tbuckley/cabot-search huggingface dataset:
Dissecting the prognostic role of sidedness in metastatic colon cancer (mCC): Retrospective analysis of the impact of chemotherapy sequence (CTS) and primary site resection (PTR) in a health care system.
Authors: Feng-Che Kuan, Gengping Lin, Wen-Nan Chiu, Chih-Jung Chen, Chih-Chien Chin, Wen Shih Huang, Chung-Wei Fan, Jy Ming Chiang, Hong-Hwa Chen, Jinn-Shiun Chen, Kuan-Der Lee
Journal: Journal of Clinical Oncology (2018)

e15502 Background: Previous literatures indicated the efficacy of frontline anti-EGFR monoclonal antibodies was affected by sidedness and the prognosis of left side mCC (L) was better than that of right side mCC (R). Whether CTS and PTR affect the prognosis stratified by sidedness is unknown. Methods: By retrospective analysis of Chang-Gung Research Database (CGRD), patients with mCC were chart reviewed, and tumors from cecum to sigmoid were divided by splenic flexure. Multivariable Cox proportional hazards model analysis of overall survival (OS) was performed for baseline characteristics and treatment modalities stratified by sidedness. Results: From 2004 to 2013, 838 patients with mCC who received both lines of irinotecan(I)-or oxaliplatin(O)-based chemotherapy (CT) were enrolled. 252 of 493 (51.1%) patients with L and 170 of 345 (49.3%) with R had received frontline I-based CT, and 241 of 493 (48.9%) patients with L and 175 of 345 (50.7%) with R had received frontline O-based CT (p = 0.600). 67.7% of L and 68.7% of R received PTR, of which 50.3% and 56.5% were performed within 30 days, respectively (p = 0.073). R was diagnosed with more peritoneum metastatses, grade 3/4 disease and less liver metastatses (p < 0.001), received less bevacizumab (p = 0.004), cetuximab (p < 0.001) and hepatectomy (p = 0.008). Multivariable Cox proportional hazards model analysis of factors associated with overall survival (OS) was listed in Table 1. Conclusions: CTS did not affect OS irrespective of sidedness, and PTR was associated with better OS in mCC who received both lines of chemotherapy. Table 1. Variable All Left Right HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value Surgery No Reference Reference Reference Yes (£ 30 days) 0.49 (0.40-0.60) < 0.001 0.42 (0.32-0.55) < 0.001 0.50 (0.35-0.70) < 0.001 Yes ( > 30 days) 0.52 (0.40-0.68) < 0.001 0.46 (0.32-0.64) < 0.001 0.51 (0.32-0.79) 0.003 Front-line treatment Irinotecan-based Reference Reference Reference Oxaliplatin-based 0.96 (0.82-1.12) 0.590 0.88 (0.71-1.09) 0.235 1.04 (0.81-1.32) 0.775 Primary site Left 0.79 (0.67-0.93) 0.004 Right Reference
Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenström Macroglobulinemia
Authors: Na Li, Michael A. Lopez, Maria Linares, Subodh Kumar, Stefania Oliva, Joaquin Martinez-Lopez, Lian Xu, Yan Xu, Tommaso Perini, William Senapedis, Erkan Baloglu, Masood A. Shammas, Zachary Hunter, Kenneth C. Anderson, Steven P. Treon, Nikhil C. Munshi, Mariateresa Fulciniti
Journal: Clinical Cancer Research (2018)

p21-activated kinase 4 (PAK4) plays a significant biological and functional role in a number of malignancies, including multiple myeloma (MM). On the basis of our promising findings in MM, we here characterize PAK4 expression and role in WM cells, as well effect of dual PAK4-NAMPT inhibitor (KPT-9274) against WM cell growth and viability.We have analyzed mRNA and protein expression levels of PAK4 in WM cells, and used loss-of-function approach to investigate its contribution to WM cell viability. We have further tested the in vitro and in vivo effect of KPT-9274 against WM cell growth and viability.We report here high-level expression and functional role of PAK4 in WM, as demonstrated by shRNA-mediated knockdown; and significant impact of KPT-9274 on WM cell growth and viability. The growth inhibitory effect of KPT-9274 was associated with decreased PAK4 expression and NAMPT activity, as well as induction of apoptosis. Interestingly, in WM cell lines treated with KPT-9274, we detected a significant impact on DNA damage and repair genes. Moreover, we observed that apart from inducing DNA damage, KPT-9274 specifically decreased RAD51 and the double-strand break repair by the homologous recombination pathway. As a result, when combined with a DNA alkylating agents bendamustine and melphalan, KPT-9274 provided a synergistic inhibition of cell viability in WM cell lines and primary patient WM cells in vitro and in vivo.These results support the clinical investigation of KPT-9274 in combination with DNA-damaging agent for treatment of WM.
Assessment of distress in primary caregivers of patients with advanced cancer.
Authors: Iris Gluck, Lia Eshet, Ofir Morag
Journal: Journal of Clinical Oncology (2016)

