tbuckley/cabot-search huggingface dataset:
Comprehensive genomic profiling (CGP) of advanced nonseminomatous testicular germ cell tumors (NSGCT) to reveal clinically relevant genomic alterations (CRGA) to guide targeted therapy.
Authors: Julia Andrea Elvin, Christina Patterson, Zachary Rockow Chalmers, Siraj Mahamed Ali, Timothy Brennan, Juliann Chmielecki, Phil Stephens, L. Eamonn Boyle, Jeffrey S. Ross, Vincent A. Miller
Journal: Journal of Clinical Oncology (2016)

477 Background: NSGCT, the most common solid malignancy in U.S. men ages 18-35, has a &gt; 95% 5-year survival due to exquisite chemosensitivity; however, chemoresistant recurrences still contribute to 400 NSGCT deaths/year. We queried CGP results of the largest collection to date of recurrent NSGCT (n = 28) to identify targeted therapy options for this subset of high risk patients. Methods: DNA was extracted from 28 FFPE NSGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 20) or 305 (FoundationOne, n = 8) genes, plus select introns frequently rearranged in cancer were sequenced to high ( &gt; 605x), uniform coverage. All classes of genomic alterations (GA; base subs, in/dels, rearrangements, and copy number alterations) were evaluated. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. CGP coverage data was used to assess for chromosome 12p arm amplifications. Results: 28 samples (29% primary, 71% metastasis) from patients (avg 33.7 y) with recurrent NSGCT of predominant pattern of yolk sac tumor (43%), embryonal carcinoma (18%), choriocarcinoma (18%), or unspecified/mixed (21%) were profiled. 57% of NSGCT had chromosome 12p amplification ( &gt; 6 copies). 89% had at least one GA not localized to chromosome 12p, including CRGA of CRKL (11%), MCL1 (11%), MDM2 (11%), GNAS (11%), KRAS (SV 7%), AURKA (7%), KIT (7%). CRGA in each of: AKT1, AKT2, BRAF, ERBB2, NF1, PIK3R2, PDGFRA, STK11 were identified in a single case. To date, we are aware of one patient in whom treatment with everolimus was initiated on the basis of the CGP results (inactivating point mutations in STK11 and PIK3R2) and who experienced marker stabilization lasting 5 months suggesting a biologic effect of this therapy. Conclusions: GA not accounted for by 12p amplification are present at a higher frequency than previously reported in recurrent or treatment-resistant NSGCT. The prevalence of CRGA and clinical response to targeted therapy in one such patient support the utility of CGP to identify additional therapeutic options for high risk NSGCT and warrants additional study.
Meta-analysis of anti-VEGF class adverse events from three double-blind (db), placebo (pbo)-controlled phase III trials with IV aflibercept (Afl).
Authors: Josep Tabernero, Carmen Joseph Allegra, Philippe R Rougier, Giorgio Scagliotti, Philip Agop Philip, Radek Lakomy, Rodryg Ramlau, Sylvie Assadourian, Soazig Chevalier, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2012)

3579 Background: Three db, pbo-controlled studies were conducted with IV Afl in metastatic cancer patients (pts) (colorectal [CRC], Afl + FOLFIRI [WCGC 2011, abstract O-0024]; lung [LC], Afl + docetaxel [WCLC 2011, abstract 511]; and pancreatic [PC], Afl + gemcitabine [WCGC 2009 abstract O-0006]). Each study used the same weekly Afl dose intensity (4 mg/kg q2w for CRC and PC; 6 mg/kg q3w for LC). A safety meta-analysis of anti-VEGF class adverse events (AEs) was performed on data from these studies. Methods: A fixed-effect logistic regression model was used, including study, treatment, and study-by-treatment interaction factors as covariates to test the consistency of treatment effect across studies for each of the considered AE. When no evidence of heterogeneity of treatment effects was found across studies, relative risks (RRs) and 95% confidence intervals (CIs) were estimated. Summary incidences (% of pts) and RR are presented for NCI grade 3-4 events. Results: Safety data from a total of 2662 pts (Afl, 1333; pbo, 1329) were included for analysis. Among pts treated with Afl, 0.4 and 0.5% experienced grade 4 hypertension and nephrotic syndrome, respectively. Conclusions: The addition of Afl to concurrent chemotherapies did not increase the risk of VTE. The risk of grade 3-4 anti-VEGF class AEs was increased when adding Afl to concurrent chemotherapies. This increased risk was statistically significant only for hypertension, proteinuria, and hemorrhage. Further analyses, when more data are available, should improve the precision of these results. [Table: see text]
Clinical outcome of patients with metastasic melanoma undergoing phase I clinical trials.
Authors: M. Blanco-Codesido, A. Brunetto, S. Frentzas, V. Moreno Garcia, D. Papadatos-Pastos, J. V. Pedersen, L. Trani, M. Puglisi, D. Sarker, L. R. Molife, U. Banerji
Journal: Journal of Clinical Oncology (2011)

