tbuckley/cabot-search huggingface dataset:
Palliative care research skill development needs: Lessons from the Palliative Care Research Cooperative Group (PCRC).
Authors: Christine Ritchie, Amy P Abernethy, Melissa Aldridge, R. Sean Morrison, Jean Kutner
Journal: Journal of Clinical Oncology (2015)

174 Background: The field of palliative care (PC) has grown substantially over the past decade. PC research has not kept pace, however. One contributing factor is the paucity of clinical investigators equipped to conduct rigorous PC studies, especially multisite studies focused on interventions, dissemination and implementation. A core mission of the Palliative Care Research Cooperative (PCRC) is to enhance investigator capacity to conduct applied patient/caregiver-centered research. Methods: The PCRC Investigator Development Center (IDC) performed two needs assessments in 2015: 1) PCRC methodologic Core Directors; and 2) a subset of PCRC junior investigators. Results: Through these two assessments, PCRC identified the following knowledge/skills gaps in planning and implementing multisite clinical trials and implementation research: basic principles of clinical trials, nuts and bolts of multisite clinical trials, special considerations in behavioral and pragmatic clinical trials, testing treatment efficacy vs testing treatment effectiveness, selection of endpoints and measurement tools, recruitment and adherence issues unique to palliative care populations, data safety monitoring, budgeting and development of protocols/training for multi-site trials. These knowledge/skills gaps were identified by junior investigators as well as by senior investigators whose prior experience is primarily with single-site studies or secondary data analyses. Conclusions: Advancement of PC research requires upskilling of investigators n conduct of multisite studies. The PCRC is partnering with the National Palliative Care Research Center (NPCRC) to make available a range of investigator development resources, including one-on-one mentoring, grant review support, webinars and palliative care research boot camps.
Analysis of gene mutations in<i> KRAS</i>, <i>NRAS, BRAF, </i>and <i>PIK3CA </i>in patients who received systemic chemotherapy with metastatic gastric cancer.
Authors: Masaru Fukahori
Journal: Journal of Clinical Oncology (2013)

27 Background: Previous studies showed that gene mutations of KRAS, NRAS, BRAF, and PIK3CA are associated with a poor prognosis or resistance of anti-EGFR antibody in metastatic colorectal cancer. On the other hand, the frequency and clinical significance of these gene mutations have not been clarified in metastatic gastric cancer (mGC). Methods: We gathered formalin-fixed paraffin-embedded tumor samples from 168 patients who were diagnosed gastric cancer and underwent gastrectomy between September 1995 and March 2008. Among 168 patients, we selected the mGC patients who received systemic chemotherapy. We retrospectively evaluated the mutation status of KRAS (exon2, 3, 4), NRAS (exon 2, 3), BRAF (exon 15) and PIK3CA (exon 9, 20) and prognosis in patients who received chemotherapy by gene mutation status. Results: A total 125 of patients were included in this analysis. Regimens of first line chemotherapy were 5-FU (24.0%), CPT-11/CDDP (31.2%), S-1 (33.6%), 5-FU/MTX (8.0%) and others (3.2%). Mutations of KRAS codon 12/13 (6.4%), PIK3CA exon9 (4%), PIK3CA exon20 (0.8%), and NRAS codon 12/13 (2.4%) were detected by direct-sequence method. Mutations of KRAS codon 61, KRAS codon 146, BRAF V600E and NRAS codon 61 were not detected. There were no significant differences in overall survival (OS) by mutation status of KRAS and PIK3CA. Patients with NRAS codon 12/13 mutation had poor prognosis (MSTF15.5 vs 9.4 months, adjusted HR: 5.327(95%CI: 1.566-18.096)). Conclusions: Mutations in KRAS codon 61, KRAS codon 146, BRAF V600E, NRAS codon 61 were not detected, and frequency of mutation in PIK3CA exon 9, PIK3CA exon 20 and NRAS codon 61 were rare in mGC. Although our study has several limitations, mutation in NRAS codon 12/13 may be a poor prognostic factor in mGC who received systemic chemotherapy and further accumulation of cases are needed.
Do older patients with T1a lesions require sentinel lymph node biopsy?
Authors: M. W. O'Malley, K. A. Griffith, M. S. Sabel, L. A. Newman, T. M. Breslin, A. E. Chang, V. M. Cimmino, C. G. Kleer, K. M. Diehl
Journal: Journal of Clinical Oncology (2010)