e21540 Background: Primary caregivers of cancer patients deal with enormous physical and emotional burden without any training or support. Inevitable consequences include impaired individual well-being, compromised support to the patient and family dysfunction. We wished to reveal various aspects of caregivers' distress. Methods: Primary caregivers of patients with advanced cancer filled a Hebrew version (translated and adapted from English) of the caregiver stress inventory (CSI) questionnaire. CSI contains 13 questions regarding the effect of caregiving on various individual life aspects and on family adjustment. Responses are graded from 0-2 (never, sometimes, regularly). Results: Forty three caregivers (median age 50, range 25-77) filled questionnaires, 16 wives, 7 husbands, and 14 children. Average score was 1.07, the husbands showing the highest score at 1.3 (not statistically significant). The highest score was found for need for family adjustment (q5) and the lowest for caregiving as a physical or financial burden (q3 and q12, respectively). High scores were also found for: sleep disturbances due to concerns related to the patient (q1), need for a change in personal plans (q6), and concerns about behavioral changes of the patient (q10). Half of the caregivers felt completely overwhelmed most of the time. Conclusions: Levels of individual caregiver distress vary. However, family adjustment is almost always a challenge. The fact that so many caregivers feel completely overwhelmed is a red flag. Interventions to support caregivers should focus on emotional coping and on maintaining essential aspects of normal being alongside the endless tasks and responsibilities of caregiving.
Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms
Authors: Rachel Yehuda, Amy Lehrner
Journal: World Psychiatry (2018)

This paper reviews the research evidence concerning the intergenerational transmission of trauma effects and the possible role of epigenetic mechanisms in this transmission. Two broad categories of epigenetically mediated effects are highlighted. The first involves developmentally programmed effects. These can result from the influence of the offspring's early environmental exposures, including postnatal maternal care as well as in utero exposure reflecting maternal stress during pregnancy. The second includes epigenetic changes associated with a preconception trauma in parents that may affect the germline, and impact fetoplacental interactions. Several factors, such as sex-specific epigenetic effects following trauma exposure and parental developmental stage at the time of exposure, explain different effects of maternal and paternal trauma. The most compelling work to date has been done in animal models, where the opportunity for controlled designs enables clear interpretations of transmissible effects. Given the paucity of human studies and the methodological challenges in conducting such studies, it is not possible to attribute intergenerational effects in humans to a single set of biological or other determinants at this time. Elucidating the role of epigenetic mechanisms in intergenerational effects through prospective, multi-generational studies may ultimately yield a cogent understanding of how individual, cultural and societal experiences permeate our biology.
Needle-to-needle time: Does prompt initiation of treatment post biopsy improve pCR in neoadjuvant chemotherapy (NAC) for breast cancer?
Authors: Maryam Eslami, Caroline Illmann, Rachel Adilman, Stephen K. L. Chia, Christine E. Simmons
Journal: Journal of Clinical Oncology (2016)