8564 Background: Dacarbazine (DTIC) and interferon (IFN) are two agents currently used in the treatment of malignant melanoma (MM). They have modest response rates (RR) and marginal improvement in time to progression (TTP) or survival. The recently published results of targeted agents such as ipilimumab and PLX4032 are encouraging, and will one day replace these agents as front line treatment. We hypothesize that clinical outcomes of patients (pts) with MM treated with targeted therapies on phase I clinical trials are equivalent to those seen with agents such as DTIC or IFN. Methods: We analyzed the outcomes of 65 patients with MM that had undergone treatment in our phase I clinical trials unit between 2005-2010. All pts had received at least one previous line of systemic treatment and acted as theis own controls. RR and TTP on previous treatment was compared to RR and TTP on the phase I trial. Differences were studied by a Chi-squared test and the log-rank test respectively. A Cox analysis was performed to identify clinical variables that could influence TTP. Results: 27 females and 38 males were included. Mean age was 56 years. Performance status (PS) was 0 in 26 pts,1 in 35 pts and 2 in 4 cases. First line of treatment included DTIC or temozolamide in 58 pts, IFN in 5 pts and cisplatin based treatment in 2 pts. 25 pts had received previous treatment on a Phase II/III trial and data regarding best response to previous treatment was not available in 3 pts. There was no statistical significant difference in RR between to the first line treatment with chemotherapy or cytokine therapy vs treatment with a targeted agent in phase I trial (7/65) 11% vs (9/65) 14%, p=0.87. In addition there was no difference in TTP on the first line treatment vs treatment with a targeted agent in phase I trial; 90 days (95% CI 65-120) vs 53 days (95% CI 42-79), p= 0.15. No clinical variable showed influence on TTP. Conclusions: This data emphasize the lack of superiority of DTIC and IFN based regimes over targeted experimental agents for the treatment of MM. In event of progression to treatment with targeted agents as ipilimumab or PLX4032, patients should be considered for clinical trials with investigational agents rather than receiving chemotherapy or cytokine therapy.
Tubal anastomosis after previous sterilization: a systematic review
Authors: Jacoba A.H. van Seeters, Su Jen Chua, Ben W.J. Mol, Carolien A.M. Koks
Journal: Human Reproduction Update (2017)