587 Background: Some have suggested that selected older women with T1a lesions may not require sentinel lymph node biopsy, or advocate forgoing axillary staging for older patients with clinically negative axillae. Methods: An IRB-approved database was queried for all patients undergoing SLNB for invasive breast cancer from 2000 to 2006. We compared 3 cohorts: premenopausal women ≤ 40 years old (PRE), perimenopausal women 40-55 years old (PERI), and postmenopausal women ≥ 55 years old (POST). Logistic regression and chi-square test were used. Results: The procedure was successful in 123/127 (97%), 556/559 (99%), and 569/582 (98%) of 1,268 PRE, PERI, and POST patients undergoing SLNB, respectively. POST patients had lower grade tumors than PERI and PRE (grade 1: 26% vs. 20% and 7%; grade 2: 48% vs. 43% and 48%; grade 3: 19% vs. 29% and 40%, p ≤ 0.01) and higher ER expression (ER+: 79% vs. 66% and 59%, p ≤ 0.01). PRE patients had a higher proportion of multifocal disease than PERI or POST (21% vs. 14% and 11%, p < 0.01) and more lymphovascular invasion than POST (20% vs. 12%, p < 0.01). A positive sentinel lymph node (PSLN) was found in 32% of PRE, 28% of PERI and 19% of POST patients (p < 0.01). Upon multivariable analysis, clinical stage, ER status, and lymphovascular invasion were significantly associated with PSLN, but age cohort no longer was (p = 0.28). In the T1a subset PRE, PERI, and POST patients were similar for the proportion of PSLN (p = 0.12). Conclusions: Despite more favorable pathology, there wasno significant association between PSLN and POST vs. PERI or PRE patients, when adjusting for other important factors. There should be no difference in the criteria for axillary staging between younger vs. older breast cancer patients. Given recent reports that older breast cancer patients are less likely to receive standard treatment for breast cancer and their prognosis may worsen as a result, these results underscore the importance of appropriate, aggressive staging of the older breast cancer patient. No significant financial relationships to disclose.
Adherence to national quality guidelines for nodal staging and treatment of cutaneous melanoma.
Authors: Tina J. Hieken, Nneka I. Comfere, Travis Edward Grotz, Jonathan W. Inselman, Elizabeth B. Habermann
Journal: Journal of Clinical Oncology (2013)

110 Background: Assessment of compliance with national quality guidelines for the management of melanoma may be complicated by controversy about selection of patients for nodal surgery and limited by a lack of data on quality metrics. Previous reports suggest suboptimal overall compliance, with sentinel lymph node biopsy (SLNB) not performed for many suitable patients and completion lymph node dissection (CLND) omitted in many biopsy-proven node-positive (LN+) cases. The purpose of this study was to assess compliance with national ASCO/SSO guidelines for lymph node (LN) surgery for T2 and T3 (intermediate thickness, 1.01-4.00 mm) primary cutaneous melanoma patients and elucidate factors associated with non-compliance. Methods: All cases of T2 and T3, M0 melanoma were identified from 2004-2010 SEER data. Multivariable logistic regression was utilized to identify independent predictors of compliance. Five-year cancer specific survival (CSS) was estimated using the Kaplan-Meier method. Results: Overall, 75.3% (6,609/8,782) of T2-T3 primary cutaneous melanoma patients underwent LN staging including SLNB in 6,330 (74.5%) of 8,492 clinically LN negative patients. Among these 6,609 patients, 1,279 (19.4%) had one or more LN+. 940 LN+ patients (73.4%) underwent CLND with removal of a mean (median, IQR) of 20.7 (18, 11-27) LNs. Compliance with LN staging and management guidelines was associated with truncal primary site (for SLNB), p&lt;0.001 and with patient age &lt;65 yrs and increasing number of metastatic LNs (for CLND), both p&lt;0.0001. Compliance with CLND for LN+ patients was associated with improved 5 year CSS: 70.0% vs 64.6%, p&lt;0.001. Conclusions: Compliance with guidelines for LN surgery in T2 and T3 melanoma is poor despite the well-defined benefit for this group of patients. These data suggest that non-compliance is multifactorial and not simply due to practice differences arising from the controversial aspects of melanoma management. Room for improvement exists. Assessment of modifiable factors associated with poor compliance, design of strategies to improve compliance and the development of performance measures around appropriate LN staging and management of T2 and T3 melanoma deserve further investigation.
Efficacy of chemotherapy in patients with pancreatic acinar cell carcinoma.
Authors: Changhoon Yoo, Bumjun Kim, Kyu-Pyo Kim, Jae-Lyun Lee, Tae Won Kim, Baek-Yeol Ryoo, Heung-Moon Chang
Journal: Journal of Clinical Oncology (2016)