6546 Background: Several studies suggest that wait time from diagnosis to surgery and from surgery to chemotherapy may impact outcome in the adjuvant treatment of breast cancer. Many patients referred for NAC for breast cancer may have a sense of urgency to start treatment, and oncologists often feel pressured to start treatment quickly. What is unknown, however, is whether expeditious NAC improves outcome. We assessed a prospective database to determine if shorter time between diagnosis and chemotherapy improved pCR rate (defined as no invasive disease in breast and lymph nodes) for patients treated with NAC for breast cancer. Methods: Patients who received NAC and completed treatment between May 2012 and Sept 2015 were captured in a prospective database at the BC Cancer Agency in Vancouver. Time between biopsy result and start of chemotherapy was calculated. Patients were grouped into those who had pCR vs. no pCR, and into those who started treatment within 28 days and those who started after 28 days. Results: A total of 217 patients fulfilled eligibility criteria. Overall pCR rate for this population was 27.6%, with the highest pCR rates seen in the Her2 subgroup (48.1%) and the lowest pCR rate seen in the ER+her2- group (4.7%). Nearly half of the patients in this cohort started chemotherapy within 1 month of biopsy (48.8%). There was no difference in the overall group, nor in any subgroup between initiation of chemotherapy within 28 days and likelihood of pCR (p = 0.7429). Conclusions: Despite the use of wait time to start treatment in the adjuvant setting as a metric that has impact on outcome, time between biopsy and start of chemotherapy does not seem to have an impact on pCR rates in the neoadjuvant setting within the context of a
Prognostic significance of number versus location of positive mesenteric nodes in node positive colon cancer.
Authors: Kozo Kataoka, Elke Debrie, Manabu Shiozawa, Els Goetghebeur, Wim P. Ceelen
Journal: Journal of Clinical Oncology (2018)

3587 Background: Metastasis to locoregional lymph nodes (LN) is one of the most powerful predictors of recurrence free survival (RFS) in colon cancer (CC). Debate persists on the prognostic value of the location of positive LN in addition to the positive lymph node ratio (LNR) or the number of invaded LN (LN+). The recently introduced technique of complete mesocolic excision (CME) presupposes a prognostic role of removal of high level (apical) LN. We analyzed the prognostic significance of positive LN location in a cohort of CC patients who underwent extensive (D3) lymphadenectomy. Methods: Colon cancer patients from Kanagawa Cancer Center, Japan, who underwent extensive (D3) lymphadenectomy from 2000 to 2016 were analyzed. Lymph nodes were classified according to anatomical location as paracolic (L1), intermediate (L2), or along the main vascular trunk (L3). RFS hazards were evaluated with their trends over the groups. Univariate and multivariate Cox proportional hazards models were used to evaluate the association of LN count and L level (L1, L2 and L3) with RFS. Results: 843 patients were included and 446 were node positive of whom only 25 (5.6%) had positive L3 nodes. The mean number of examined/positive nodes per patient was 42.5/2.6 in L1 (n = 310), 40.9/4.8 in L2 (n = 111), and 44.0/9.8 in L3 (n = 25). In univariate analysis, RFS was significantly lower for L3 vs. L2 positive patients (HR: 2.00, 95%CI [1.05-3.75], p = .034) and L3 vs. L1 (HR: 2.62 [1.45-4.71], p = 0.001) but the difference between L1 and L2 was not nominally significant (HR: 1.32 [0.89-1.95], P = 0.17). A multivariate Cox model built with T stage, tumor location (right vs. left), LNR, LN+ and L level identified T stage (p < 0.001) and LNR (p = 0.001) as prognostic factors with no significant contribution from the L level (p = 0.42). Conclusions: In this cohort of patients who underwent standard extensive (D3) lymphadenectomy for CC, apical (L3) nodes are infrequently invaded and confer a significantly worse RFS. The anatomical location of invaded nodes adds no prognostic information to T-stage and LNR. These findings question the value of standard extensive lymphadenectomy in CC.
P01.061 Autologous dendritic cells vaccination and standard radio-chemotherapy in patients with newly diagnosed glioblastoma: a retrospective single-center series
Authors: I Esparragosa, S Inoges, A L de Cerio, J Espinos, J Aristu, M Puigdelloses, M Alonso, S Tejada-Solis, R Díez-Valle, J Gállego Pérez-Larraya
Journal: Neuro-Oncology (2018)

