tbuckley/cabot-search huggingface dataset:
Prognostic implications of lymph node metastasis in advanced ovarian cancer: Analysis of National Cancer Database.
Authors: Sukamal Saha, Sabarina Ramanathan, Suresh Mukkamala, Hayman S. Salib, Rajen Oza, Jeen Lee, Vinay Bajaj, Madan L. Arora, David Wiese
Journal: Journal of Clinical Oncology (2017)

5567 Background: During debulking surgery (Surg) for advanced ovarian cancer (OvCa), lymph node (LN) sampling are not routinely performed. Hence, prognostic implications of LN involvement following debulking surg and chemotherapy (ChemoRx) were analyzed from National Cancer Database (NCDB). Methods: Only Stage III and Stage IV patients (pts) from 2004 –2014 NCDB pts undergoing Debulking surg. and ChemoRx were included. Group A included pts with debulking surg without bowel resection; Group B with major bowel resection and Group C with bowel and bladder resection. Pts were further subdivided according to the use of 1) NeoAdjuvant (NeoAdj) 2) Adjuvant (Adj) and 3) Neo Adj and Adj ChemoRx. Survival analysis was done based on -ve or +ve LN status. using Pearson Chi Square testing. Results: Out of 10,737 Stage III and 3,102 Stage IV pts, there were 6828 Group A, 6413 Group B and 598 Group C pts. Five year overall survival (OS) for all pts in Stage III with LN-ve vs LN +ve was 59.9% vs 53.9% and Stage IV was 48.7% vs 41.2%. In Group A, B, and C, the 5 yr OS was better in LN – ve than LN +ve pts (Table1). The OS for both LN –ve and LN +ve groups were better in Adjuvant chemoRx in all 3 groups. OS was slightly better in Stage III vs Stage IV pts. Conclusions: Even though LN dissection are not routinely done during debulking surg, overall pts with LN metastasis do worse than LN –ve pts irrespective of the timing of ChemoRx. Hence, LN sampling during debulking surg should be strongly considered as it may provide important prognostic information. [Table: see text]
Effect of maintenance of normal circadian function while undergoing chemotherapy on advanced cancer patient outcomes.
Authors: Keith I. Block, Edward Carome, David E Blask, Dinah Faith Huff, Thomas Kaslausky, Charlotte Gyllenhaal, Penny B. Block, Justin Reynolds, James F. Grutsch, William J. Hrushesky
Journal: Journal of Clinical Oncology (2017)

e21650 Background: Cancer patients develop symptoms that are pathognomonic of a failing circadian organization [CO]. Our concurrent study of 84 advanced cancer patients on randomly timed chemotherapy revealed that each suffered more disrupted circadian rhythms, sleep disorders, anxiety/depression, and quality of life scores compared to healthy age-adjusted controls, as well as poor survival. Herein, we report relationships between CO of advanced cancer patients and their functioning, symptoms, mood, and quality of life during chemotherapy in a clinic that uses comprehensive integrative therapies to maintain patient CO. Methods: 30 patients with advanced cancer participated in a randomized single-blind crossover trial of whether nightly use of blue-light blocking eyeglasses improved circadian organization during chemotherapy. Chemotherapy was applied at or near times of day known to be least toxic and most effective. CO was measured serially using actigraphy and patients provided data on their sleep quality [PSQI], mood [HADS], fatigue [Piper], and quality of life [EORTC QLQ-C30 and Ferrans/Powers QLI]. Kruskal-Wallis tests were used to detect the differences between groups [p &lt; 0.05]. Results: These cancer patients’ actigraphy data were indistinguishable from a convenience control of healthy individuals. Sleep quality, Piper Fatigue, and HADS scores were in the non-symptomatic range; and all functional and symptomatic parameters of the EORTC QLQ-C30 and three of four QLI subscales were within population-based norms. Only the EORTC health-related quality of life and the QLI health/function parameters were lower than non-cancer controls. Median overall survival was 38.4 months. Conclusions: Actigraphy-measured COs of advanced cancer patients are damped, disorganized and accompanied by a heavy symptom burden. These cancer patients reported good quality sleep, normal function, good mood, low intensity of cancer-related symptoms and extended survival while undergoing circadian timed cancer chemotherapy and integrative support. This CO maintenance among such cancer patients is unprecedented and requires attention especially as it is achievable entirely without risk. Clinical trial information: ISRCTN16219928.
A review of phase III clinical trials of CDK4/6 inhibitor combination therapy in premenopausal women.
Authors: Denise A. Yardley
Journal: Journal of Clinical Oncology (2018)

