants in these 15 genes were counted for each sample. Median number of variants was 377 and was selected as a cut off to define cases with high ( &gt; 377) and low (≤377) variants number (HVN and LVN respectively). For the whole cohort, HVN was associated with shorter overall survival compared to LVN (Median 50 months vs. not reached; Log Rank P = 0.041). In the 11 patients who received anti-angiogenic tyrosine kinase inhibitors (TKIs), HVN was associated with a trend of shorter progression free survival (Median 5 vs. 10 months; Log Rank P = not significant). Conclusions: Alterations in SRRT, CR1, MERTK and MUCIN family genes are very common in RCC. HVN ( &gt; 377) is associated with worse prognosis and may predict decreased benefit from anti-angiogenic TKIs.
Vincristine, irinotecan, and temozolomide as a salvage regimen for relapsed or refractory sarcoma in children and young adults.
Authors: Byung-Kiu Park, Hee Young Ju, Meerim Park, Hyeon Jin Park
Journal: Journal of Clinical Oncology (2019)

10040 Background: No standard salvage regimen is available for recurrent or refractory sarcoma. Only a few studies using vincristine (V), irinotecan (I), and temozolomide (T) for rhabdomyosarcoma or Ewing sarcoma have been conducted mostly in pediatric age. We investigated the efficacy and toxicity of VIT regimen for several relapsed or refractory sarcomas in children and young adults. Methods: We retrospectively reviewed the relapsed or refractory sarcoma patients who were treated at the Center for Pediatric Cancer of the National Cancer Center, Korea between 2012 and 2018. VIT regimen given every 3 week schedule was as follows; V, 1.5mg/m 2 i.v. on day 1, I, 50mg/m 2 i.v. on days 1-5, and T, 100mg/m 2 p.o. on days 1-5. Cefixime prophylaxis at 4mg/kg/day p.o. was administered to reduce irinotecan-induced diarrhea. Results: Total 26 patients (12 males) were treated with VIT during the study period. Patients were diagnosed with rhabdomyosarcoma ( n= 8), osteosarcoma ( n= 7), Ewing sarcoma ( n= 3), synovial sarcoma ( n= 3), alveolar soft part sarcoma ( n= 2), and mixed rhabdomyosarcoma and liposarcoma, hemangiopericytoma and desmoplastic small round cell tumor, one for each. Median age at the start of VIT was 18.5 years (range 2.0-39.9). VIT was delivered as the 2 nd to 7 th line of treatment, with the 4 th line most common (9/26, 34.6%). Number of administered courses were 1-18, with two courses most common (6/26, 23.1%). Of the 25 evaluable patients, we had 2 partial response (PR), 13 stable disease (SD), and 11 progressive disease (PD) with an overall control rate (CR + PR + SD) of 60.0% as assessed by RECIST 1.1. According to diagnoses, we observed 4SD and 4PD for rhabdomyosarcoma; 1PR, 2SD and 4PD for osteosarcoma; 1PR, 1SD and 1 non-evaluable for Ewing sarcoma; 2SD and 1PD for synovial sarcoma; 2SD for alveolar soft part sarcoma. With a median follow-up of 24 months, 5 patients were alive without disease; 9 were alive with disease; 12 died of PD. Progression-free survival rate at one year was 33.8%, and overall survival rate was 79.3% at one year and 45.5% at 2 years. Of the 26 patients, two patients had grade 4 neutropenia; two had grade 3 colitis and another two had grade 3 neutropenic fever; 8 had grade 2 diarrhea. Grade 4 non-hematologic toxicity or treatment-related mortality was not observed. Conclusions: VIT was effective especially for disease control and relatively safe in our cohort of sarcoma patients.
Pretreatment symptom prevalence in patients with myelodysplastic syndromes (MDS) across all disease risk categories: Analysis of 914 patients.
Authors: Fabio Efficace, Pasquale Niscola, Andrea Patriarca, Francesco Cottone, Giuseppe A. Palumbo, Massimo Breccia, Giovanni Caocci, Uwe Platzbecker, Giorgina Specchia, Reinhard Stauder, Luana Fianchi, Grazia Sanpaolo, Duska Petranovic, Chiara Frairia, Jo Caers, Valeria Santini, Micaela Bergamaschi, Isabella Capodanno, Nicola Di Renzo, Marco Vignetti
Journal: Journal of Clinical Oncology (2019)