Immunotherapy is being increasingly investigated as a treatment for glioblastoma (GBM). Recent non-randomized clinical trials and monocentric series describe the feasibility and safety of dendritic cells vaccinations, and suggest efficacy of this therapeutic approach. We describe a retrospective single-center series of newly diagnosed GBM patients who were treated with complete or near complete resection followed by standard radiotherapy plus concomitant and adjuvant temozolomide, and who additionally received vaccination with autologous dendritic cells pulsed with tumor lysate as compassionate use. Between January 2011 and May 2017, twenty four patients with newly diagnosed GBM were treated with autologous dendritic cells vaccination as compassionate use in addition to standard radio-chemotherapy. An attempt at maximum resection was made in every case using fluorescence-guided surgery with 5-aminolevulinic acid. Less than 1 cc of residual tumour and histological confirmation of GBM was required for definite inclusion in the vaccination treatment programme. Vaccines were prepared with autologous dendritic cells pulsed with tumour lysate and matured ex vivo. Vaccination calendar started 3 weeks after surgery and 1 week before initiation of radiotherapy. Patients also received standard radiotherapy with concomitant and adjuvant temozolomide. Safety and outcome data are analyzed. The median age of the 24 patients was 61 years (range: 43 to 78). Median Karnofsky Performance Score was 80% (range: 40% to 100%). Complete resection was achieved in 20 (83%) patients. O6-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 13 (54%) patients. Enough tumor lysate and dendritic cells were available in every case to produce at least 6 vaccination doses. The median number of administrated vaccines was 7 (range: 2 to 16). Median Progression-Free Survival was 9.2 months and median Overall Survival was 21.1 months (95% CI: 15.4–26.7 months). No adverse events attributable to immunotherapy were identified. These results are similar to those obtained in a previous non-randomized trial conducted at our institution. These results confirm that autologous dendritic cells vaccination is feasible and safe in the clinical practice setting. Wether the addition of this immunotherapeutic modality to tumor resection and standard radio-chemotherapy increases survival of patients with newly diagnosed GBM still needs to be clarified in a randomized trial. Centers investigating this approach should associate to develop such a study.
The first- or second-line use of pemetrexed sequentially with EGFR-TKI did not differ in PFS for advanced NSCLC patients harboring EGFR-mutant tumors.
Authors: Zhen-Yu Ding, Yue-Yun Chen
Journal: Journal of Clinical Oncology (2017)

e20531 Background: Both EGFR-TKI and pemetrexed doublet chemotherapy (P) are two effective therapies in advanced NSCLC patients with EGFR mutant tumors. But which one should be used in first-line remains controversial. Methods: This was a retrospective study where patients prescribed with EGFR-TKI (gefitinib or icotinib) from Jan 2013 to Jan 2016 were screened. Patients must have metastastic diseases harboring TKI-sensitizing EGFR mutation. They must be older than 18 years, and have evaluable target lesions. Whether TKI or P was used in the first line, it must be switched to the other in the second line. PFS in both first line (PFS1) and second line (PFS2) was collected. Results: We screened totally 550 patients (gefitinib n = 455, icotinib n = 95) to enroll a cohort of 36 patients. They were all adenocarcinoma except 1 adenosquamous carcinoma. Gender (M or F), PS (0 or 1), mutation type (Exon19Ddel or other) were equally distributed. The median age was 50.5 years. For the whole cohort, the total PFS (PFS1+PFS2) was 18.1 m (95%CI: 15.2-21.1 m). For those (n = 24) receiving first-line TKI, PFS1, PFS2, and total PFS were 10.3 m, 6.6 m, and 19.2 m. And for those receiving first-line P (n = 12), they were were 3.4 m, 11.5 m, and 16.5m. The total PFS in both groups did not differ significantly (p = 0.548). Conclusions: Our results argued the sequential usage of TKI and P achieve a comparable PFS irrespective of the sequence.
Acute myeloid leukemia: Does one size fit all? A retrospective analysis of outcomes of therapy at Moi Teaching and Referral Hospital in Eldoret, Kenya.
Authors: Christopher Mwaniki Wanjiku, Antoine Saliba, Evangeline Wawira Njiru
Journal: Journal of Clinical Oncology (2018)