141 Background: Clinical guidelines for the treatment of hormone receptor–positive (HR+), HER2− advanced breast cancer (ABC) are similar regardless of menopausal status, except for the role of ovarian suppression. However, breast cancers in premenopausal women frequently have an aggressive phenotype and a distinct underlying disease biology unaffected by ovarian suppression. Methods: We compared published trial designs, baseline characteristics, and efficacy and safety results of Phase 3 trials of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors including premenopausal women with HR+, HER2− ABC. Results: The MONALEESA-7 trial (NCT02278120) investigated ribociclib (or placebo) with a nonsteroidal aromatase inhibitor or tamoxifen + goserelin ovarian suppression in premenopausal women with ≤1 line of prior chemotherapy for ABC (N = 672); 40% had de novo metastases. Median progression-free survival (PFS) was 23.8 vs 13.0 months with ribociclib (n = 335) vs placebo (n = 337). In the PALOMA-3 trial (NCT01942135), 108 of 521 patients were premenopausal and treated with palbociclib (n = 72) or placebo (n = 36) + fulvestrant + goserelin; 75% had prior endocrine therapy (ET) or chemotherapy for ABC. Median PFS in the palbociclib vs placebo group was 9.5 vs 5.6 months. Adverse events common to both ribociclib and palbociclib ( &gt; 30%) were neutropenia, leukopenia, and nausea. The MONARCH 2 trial (NCT02107703) evaluated abemaciclib (or placebo) with fulvestrant in 669 women with no prior chemotherapy for ABC (38% had 1 line of ET for ABC). In the premenopausal subset (abemaciclib, n = 72; placebo, n = 42; all with ovarian suppression), abemaciclib prolonged PFS (hazard ratio, 0.415 [95% confidence interval, 0.246–0.698]). Conclusions: While trial and patient characteristics differed substantially, safety and efficacy established in the MONALEESA-7 trial of premenopausal women and premenopausal subsets of the PALOMA-3 and MONARCH 2 trials support the activity and use of CDK4/6 inhibitor combination therapy in these patients. The treatment benefit observed in these trials was consistent with that in Phase 3 trials of postmenopausal women with HR+, HER2− ABC treated with CDK4/6 inhibitor combination therapy.
<i>OGG1</i>, <i>APEX1</i> and <i>XRCC1</i> polymorphisms in oropharyngeal squamous cell carcinoma risk and prognosis.
Authors: Ericka Francislaine Dias Costa, Erika Stocco dos Santos, Vitor Teixeira Liutti, Frederico Leal, Vivian Antunes Santos, José Augusto Rinck, Carmen Silvia Passos Lima, Gustavo Jacob Lourenco
Journal: Journal of Clinical Oncology (2016)