Female sterilization is one of the most common contraceptive methods. A small number of women, however, opt for reversal of sterilization procedures after they experience regret. Procedures can be performed by laparotomy or laparoscopy, with or without robotic assistance. Another commonly utilized alternative is IVF. The choice between surgery and IVF is often influenced by reimbursement politics for that particular geographic location. We evaluated the fertility outcomes of different surgical methods available for the reversal of female sterilization, compared these to IVF and assessed the prognostic factors for success. Two search strategies were employed. Firstly, we searched for randomized and non-randomized clinical studies presenting fertility outcomes of sterilization reversal up to July 2016. Data on the following outcomes were collected: pregnancy rate, ectopic pregnancy rate, cost of the procedure and operative time. Eligible study designs included prospective or retrospective studies, randomized controlled trials, cohort studies, case–control studies and case series. No age restriction was applied. Exclusion criteria were patients suffering from tubal infertility from any other reason (e.g. infection, endometriosis and adhesions from previous surgery) and studies including <10 participants. The following factors likely to influence the success of sterilization reversal procedures were then evaluated: female age, BMI and duration and method of sterilization. Secondly, we searched for randomized and non-randomized clinical studies that compared reversal of sterilization to IVF and evaluated them for pregnancy outcomes and cost effectiveness. We included 37 studies that investigated a total of 10 689 women. No randomized controlled trials were found. Most studies were retrospective cohort studies of a moderate quality. The pooled pregnancy rate after sterilization reversal was 42–69%, with heterogeneity seen from the different methods utilized. The reported ectopic pregnancy rate was 4–8%. The only prognostic factor affecting the chance of conception was female age. The surgical approach (i.e. laparotomy [microscopic], laparoscopy or robotic) had no impact on the outcome, with the exception of the macroscopic laparotomic technique, which had inferior results and is not currently utilized. For older women, IVF could be a more cost-effective alternative for the reversal of sterilization. However, direct comparative data are lacking and a cut-off age cannot be stated. In sterilized women who suffer regret, surgical tubal re-anastomosis is an effective treatment, especially in younger women. However, there is a need for randomized controlled trials comparing the success rates and costs of surgical reversal with IVF.
Precision medicine program for whole-exome sequencing (WES) provides new insight on platinum sensitivity in advanced prostate cancer (PCa).
Authors: Himisha Beltran, Andrea Sboner, Juan Miguel Mosquera, David Rickman, Kenneth Eng, Davide Prandi, Myriam Kossai, Bishoy Faltas, Chantal Pauli, Jacqueline Fontugne, Colin Collins, Martin Gleave, Yuzhuo Wang, Brian D. Robinson, Alessandro Romanel, David M. Nanus, Scott T. Tagawa, Francesca Demichelis, Olivier Elemento, Mark A. Rubin
Journal: Journal of Clinical Oncology (2015)

158 Background: WES has provided insight into the genomic landscape of PCa. The next step for precision medicine requires prospective patient (pt) follow-up and clinical and functional validation of both common and low frequency mutations. We describe a precision medicine WES program and illustrate how this can be used to identify novel biomarkers associated with response. Methods: Metastatic PCa pts were prospectively enrolled. WES of metastatic biopsies or rapid autopsies and normal DNA were sequenced by Illumina HiSeq 2500. Results: Tumor-normal pairs from 71 pts with metastatic PCa (11 hormone naïve, 38 CRPC, 23 NEPC) were sequenced including 3 rapid autopsies, with a biopsy success rate of &gt;95%, avg tumor purity 10-95%, avg coverage 85X. The spectrum of mutations across metastatic PCa and how serial biopsies and rapid autopsies were used to assess heterogeneity and clonal evolution will be presented. WES from a metastatic PCa pt (PM12) with exceptional response to platinum with complete remission of liver and lung metastases at 2 years follow-up, demonstrated a hypermutated genotype and hemizygous deletion of the DNA repair gene FANCA in both his primary and metastatic PCa. A loss of function germline variant was detected within the second allele, and only the mutated allele was expressed in his tumor. Genome editing of FANCA using CRISPR in PCa cell lines resulted in cisplatin hypersensitivity and a significant decrease in FANC complex formation. In patient derived xenograft (PDX) models, PM12’s PDX was significantly more sensitive to cisplatin compared to a control Pca PDX of similar morphology but lacking FANCA deletion. By screening larger cohorts, FANCA loss was detected by FISH in 16% of localized PCa (n= 69), 14% metastatic Pca (n= 29), and not detected in any benign prostate (n=69). Conclusions: Our study provides a proof of principle for developing a precision medicine approach to cancer care with the capability to identify potential biomarkers of response. Our findings suggest that a subset of PCa with FANCA loss may be particularly vulnerable to cytotoxic therapy and provides biologic rationale to help explain the exceptional response of pt PM12 to platinum chemotherapy.
Genome-wide single nucleotide polymorphism (SNP) arrays as a novel diagnostic tool in synchronous carcinomas.
Authors: Y. Ikeda, K. Oda, S. Nakagawa, S. Murayama-Hosokawa, K. Shoji, S. Yamamoto, S. Ishikawa, Y. Uehara, Y. Miyamoto, M. Tanikawa, T. Kashiyama, Y. Takazawa, D. Maeda, O. Hiraike-Wada, K. Miyagawa, F. McCormick, M. Fukayama, H. Aburatani, T. Yano, Y. Taketani
Journal: Journal of Clinical Oncology (2011)