e18529 Background: Care for acute myeloid leukemia (AML) remains challenging despite advances in therapy. There is a wide gap between the standard of care in high-income countries (HIC) – and the options available in low- to middle-income countries (LMIC). Institutional experience at Moi Teaching and Referral Hospital (MTRH) has shown that patients receiving the traditional 7+3 chemotherapy typically die within the same hospital stay from treatment related adverse effects. Institutional practice has relied on low-dose cytarabine (20 mg intravenously every 12 hours for 10 days per cycle) every 4 – 6 weeks. We aimed to study the outcomes of this approach. Methods: We analyzed data for adult patients with AML treated at MTRH over a period of 36 months between June 2012 and July 2015. Medical information was extracted from a deidentified database built for quality improvement purposes. Results: 20 patients, 9 females and 11 males, with mean age at diagnosis of 43.9 ± 17.4 years were treated for AML. 17 patients (85.0%) received low-dose cytarabine with the mean number of cycles being 1.1. One patient received one cycle of doxorubicin and one other received one cycle of cytarabine and doxorubicin prior to low-dose cytarabine. The median overall survival was 181 days (range: 1 – 721 days). 11 patients (64.7%) completed at least one full cycle of cytarabine. An analysis excluding 8 patients lost to follow up showed a mean survival of 273.5 days for patients who completed at least one cycle of low-dose cytarabine therapy compared to 143.5 days for those who did not. 15 patients died of the disease within one year of diagnosis. Five-year survival remains at a striking 0% as compared to rates consistently > 50% in patients < 70 years of age in HIC. Conclusions: AML therapy results remain poor in Kenya compared to outcomes from HIC. There is need for prospective studies in LMIC aimed at optimizing care. Improvement in hospital infrastructure to minimize the risk of infections and maximize access to blood products, and establishment of hematopathology service are important steps to undertake in preparation for more cytotoxic and transplant therapies to be available.
Incidence of nonvalvular atrial fibrillation on ibrutinib compared to other tyrosine kinase inhibitors: A large multi-institution general practice study.
Authors: Joyce Njoroge, Robert William Lentz, Jered Linares, Christopher Gans, Nausheen Akhter
Journal: Journal of Clinical Oncology (2018)

e22076 Background: Tyrosine kinase inhibitors (TKIs) are a widely used class of antineoplastic agents. Meta-analysis of clinical trials has demonstrated an increased incidence of atrial fibrillation (AF) in patients treated with ibrutinib of 6-16% compared to alternate TKIs. However, this is not well defined outside of clinical trials. We studied the nonvalvular AF incidence with TKI exposure in a general practice setting. Methods: 600 patients treated with TKIs (listed in Table 1 with data) for any indication between July 2012 and July 2016 were included from two institutions. Exclusion criteria included AF diagnosed prior to TKI initiation and moderate to severe valve disease. Electrocardiograms were reviewed to document the presence or absence of AF relative to the initiation of the TKI. Subjects were followed for an average of 27.6 months. The incidence of AF was compared between groups using chi-square testing. Results: The incidence of AF in patients treated with ibrutinib (9.5%) was significantly higher than in patients treated with erlotinib (3.6%, p = 0.03), sorafenib (2.8%, p = 0.02) and a composite of all comparison TKIs (3.2%, p = 0.002). Data provided in Table 1. Although the mean time from the start of the TKI to diagnosis of AF was shorter in the ibrutinib cohort (0.81 years vs. 1.62), this difference was not statistically significant (p = 0.09). Conclusions: This large open-label retrospective cohort analysis demonstrates that nonvalvular AF occurs at significantly higher rates in patients treated with ibrutinib relative to other TKIs, confirming prior findings. Regular monitoring for AF during treatment with ibrutinib is recommended for early detection and management. Table 1: Incidence of AF during treatment with TKIs Drug Number of patients Incident AF (%) p-value compared to ibrutinib Ibrutinib 169 9.5 N/A Lapatinib 43 2.3 0.12 Erlotinib 165 3.6 0.03 Sorafenib 142 2.8 0.02 Sunitinib 81 3.7 0.11 Combined laptinib, erlotinib, sorafenib, and sunitinib 431 3.2 0.002
CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of <i>RB1</i> Status
Authors: Carolina Rubio, Mónica Martínez-Fernández, Cristina Segovia, Iris Lodewijk, Cristian Suarez-Cabrera, Carmen Segrelles, Fernando López-Calderón, Ester Munera-Maravilla, Mirentxu Santos, Alejandra Bernardini, Ramón García-Escudero, Corina Lorz, Maria José Gómez-Rodriguez, Guillermo de Velasco, Irene Otero, Felipe Villacampa, Felix Guerrero-Ramos, Sergio Ruiz, Federico de la Rosa, Sara Domínguez-Rodríguez, Francisco X. Real, Núria Malats, Daniel Castellano, Marta Dueñas, Jesus M. Paramio
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP). Experimental Design: Bladder cancer cell lines were tested for in vitro sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its in vivo activity. Results: Cell lines tested were sensitive to CDK4/6 inhibition, independent on RB1 gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation in vitro and in vivo and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer. Conclusions: CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options.