e17515 Background: OGG1 c.977C > G, APEX1 c.444T > G; XRCC1 c.-77T > C, c.580C > T, c.839G > A and c.1196G > A polymorphisms have been associated with inefficient DNA base-excision repair (BER). However, it is unknown whether they are associated with increased risk and prognosis of oropharyngeal squamous cell carcinoma (OPSCC), therefore, this study aimed to clarify this issue. Methods: Genomic DNA from 200 OPSCC patients and 200 controls was analyzed by PCR-RFLP. XRCC1 expression was determined by qPCR from total RNA of 37 controls. The differences between groups were analyzed by χ2 or Fisher’s exact test. Multivariate analysis using the logistic regression model served to obtain age and tobacco status adjusted crude odds ratios with 95% confidence intervals (CI), and to assess the associations between genotypes and OPSCC. XRCC1 expression was analyzed by non-parametric tests. Progression-free survival (PFS) and overall survival (OS) times were calculated using Kaplan-Meier estimate probabilities and differences between survivals were analyzed by the log-rank test. The prognostic impact of genotypes was examined using Cox regression analyses. Results: XRCC1 c.580CT or TT genotypes (19.5% vs. 11.0%, P = 0.04) and XRCC1 TTGG haplotype from c.-77T > C, c.580C > T, c.839G > A and c.1196G > A polymorphisms (17.5% vs. 10.0%, P= 0.04) were more common in patients with OPSCC than in controls.Carriers of combined genotypes of c.580C > T and TTGG haplotype of XRCC1 were under 3.35 (95% CI: 1.07-10.46) and 3.22 (95% CI: 1.04-9.92)-fold increased risk of OPSCC than others. Individuals with XRCC1 TTGG haplotype presented lower mRNA expression levels than those with other haplotypes (P= 0.03). Considering only patients with advanced tumors, at 24 months of follow-up, PFS was shorter in patients with OGG1 c.977CC genotype when compared with others (35.5% vs. 52.1%, P= 0.03). Conclusions: Our data present, for the first time, evidence that inherited OGG1 c.977C > G and XRCC1 c.-77T > C, c.580C > T, c.839G > A and c.1196G > Aabnormalities of DNA BER pathway are important determinants of OPSCC and predictors of patient outcomes. Our findings, once validated in additional studies, will contribute to personalize the therapy of OPSCC patients.
IPA-3 (PAK1 inhibitor) or OTSSP167 (MELK inhibitor) plus auranofin (PKCÎ¹ inhibitor), a therapeutic option for EGFR mutant, KRAS mutant and squamous cell non-small cell lung cancer (NSCLC).
Authors: Masaoki Ito, Carles Codony-Servat, Jordi Codony-Servat, Ilaria Attili, Laura Bonanno, Matteo Fassan, Jordi Berenguer, Jillian Bracht, Nuno Monteiro Gil, Morihito Okada, Andres Felipe Cardona Zorrilla, Niki Karachaliou, David Jablons, Peng Cao, Rafael Rosell
Journal: Journal of Clinical Oncology (2018)

e24001 Background: p21-activated kinase 1 (PAK1) stimulates growth and metastasis in several types of tumors, including NSCLC. Protein kinase C iota (PKCi) is highly expressed in NSCLC and regulates PAK1 signaling. We have shown that cancer pathway-specific intervention, like EGFR inhibitors in EGFR mutant NSCLC, results in parallel compensatory activation of other pathways, including the receptor tyrosine kinases AXL and MET, the transmembrane protein CUB domain-containing protein-1 (CDCP1) or the transcriptional regulators STAT3 and YAP1. We have now explored whether a non-pathway-specific approach can be efficient in three classes of NSCLC. Methods: Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells with EGFR and KRAS mutations respectively, and H520 PAK1 amplified squamous NSCLC cells. Cell viability assays and western blotting were applied to evaluate the effect of IPA-3 plus auranofin and OTSSP167 plus auranofin. The Chou-Talalay modified method was used for drug combination studies (combination index [CI] = 1), synergism (CI < 1), and antagonism (CI > 1). Results: We found a differential PAK1 expression or activation profile in the three models, with H520 cells being the ones with the highest PAK1 expression and activation. IPA-3 plus auranofin was highly synergistic in HCC827, H23 and H520 cells with CIs of less than 0.4. In the HCC827 cells, the combination of IPA-3 plus auranofin abrogated EGFR and downstream signaling (ERK, AKT, STAT3, YAP1) and inhibited the expression and activation of AXL, MET and CDCP1. IPA-3 plus auranofin was also highly synergistic in H23 (CI = 0.3) and H520 (CI = 0.3) cells. In addition, the combination of OTSSP167 plus auranofin was synergistic in the three cell lines (0.7 in each cell line). Specifically, we noted that OTSSP167 ablated PAK1 phosphorylation in Ser144, Thr423 and Thr212. Conclusions: To date there are no PAK1 inhibitors available. Phase I trials of OTSSP167 in breast cancer (NCT02926690) and leukemia are ongoing. Hence, the combination of OTSSP167 and auranofin could be effective and of interest to be tested in EGFR, KRAS mutant and squamous NSCLC patients.
Lenalidomide with R-IMED (rituximab, ifosfamide, methotrexate, etoposide and dexamethasone) in refractory or relapsed non-GCB diffuse large B-cell lymphoma: A phase II clinical trial.
Authors: Tongyu Lin, Fushen Sha, He Huang, Zhao Wang, Suxia Lin, Xueying Li, Huangming Hong, Xiaojie Fang, Fangfang Li, Chen Peng, Quanguang Ren, Limei Zhang, Qing Liu
Journal: Journal of Clinical Oncology (2018)