5105 Background: Synchronous cancers involving ovaries as well as uterine corpus are well-known events in gynecologic malignancies. These tumors may be independently derived, non-metastatic tumors (dual primary tumors; DP) or a tumor from one organ with metastasis to the other (single primary tumor with Metastasis; SPM). In the majority of these synchronous cancers, both tumors are histologically endometrioid adenocarcinomas, which may cause a diagnostic difficulty to distinguish DP and SPM. By genome-wide single nucleotide polymorphism (SNP) arrays, we can obtain chromosomal copy number alterations (CNA) throughout the genome in a single assay. We hypothesized the CNA by SNP arrays might be highly informative for genetic diagnosis in the synchronous endometrioid adenocarcinomas. Methods: We genetically diagnosed ten tumors from five patients with synchronous endometrial and ovarian carcinomas, using 250K SNP typing arrays and mutational analysis of PIK3CA, PTEN, K-Ras and CTNNB1under informed consent and institutional reveiw board approval. We evaluated whether conventional pathological diagnosis is compatible with the genetic diagnosis. Results: Three of the five patients show identical CNA, including type, loci and degree of each alteration, between the endometrial and the ovarian carcinomas. The other two show CNA only in either endometrial or ovarian carcinoma. All the five tumors possess one or more genetic mutations in the genes examined. One patient showed mutations both in PIK3CA and PTEN at discordant sites between endometrial and ovarian carcinomas, whereas the other four showed concordant mutations. Together, four of the five were genetically diagnosed as SPM and the remaining one was as DP. The pathological diagnosis was not in agreement with the molecular diagnosis in four of the five cases. Conclusions: Our data suggest that most of the copy number alterations might occur before metastases and that genome-wide genotyping may represent a useful approach to distinguish between SPM and DP in synchronous endometrial and and ovarian carcinomas. As chromosomal instability is commonly observed, SNP array genotyping might be applicable to synchronous tumors in other organs.
Impact of relative dose intensity on the outcome of metastatic colorectal cancer.
Authors: Goro Nakayama, Takahiro Asada, Naomi Hayashi, Chie Tanaka, Suguru Yamada, Tsutomu Fujii, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2013)

508 Background: Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. There is established evidence supporting the significance of RDI in patients with various cancer, however data in patients with metastatic colorectal cancer (mCRC) are limited. In this study, we evaluate the significance of RDI of irinotecan and oxaliplatin-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into two prospective clinical trials, testing FOLFIRI (CCOG-0502) and mFOLFOX6 (CCOG-0704), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Results: The median RDI of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80% and 79%. ORRs In higher RDI (&gt;median) group and lower RDI (&lt;median) group were 64.7% and 5.9% of irinotecan (p=0.001), and 46.7% and 33.3% of oxaliplatin (p=0.456). DCRs in higher and lower group were 100% and 41.2% in FOLFIRI (p=0.003), and 100 and 73.3% in mFOLFOX6 (p=0.032). PFS in higher and lower group were 9.9 and 5.6 months in FOLFIRI (p=0.002), and 8.5 and 6.2 months in mFOLFOX6 (p=0.064). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control in patients with mCRC, especially in irinotecan-based regimen. Dose reductions and treatment delays could be minimized to achieve an RDI of at least 80%.
Adjuvant treatment patterns and clinical outcomes in patients with curative resected ampulla of Vater cancer.
Authors: Hyerim Ha, Do-Youn Oh, Tae-Yong Kim, KyoungBun Lee, Kyubo Kim, Kyung-Hun Lee, Sae-Won Han, Eui Kyu Chie, Jin-Young Jang, Seock-Ah Im, Tae-You Kim, Sun-Whe Kim, Sung Whan Ha, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2015)

