tbuckley/cabot-search huggingface dataset:
Carboplatin (AUC 5) with oral vinorelbine (VNR) d 1,8 at 50 mg/m2 (level 1, L1) or 60 mg/m2 (level 2, L2) every 3 weeks: A phase I study
Authors: N. Patel, S. Moore, B. Norwood, R. Chang, J. Gatewood, M. Fink, M. Utate, M. Wendell, A. Downey, F. M. Muggia
Journal: Journal of Clinical Oncology (2005)

5114 Background & Objectives: We sought to develop a less toxic combination regimen for use in cervical cancer than cisplatin with paclitaxel. Carboplatin AUC 5 and VNR D1 (IV, 25 mg/m2) & D8 (PO, 60 mg/m2) have been previously studied in chemonaive non-small cell lung cancer (O’Brien et al, Ann Oncol 2004; 15: 921). Methods: Metastatic solid tumor cohort, 3+3 dose escalation design, with standard entry/evaluation criteria and separate escalation based on extent of prior treatment. Common Toxicity Criteria V.3 were applied. Results: L1 accrued 3 extensively pre-treated patients (= or > 3 myelosuppressive regimens and/or radiation): all progressed after 2 cycles with no Grade 3 or 4 toxicities, one Grade 2 neutropenia. At L2, 6 extensively pretreated were evaluable, 1 minimally pre-treated was inevaluable due to withdrawal of consent after C1,d1. Myelosuppression was the prominent toxicity after 2, 2+, 2+, 2+, 3, 8 + cycles. Table 1 shows all hematologic toxicities at L2 dosing level of the 6 evaluable patients. The patient with dose-limiting thrombocytopenia had similar episodes on prior chemotherapy. Responses: 3 patients had stable disease with subjective or marker improvement: breast cancer (1), endometrial cancer (1), and granulosa cell tumor (1). One prostate cancer patient received 8+ cycles, with slowly rising PSA. Conclusions: L2 is the recommended phase II dose and may be suitable for Phase II study in cervical cancer, with potential advantages over IV vinorelbine (absence of phlebitis, decreased tumor pain). No significant financial relationships to disclose.
Integrated quantative and spatial proteomic analysis of PI3kinase signaling in high grade prostate cancer (PCa) treated with Temsirolimus with or without androgen ablation
Authors: E. Efstathiou, D. Tsavachidou, S. Wen, P. Troncoso, G. B. Mills, C. J. Logothetis
Journal: Journal of Clinical Oncology (2008)

5071 Background: Temsirolimus modulates the PI3kinase (PI3K) pathway in PCa models. An integrated proteomic strategy of reverse phase protein arrays (RPPA) and tissue microarrays (TMA) was applied to assess PI3K pathway, proliferation and apoptosis following Temsirolimus (T) in high risk PCa. Methods: Thirty-Five patients (pts) received oral T (20pts) or T+androgen ablation (T+AA) (15pts) for a median of 4 weeks followed by radical prostatectomy(RP). We constructed TMAs from RP specimens of: a) (T±AA) 33 pts treated with T (19pts) or T+AA (14pts) b)(Control) 42 untreated matched pts. 2320 cores were obtained [median cores: 18 (range 12–90), median blocks: 5 (range 3–9) per RPS]. Immunohistochemical expression of PI3K pathway, Ki67 and caspase 3 were assessed. Mixed model was used for fitting the correlated data. RPPAs were performed on protein lysates from tumor of 15 T±AA pts and 17 matched controls to compare expression of 25 proteins (PI3K, MAPK and cell cycle control signaling pathways). Cancer duplicates were harvested by UV/laser capture microdissection from a median of 4 sections per case. Unsupervised hierarchical clustering approaches were used for analysis. Separate controls were used for RPPA and TMA. Results: RPPAs segregate the samples in two clusters. Treated tumors had a distinct profile that was observed by both methodologies and included: a)Reduced levels of phospho-S6 in the treated group versus the control (p value <0.005) b) Increased phospho-mTOR [by both methodologies (p<0.005)] and phospho-AKT [by TMA (0.019)]. These were more evident in the T+AA arm (p: 0.0007 and 0.007 respectively). TMA data analysis indicate: a) extent of pS6 expression is lower in the T arm compared to T+AA b) T+AA had a higher rate of apoptosis compared to both T alone and control (p values 0.004 and 0.024 respectively). We noted a trend for lower Ki67 (p 0.07 by TMA ) and increased Caveolin and phospho-p38 in treated compared to controls (p<0.005 by RPPA). Conclusions: RPPA and TMA are complementary methodologies strengthening the validity of conclusions. Temsirolimus effectively blocks mTOR signaling in high grade PCa. Increase in upstream pathway components most noted with T+AA warrants study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Wyeth
心不全およびIVCD(心室内伝導障害)を有する高齢患者におけるCRT(心臓再同期療法)の長期予後
Authors: Ogura Yasuhiro, Kanemura Noriyoshi, Matsumoto Masaya, Yamamoto Takashi, Hashimoto Tousei, Ishikawa Kiyotake, Aoyama Yutaka, Suzuki Hirohiko, Inoue Natsuo, Tatematsu Yasushi, Nanasato Mamoru, Yoshida Yukihiko, Miwata Satoru, Hirayama Haruo, Tsuboi Naoya, Itoh Teruo, Inden Yasuya, Murohara Toyoaki, Hirai Makoto
Journal: Circulation (2008)
Neonatal Cyanosis Due to a Novel Fetal M-Hemoglobin: Hemoglobin F-M Circleville (Gγ63 His→Leu).
Authors: Ferdane Kutlar, Richard Shell, Joan Atkin, Dedrey Elam, Leslie Holley, Deborah Davis, Jeanette Harbin, Abdullah Kutlar
Journal: Blood (2005)
Phase I/II study of BNC105P in combination with everolimus or following everolimus for progressive metastatic renal cell carcinoma following prior tyrosine kinase inhibitors.
Authors: T. E. Hutson, J. Sarantopoulos, T. Logan, G. Sonpavde, M. D. Galsky, C. Sweeney, D. C. Bibby, G. Kremmidiotis, E. E. Doolin, N. M. Hahn
Journal: Journal of Clinical Oncology (2011)