308 Background: Pancreatic acinar cell carcinoma (ACC) is a rare cancer of the exocrine pancreas. Because of its rare incidence, efficacy of chemotherapy in this patient population still remains largely unknown. Therefore, we retrospectively analyzed the outcomes of patients with pancreatic ACC who received chemotherapy. Methods: Between January 1997 and March 2015, a total of 22 patients with histologically confirmed locally advanced unresectable or metastatic pancreatic ACC were identified in Asan Medical Center, Seoul, Korea. Among them, 15 patients received chemotherapy and 2 patients with locally advanced disease underwent concurrent chemoradiotherapy followed by chemotherapy; these 17 patients were included in this analysis. Results: Median age was 58 year old (range, 29-72), and 15 patients (88%) were male. Mixed acinar-neuroendocrine tumor and mixed acinar-adenocarcinoma was found in 1 (6%) and 2 (12%) patients, respectively. The most common metastatic site was liver (n = 9, 53%), followed by intraabdominal lymph nodes (n = 5, 29%), and peritoneum (n = 3, 18%). As 1 st -line therapy, 5-FU or its derivative were given in 7 patients (41%), gemcitabine in 6 (35%), gemcitabine plus capecitabine in 2 (12%) and FOLFOX in 2 (12%). Objective response rate (ORR) was 30% and median time-to-progression (TTP) was 5.8 months (95% CI, 2.9-8.6). After progression, 2 nd -line chemotherapy was given in 9 patients; 5 and 4 patients received FOLFOX and gemcitabine, respectively. On 2 nd -line chemotherapy, ORR was 44% and median TTP was 6.3 months (95% CI, 0.3-12.4); patients with FOLFOX had significantly better TTP compared to those with gemcitabine (median 6.5 vs 1.4 months, p = 0.003). The ratio of TTP at 1 st -line chemotherapy to TTP at 2 nd -line chemotherapy was significantly higher in patients with FOLFOX (2.10 [range, 0.16-8.30] compared to those with gemcitabine (0.12 [0.08-0.25]; p = 0.03). Median overall survival in all patients was 16.9 months (95% CI, 14.4-19.4). Conclusions: Pancreatic ACC seems to have better prognosis compared to pancreatic adenocarcinoma. Our results suggest that oxaliplatin-containing regimen may have improved activity against pancreatic ACC.
Primary tumor cells show specific susceptibility to KIR-incompatible NK-cell mediated lysis in an ex- vivo single cell cytotoxic assay (SCCA)
Authors: F. Re, V. Vecchio, C. Staudacher, J. Peccatori, M. Bernardi, F. Ciceri, A. Velardi, M. Bregni
Journal: Journal of Clinical Oncology (2005)

2569 Background: NK cells recognize target cells through a balance of activating and inhibiting receptors. When NK cell-inhibitory receptors (killer immunoglobulin-like receptors-KIRs) bind to compatible groups of class I MHC molecules, their cytotoxicity function is blocked. Failure to recognize the appropriate KIR ligand on target cells can trigger NK cell cytotoxic activity. Methods: We analyzed the susceptibility of primary tumor cells to NK-mediated killing by a single-cell cytotoxicity assay (SCCA) using flow-cytometry. Nine consecutive samples out of one hundred biopsies were considered suitable for assay in terms of viability and tumor cell content (1 gastric cancer, 4 colon cancer and 4 renal cancer). Effectors cells obtained from healthy donors were purified as CD3-/CD56+ cells and further enriched for the expression of the specific KIRs. Results: NK cells who recognized specific HLA-C allotypes were able to kill both tumor cells and EBV-LCL target cells that lack a matching HLA-C KIR ligand (specific lysis >35% at 20:1 effector-target ratio,). In contrast, target cells bearing KIR ligand matched alleles showed a specific lysis <12% at 20:1 effector-target ratio. Futhermore the larger the number of receptor- ligand mismatch pairs, the higher the susceptibility of tumor cells to NK cell- mediated lysis (72% lysis of tumor cells expressing only one KIR ligand versus 50% lysis of tumor cells expressing two KIR ligand alleles at 40:1 effector- target ratio). Tumor cells were consistently found to express adhesion molecules. Conclusion: We show that the NK-mediated lysis observed against acute myeloid leukemia following KIR-incompatible haploidentical transplantation might also occur against selected solid tumors, thus providing additional insights for designing new cell therapy approaches based on NK alloreactivity in solid tumors. No significant financial relationships to disclose.
Recurrence of pancreatic ductal adenocarcinoma after pancreaticoduodenectomy: Is there a role for locoregional treatment?
Authors: Alexandra Gangi, Vijay G. Menon, Marwan Sheckley, Richard Tuli, Andrew Eugene Hendifar, Ashley Wachsman, Nicholas N. Nissen
Journal: Journal of Clinical Oncology (2014)