415 Background: Ampulla of Vater cancer (AoV ca) is rare tumor, and its adjuvant treatment after curative resection has not been well established. The purpose of this study is to see the clinical outcomes of curatively resected AoV ca patients and to figure out the role of adjuvant treatment. Methods: We reviewed 227 AoV ca patients who underwent curative resection at the Seoul National University Hospital between 1997 and 2012. Clinical factors, pathologic findings, adjuvant treatment pattern, disease-free survival (DFS) and overall survival (OS) were analyzed. Results: Median age was 61.5 year old (range, 33.8-88.2) and 125 patients were male. T1/T2 stage was found in 63.9% of patients and T3/4 stage was in 36.1%. Seventy-seven patients (33.9%) had node positive disease (N+) and seventy-three patients (32.1%) had well-differentiated histology. OS of all patients was 90.9 months (95% CI: 58.4-128.09). 5-Year OS- and DFS- rate were 58.2% and 62.5%, respectively. On multivariate analysis, adverse prognostic factors for OS included poorly differentiated histology (HR 1.35, 95% CI: 1.01-1.81, p=0.045), elevated CEA (HR 2.55, 95% CI: 1.29-5.04, p=0.007), elevated CA 19-9(HR 1.86, 95% CI: 1.08-3.21, p=0.027), and stage (HR 2.34, 95% CI: 1.43-3.82, p=0.001). A total of 104 patients (46.3%) received adjuvant treatment (concurrent chemoradiotherapy (CCRT) 32, CCRT with maintenance chemotherapy 58, chemotherapy alone 9, radiotherapy alone 5). Most of the chemotherapies were 5-FU-based ones. Among patients with T1/T2 &amp; N (-) (n=111), only 25 patients (22.5%) received adjuvant treatment. In contrast, among patients with T3/T4 or N (+) (n=116), 79 patients (68.1%) received adjuvant treatment. 5Y-OS rate was 74.1% in patients with T1/T2 and N (-) and that of patients with T3/T4 or N (+) was 43.0% (p&lt;0.001). In T1/T2 and N (-) stage, OS was not different according to adjuvant treatment. In T3/T4 or N (+) stage, adjuvant CCRT with maintenance chemotherapy conferred the longest OS, which was not statistically significant. (5Y-OSR: 47.0% vs 41.4% in no adjuvant treatment.) Conclusions: Adjuvant treatment should be further defined in AoV ca, especially in T3/T4 or N (+) stage.
Patient preferences for targeted agents in renal cell carcinoma (RCC): A benefit–risk conjoint study.
Authors: A. B. Hauber, A. F. Mohamed, F. R. Johnson, M. Neary
Journal: Journal of Clinical Oncology (2010)

4596 Background: Angiogenesis inhibitor agents have been shown to be effective in increasing progression-free survival (PFS) in patients (pts) with RCC; however, these treatments (trts) have different toxicity profiles. The extent to which pts may prefer one agent to another based on efficacy and toxicity is not known. Objectives: To quantify pts’ benefit-risk preferences for RCC trts and relative importance of attributes in a common metric. Methods: U.S. residents aged 18 years and over with RCC completed a web-enabled survey that presented a series of trt- choice questions, including a pair of hypothetical RCC medication profiles. Each profile was defined by efficacy [PFS, overall survival (OS)], tolerability effects [fatigue, diarrhea, hand-foot syndrome (HFS), mouth sores], serious adverse events (liver failure, blood clot). Each subject answered 12 choice trade-off questions based on predetermined experimental design with known statistical properties. The study was approved by RTI's institutional review board and subjects were required to provide informed consent by clicking on “Yes, I agree to participate.” Random-parameters logit was used to estimate relative preference weights for each attribute level, mean relative importance weights; and calculate risk tolerance for each adverse event for different improvements in efficacy outcomes. Results: 138 U.S. subjects completed the survey. Over the ranges of attribute levels included in the study, PFS was the most important attribute and was assigned an importance weight of 10. Relative to PFS, remaining attributes were ranked in order of importance. To increase PFS by 10 months, pts were willing to accept a maximum level of blood clot risk as high as 5.5% (95% CI: 3.6%-8.6%) and liver failure risk as high as 3.6% (95% CI: 2.6%-4.8%). Conclusions: Fatigue and diarrhea were rated, in order, as the most troublesome tolerability effects of RCC trt. Pts were willing to accept higher trt-related risks for blood clot and liver failure for greater efficacy benefit. Importance weight Attribute Mean 95% CI PFS 10.0 6.8-13.2 Fatigue 6.2 4.4-8.1 Diarrhea 5.3 3.8-6.8 Liver failure 5.2 3.7-6.7 HFS 4.7 3.1-6.3 Blood clot 3.4 2.2-4.6 Mouth sores 2.5 1.0-4.1 No significant financial relationships to disclose.