e18220 Background: Whilst a substantial body of knowledge is available on the genetics and biology of MDS, very little is known on quality of life of these patients. We aimed to 1) examine patient-reported symptom prevalence in newly diagnosed MDS patients by disease risk at diagnosis; 2) investigate prevalence of other key symptoms by fatigue severity. Methods: Newly diagnosed MDS patients were recruited in an international prospective observational study from Nov. 2008 to Dec. 2018. As per standard practice, all patients were classified according to the International Prognostic Scoring System (IPSS) that identifies four risk subgroups of patients, i.e. low, intermediate-1 (i.e., lower risk, LR), intermediate-2, and high-risk (i.e., higher risk, HR). At baseline (i.e., pretreatment) patients also completed the validated FACIT-Fatigue scale and the EORTC QLQ-C30 questionnaires. Based on the FACIT-Fatigue median score, two groups were also identified: a lower and a higher fatigue group. Results: Out of 929 patients enrolled, 914 patients were available for current analysis of whom 496 with LR (median age of 74 years) and 418 with HR (median age of 72 years). Prevalence (i.e., with any level of concern) of symptoms by disease risk group is reported in Table. Patients with higher fatigue had a significantly higher prevalence of many other symptoms, such as pain (p &lt; .001), dyspnea (p &lt; .001), insomnia (p &lt; .001), appetite loss (p &lt; .001), diarrhea (p &lt; .001) and constipation (p &lt; .001) than patients with lower fatigue. To illustrate, moderate to severe dyspnea was reported by 38% of patients with higher fatigue and only by 5% of patients who reported lower fatigue. Conclusions: Pretreatment symptom prevalence in newly diagnosed MDS is high, and broadly similar in LR and HR patients. Regardless of disease severity at diagnosis, fatigue is associated with a substantial burden of other symptoms. [Table: see text]
Adenocarcinoma (ACB), urothelial carcinoma (UCB) and squamous cell carcinoma (SCCB) of the bladder: A Comprehensive Genomic Profiling (CGP) Study.
Authors: Joseph Jacob, Gennady Bratslavsky, Oleg Shapiro, Nick Liu, Elizabeth Kate Ferry, Alina Basnet, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Shakti Ramkissoon, Eric Allan Severson, Siraj Mahamed Ali, Jon Chung, Alexa Betzig Schrock, Prasanth Reddy, Kimberly McGregor, Brian Alexander, Vincent A. Miller, Andrea Necchi, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

4533 Background: We performed a CGP to compare the genomic alterations (GA) in ABC, UBC and SCCB. Methods: 143 cases of ACB, 2,142 cases of UCB and 83 cases of SCCB were subjected to CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC. Results: ABC patients were younger and more often female than UBC and SCCB (P &lt; 0.0001). UBC and SCCB had a higher GA/tumor than ABC (P = 0.01). Un-targetable GA were similar in all 3 groups involving TP53 and KRAS. APC GA were more frequent in ABC whereas TERT, CDKN2A/B and DNA-repair genes ( ARID1A and KDM6A) more frequently altered in UBC and SCCB. Targetable MTOR pathway GA ( PIK3CA, TSC1, PTEN) were more frequent in UBC and SCCB as were targetable kinase alterations ( FGFR3 and ERBB2). The UBC and SCCB had a significantly higher TMB than ABC (P &lt; 0.0001) including mean TMB and TMB &gt; 20 mut/Mb (P &lt; 0.0001). CD274 (PD-L1) was amplified more frequently in SCCB than ACB or UBC (P &lt; 0.0001). MSI high status was very uncommon in all tumor types. Conclusions: Deep sequencing reveals that ABC features a widely different genomic profile from UBC and SCCB. UBC has the highest frequencies of targetable kinase GA and high TMB. SCCB has the highest frequencies of IO efficacy predicting biomarkers including mean TMB and PD-L1 amp. Nonetheless, ABC does feature potential kinase targets such as FGFR3 and ERBB2. [Table: see text]