7553 Background: The prognosis of refractory or relapsed(R/R) non-germinal center B cell (non-GCB) subtype diffuse large B cell lymphoma (DLBCL) is dismal without established standard salvage chemotherapy regimen. We designed a phase II trial to prospectively evaluate the efficacy and safety of the combination of lenalidomide and rituximab with the IMED (ifosfamide, methotrexate, etoposide and dexamethasone) regimen(L-R-IMED) in refractory or relapsed non-GCB DLBCL. Methods: Eligible participants were adults with non-GCB subtype, CD20 positive DLBCL who were refractory to or had relapsed after R-CHOP-based regimens. Patients received lenalidomide 10 mg orally per day on days 1 through 14 with R-IMED every 21 days for four to six cycles. The response was evaluated using PET-CT scan after every 2 cycles. The primary endpoint was objective response rate (ORR) and progression-free survival (PFS). Results: Between January 2014 and November 2017, 40 patients with non-GCB subtype, CD20 positive, R/R DLBCL were enrolled, and 40 were evaluable for response. The median age was 51 years (range 20–85 years) and 60% (24 of 40) were men and 40% (16 of 40) were women. 50% of the patient (n = 20) had refractory disease and 50% (n = 20) had relapsed disease. The ORR was 70% (28 of 40) with 55% (22 of 40) achieving a complete response. The median follow-up time was 14.8 months. The median PFS was 10.9 months (95% CI: 7.9-13.9 months) and the median PFS of patients had a complete response was 28.6 months (95%CI:8.6-48.5months). The median overall survival was not reached. The most common hematologic adverse event was neutropenia. The most common nonhematologic adverse event was fatigue. There was no treatment-associated death. None of our patients discontinued treatment due to significant hematological toxicities. Conclusions: Among patients with R/R non-GCB DLBCL, L-R-IMED showed promising efficacy and tolerability profile. The regimen needs to be further verified by phase III study.
Inhibition of neogenin fosters resolution of inflammation and tissue regeneration
Authors: Martin Schlegel, Andreas Körner, Torsten Kaussen, Urs Knausberg, Carmen Gerber, Georg Hansmann, Hulda Soffia Jónasdóttir, Martin Giera, Valbona Mirakaj
Journal: Journal of Clinical Investigation (2018)

The resolution of inflammation is an active process that is coordinated by endogenous mediators. Previous studies have demonstrated the immunomodulatory properties of the axonal guidance proteins in the initial phase of acute inflammation. We hypothesized that the neuronal guidance protein neogenin (Neo1) modulates mechanisms of inflammation resolution. In murine peritonitis, Neo1 deficiency (Neo1–/–) resulted in higher efficacies in reducing neutrophil migration into injury sites, increasing neutrophil apoptosis, actuating PMN phagocytosis, and increasing the endogenous biosynthesis of specialized proresolving mediators, such as lipoxin A4, maresin-1, and protectin DX. Neo1 expression was limited to Neo1-expressing Ly6Chi monocytes, and Neo1 deficiency induced monocyte polarization toward an antiinflammatory and proresolving phenotype. Signaling network analysis revealed that Neo1–/– monocytes mediate their immunomodulatory effects specifically by activating the PI3K/AKT pathway and suppressing the TGF-β pathway. In a cohort of 59 critically ill, intensive care unit (ICU) pediatric patients, we found a strong correlation between Neo1 blood plasma levels and abdominal compartment syndrome, Pediatric Risk of Mortality III (PRISM-III) score, and ICU length of stay and mortality. Together, these findings identify a crucial role for Neo1 in regulating tissue regeneration and resolution of inflammation, and determined Neo1 to be a predictor of morbidity and mortality in critically ill children affected by clinical inflammation.
Use of cell-free DNA for management of breast and lung cancer by academic and community providers.
Authors: Roby Antony Thomas, Natalie Klar, Brenda Diergaarde, Lesli Ann Kiedrowski, Rebecca J Nagy, Adrian V. Lee, Adam Brufsky
Journal: Journal of Clinical Oncology (2018)