329 Background: The majority of patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma (PDA) will face recurrence. While other types of metastatic tumors are often treated with loco-regional therapy, this approach is rarely applied to metastatic PDA. We examined recurrence patterns of PDA and the potential application of loco-regional treatment. Methods: Evaluation of a prospective database of patients undergoing pancreaticoduodenctomy at an academic institution by a single surgeon. Patients: Pancreaticoduodenectomy for PDA was performed in 95 patients between 2002 and 2012. Margin status was R0 in 88 (93%) and R1 in the remainder. Results: Overall median survival was 27 months and 1 and 3 year survival was 68% and 41%. Known recurrence occurred in 44 of 64 patients (69%) at a median of 20.9 months, while the status of 31 patients was unknown. The most common site of initial recurrence was liver (n=19, median 9.2 months post-surgery), followed by local recurrence (n=15; median 18.7 months) and lung (n=5; median 5.2 months). Patients with R0 margin vs R1 recurred at a median 21 vs 5 months. In our series, 6 patients (5/6 treated in the last 2 years) underwent loco-regional treatment of recurrent disease, including liver resection (n=2), stereotactic radiotherapy (n=2), hepatic ablation (n=1) or radioembolization (n=1). All 6 patients treated with loco-regional therapy are alive at a median of 15.6 months after recurrence and a median of 25.3 months since initial surgery. Conclusions: The initial site of recurrent PDA after pancreaticoduodenectomy is usually liver, and the major risk factor for recurrence is the margin status at resection. Loco-regional modalities for the treatment of recurrent PDA hold promise in select patients. The tendency to utilize loco-regional therapy for recurrent PDA is increasing and warrants continued consideration.
Confirmatory factor analysis of the sexual adjustment and body image scale in women with a diagnosis of gynecologic cancer.
Authors: S. E. Ferguson, C. Massey, C. Classen, M. Wegener, N. Quartey, M. Pulandiran, D. Wiljer, S. Urowitz
Journal: Journal of Clinical Oncology (2011)

5044 Background: There is evidence that treatment of gynecologic cancer (GC) negatively affects body image and sexuality. The Sexual Adjustment and Body Image Scale in women with GC (SABIS-G) was developed to assess disturbances after GC. Exploratory factor analysis resulted in a two factor structure with the underlying constructs of body image and sexual adjustment. Our objective was to confirm the factor structure using a confirmatory factor analysis (CFA). Methods: Women with a history of GC without active disease completed the SABIS-G, a 9-item self-report measure. CFA was performed in which the hypothesized two-factor model was tested against a one-factor model. Cronbach’s coefficient alpha was calculated to measure internal consistency reliability for subscales. Test-retest reliability between baseline and follow-up scores was assessed using the intra-class correlation coefficient (ICC). Correlation coefficients between SABIS-G and other instruments were calculated as measures of validity. Results: 357 patients were approached to participate, 254 (71%) consented to the study and 154 (61%) completed the SABIS-G. The median age was 54 (30-77) and the primary site of disease was: 64 (42%) uterine, 54 (35%) ovary and 32 (21%) cervix. Two variables were eliminated based on analysis of CFA residuals and modification indices. The median SABIS-G score was 46(3-100) with lower scores indicating greater disturbance. The CFA fit indices indicated excellent fit for the two-factor measurement model (standardized root mean square residual 0.05, non-normed fit index 0.96, comparative fit index 0.98). The two-factor solution provided significantly better fit over the one-factor solution (χ12 = 174.6, p < 0.001). Internal consistency reliability was very high for both the Body Image (α=0.88) and Sexual Adjustment (α=0.86) subscales, as was test-retest reliability (ICC = 0.88). Correlation coefficients support the concurrent, convergent and discriminant validity of SABIS-G. Conclusions: These results confirm the two factor structure of the SABIS-G and provides evidence that this is a valid and reliable instrument to measure changes in body image and sexuality in women after a diagnosis of GC.
Glandular metastasis as a surrogate for long survivors in metastatic renal carcinoma.
Authors: Brice Chanez, Pierre-Emmanuel Brachet, Brigitte Laguerre, Jochen Walz, Florence Joly, Benjamin Esterni, Slimane Dermeche, Naji Salem, Serge Brunelle, Jeanne Thomassin, Gwenaelle Gravis
Journal: Journal of Clinical Oncology (2014)

510 Background: Metastatic renal cell carcinoma (RCC) is still associated with a poor prognosis with an overall survival (OS) of 37 months, although some patients are long survivors despite a disseminated disease. The purpose of this study was to determine whether the presence of at least one glandular metastasis (GM), defined by metastasis in pancreas, thyroid, breast or adrenal contralateral, affect survival outcome in patients with metastatic clear cell RCC (cc-RCC). Methods: In this retrospective analysis, we included patients treated for GM and non GM (NGM) metastatic RCC at the Institut Paoli Calmettes (IPC), Marseille, France between January 2004 and May 2013. Two more centers provided data for GM cc-RCC. GM were authentified using CTscan and/or by histopathological analysis obtained at biopsy or at surgery. Patients were analyzed from the time of metastatic disease to last follow up or death. The purpose of this study was to analyze patients outcomes based on the presence or absence of GM. We analysed survival using a log rank test from the time of the diagnosis of GM to the death or last follow-up visit. Results: Among 180 patients analysed, 59 had GM. Median age 65.2 vs 61.8 years old, male 55% vs 72%, 90% vs 78% prior nephrectomy in GM and NGM group. GM sites were pancreas for 45.5%, adrenal 44.5%, thyroid: 10%, breast10%. GM was the only site of metastasis for 10% of pts. For GM group, 55.5% had histopathology proven RCC metastasis. The median follow up was 72 months and the median survival is 114 months (IC95% [62.9-NR.]) in GM group vs 33.2 months (IC95% [23-41.9]; p&lt;0.0001, HR 2.7 [1.7-4.3]) in non GM group. Conclusions: This retrospective study in a rare metastatic localization finds a longer survival in patients with GM. Despite some obvious limitations, this study questions GM as a surrogate for a better prognosis in RCC. Prospective follow-up and the collection for biological and genomic markers are needed to confirm and extend our present findings.
Novel small-molecule CRM-1 inhibitor for GI cancer therapy.
Authors: Asfar S. Azmi, Michael Kauffman, Dilara McCauley, Sharon Shacham, Ramzi M Mohammad
Journal: Journal of Clinical Oncology (2012)

245 Background: Pancreatic (PC) and Colon (CC) cancer remain deadly diseases despite the advent of novel targeted and cytotoxic therapies. Therefore, identification of new targets and development of novel agents against these targets are urgently needed. CRM-1 is a nuclear export protein encoded by the XPO1 (exportin 1) gene that mediates leucine-rich nuclear export signal ( NES )-dependent protein export. Elevated CRM-1 expression has been correlated with poor prognosis in PC and CC making it an attractive therapeutic target. Methods: Using structure based drug design, we have identified novel, irreversible small molecule inhibitors of CRM-1 that lock target proteins, including TSP, in the nucleus. Normal cells undergo cell cycle arrest, but most cancer cells initiate apoptosis. Thus, the drugs selectively kill cancer cells with minimal toxicity to normal tissue and possess clinically acceptable pharmacokinetic parameters. In this report, using multiple molecular biological techniques, we have evaluated the role of CRM-1 inhibition on nuclear localization and apoptosis by PAR-4. Results: The most potent small molecule CRM-1 inhibitor (KPT-185) induced growth inhibition and apoptosis in a panel of PC and CC cell lines with IC 50 ’s &lt;150 nM. Western blot and confocal microscopy analyses demonstrated that KPT-185 treatment resulted in TSP and PAR-4 nuclear localization (a pre-requisite for PAR-4 mediated apoptosis). Most significantly, siRNA knockdown of PAR-4 abrogated the apoptotic potential of KPT-185 in BxPC-3 and Colo-357 (PC) and HCT-116 and HT-29 (CC) cell lines, confirming that this was indeed a PAR-4 dependent apoptotic mechanism. KPT-185 showed synergistically enhanced apoptosis when combined with oxaliplatin in all the tested cell lines. Human genomic expression microarray profiling using HT-12 arrays are underway. Additionally, animal xenograft studies involving single agent KPT-185 and combination with oxaliplatin are currently ongoing. Conclusions: This is the first report demonstrating CRM-1 as a potential therapeutic target in both PC and CC, perhaps by enhancing PAR-4 function. The drugs KPT-185 and related CRM1-inhibitors warrant further clinical investigations for this deadly malignancy.