12046 Background: Next-generation sequencing of cell-free DNA (cfDNA) can assess presence of somatic genomic alterations in patients with cancer without an invasive biopsy. Results may guide therapeutic decision-making. We evaluated use of cfDNA test results for management of breast and lung cancer in a major healthcare system with academic and community-based practices. Methods: Retrospective review of cfDNA tests (Guardant360) ordered for patients with breast or lung cancer at the University of Pittsburgh Medical Center between 8/2014 and 3/2017 was performed. For patients with actionable results (lung: alterations with FDA-approved or NCCN-recommended targeted therapy; breast: ERBB2, ESR1 or PIK3CA alterations), information on clinical care was abstracted. Differences in clinical use of test results were evaluated between academic and community providers. Results: In total, 230 tests were ordered for 218 subjects; 128 by academic and 102 by community providers. Community providers ordered significantly (P < 0.05) more tests for lung cancer patients than academic providers (78% vs. 47%) and their patients were older (mean age: 65.5 vs. 60.3 yrs.). Actionable alterations were identified in 82 subjects (38%; 48 breast, 34 lung). Six were excluded from further analyses because their mutations had been known previously. For 32 (42%) of the remaining 76 subjects, actionable results led to a change in therapy, for the other 44 it did not. Reasons for not changing therapy included: patient died or lost to follow up, palliative care elected, treatment targeted a different molecular finding, targeted therapy recommended but cost prohibitive, and patient currently stable but results could guide therapy at progression. Actionable results significantly more often resulted in a management change for lung cancer than breast cancer (63% vs. 28%). Use of test results differed significantly between academic and community providers (result led to change: 31% vs. 61%) Conclusions: Results of cfDNA tests were used to guide therapy changes, especially for patients with lung cancer. Community practice-based providers appear to act on actionable results more often than academic center-based providers in this health care system.
Association of neuroendocrine phenotype with platinum chemotherapy outcomes in men with metastatic prostate cancer.
Authors: Michael Sandon Humeniuk, Rajan T Gupta, Megan Ann McNamara, Sundhar Ramalingam, Michael Roger Harrison, Daniel J. George, Yuan Wu, Patrick Healy, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2017)

e16532 Background: DNA repair defects are common in men with mCRPC, and platinum chemotherapy may have a role in selected patients. We aimed to determine whether neuroendocrine variant prostate cancer (NEPC) is associated with a greater response to platinum chemotherapy, as compared to CRPC with adenocarcinoma histology (AdenoCRPC). Methods: We conducted a retrospective cohort analysis of all patients with prostate cancer treated with platinum chemotherapy at the Duke Cancer Center between 2005-15. The primary endpoint was objective response rate (RESIST v1.1; ORR); secondary endpoints were PSA decline, progression-free (PFS) and overall survival (OS). Outcomes were compared by histologic phenotype (NEPC vs. AdenoCRPC). Results: Between 2005-2015, 73 men, including 56 with AdenoCRPC and 17 with NEPC, were treated with platinum-based chemotherapy for mCRPC. Carboplatin-docetaxel and carboplatin/cisplatin etoposide were the most common regimens. Fifteen men (21%) were M1 at diagnosis. Among NEPC patients, 3 had primary NEPC/small cell carcinoma at diagnosis, while 14 had NEPC transformation after hormonal therapy. Overall, 24% of NEPC men received prior docetaxel vs. 75% of AdenoCRPC men. Partial responses were observed in 59% in men with NEPC vs. 25% for AdenoCRPC. Primary progressive disease occurred in 24% (NEPC) vs. 48% (AdenoCRPC). PSA declines with platinum chemotherapy were more common in NEPC (median 72% decline) vs. AdenoCRPC (median 24% decline). There was no significant difference in median PFS or OS between phenotypes (NEPC PFS 5.1 mo, OS 8.5 mo; AdenoCRPC PFS 4.3 mo, OS 10.0 mo; p = NS). For second platinum chemotherapy, ORR and PFS in NEPC vs AdenoCRPC were 67% and 5.2 months vs. 14% and 4.6 months. Conclusions: Our data suggest that men with NEPC histology have a greater probability of objective response and PSA decline with platinum chemotherapy vs. men with AdenoCRPC. However, PFS and OS are similar across histologic phenotypes, indicating similar times to resistance to platinum chemotherapy. Biomarkers of platinum sensitivity are needed, and evaluation of DNA repair defects in this setting may provide a greater opportunity for precision medicine approaches to DNA damaging agents.
TCT-757 Axillary Artery Access for Mechanical Circulatory Support Devices in Patients with Prohibitive Peripheral Arterial Disease Presenting with Cardiogenic Shock
Authors: Amir Kaki, M Chadi Alraies, Nimrod Blank, Adi Shemesh, Marvin Kajy, Amir Laktineh, Reema Hasan, Christopher Gade, Mahir Elder, Theodore Schreiber
Journal: Journal of the American College of Cardiology (2018)