TPS194 Background: Treatment options remain limited in progressive metastatic renal cell carcinoma (mRCC) for patients who are refractory to tyrosine kinase inhibitors (TKI). Treatment with everolimus following previous sunitinib and/or sorafenib has been associated with a significant improvement in PFS compared with placebo (4.9 vs 1.9 months; Kay et al. ASCO Abs No. 278, 2009). A potential enhancement in efficacy may result from the combination of this mTOR-targeting agent and a Vascular Disruption Agent (VDA). VDAs act to damage tumor endothelial cells leading to an occlusion of blood flow and subsequent necrosis. BNC105P is a VDA that destabilizes tubulin polymers leading to selective damage of tumor endothelial cells and a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a ‘survival’ response by the tumor to hypoxic insult. It follows that the combined use of this VDA with an agent active against mTOR may improve clinical outcome. Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs is ongoing. Using a classic 3 x 3 design, the phase I component of the study will investigate BNC105P at 4 dose levels (4.2, 8.4, 12.6 and 16 mg/m2; 10 minute IV infusion Days 1 and 8 of a 21 day repeating cycle) and everolimus at the approved dosage (10 mg p.o.). The randomized phase II component of the study will compare everolimus given in combination with BNC105P to everolimus alone. Additionally, patients progressing on everolimus alone will be offered BNC105P monotherapy (a sequential approach). The study is powered to detect an improvement in 6-month PFS from 36% (everolimus) to 60% (combination of everolimus + BNC105P). Secondary endpoints include response rate, PFS and overall survival. This study builds on our experience with everolimus in this population and our in vivo preclinical data.
CA19-9 for the prediction of efficacy of chemotherapy in patients with advanced pancreas cancer: A pooled analysis of six prospective trials.
Authors: T. M. Bauer, T. S. Bekaii-Saab, X. Li, M. A. Villalona-Calero, P. A. Philip, A. F. Shields, M. M. Zalupski, N. Hammad, B. F. El-Rayes
Journal: Journal of Clinical Oncology (2011)

4071 Background: Carbohydrate antigen 19-9 (CA19-9) is a widely-used serum tumor marker in pancreas cancer. Multiple studies suggest a role for CA19-9 in predicting outcome. A decline of at least 25% from baseline while on treatment is predictive of improved survival. Methods: Individual patient data from six prospective trials evaluating gemcitabine-containing regimens from two institutions were pooled. The primary goal of this study was to correlate outcomes with decline in CA19-9 while on treatment. Results: A total of 213 patients with locally advanced (n=51) or metastatic (n=162) adenocarcinoma of the pancreas were included. Median age was 59 years (range: 28 – 90). Ninety-two percent of subjects had performance status of 0 or 1. Median baseline CA19-9 level was 1,113 ng/mL (range: 2 – 492,241). In a first analysis, groups were divided into those levels below (Low) or above (High) the median. Median overall survival (mOS) was 8.7 vs. 5.6 months (p=0.0056) and median time to progression (TTP) was 6.2 vs. 3.7 months (p=0.0043) in the low vs. high groups, respectively. We then confirmed that a decline on treatment of greater than or equal to 25% vs. less than 25% from baseline demonstrated a significant impact on outcome (mOS 10.2 vs. 5.2 months, p<0.0001; TTP 7.3 vs. 3.2 months, p<0.001). Interestingly we showed that any decline vs. no decline in CA19-9 levels conferred a similar likelihood of improved mOS (9.2 vs. 5.1 months, p=0.001) and TTP (7.2 vs. 2.8 months, p=0.0001) respectively. Finally, we showed that any decline vs. no decline of CA19-9 after only the first cycle of chemotherapy did not significantly affect outcome (mOS 9.2 vs. 6.6 months, P=0.3; TTP 6.7 vs. 4 months, p=0.2), whereas a persistent decline after the second cycle of therapy was predictive of improved outcome (mOS 10.3 vs. 5.2 months, p=0.0036; TTP 7.6 vs. 3.9 months, p=0.0091). Conclusions: In this study we demonstrated that any decline in CA19-9 levels during therapy is predictive of improved outcome. We also showed that decline of CA19-9 levels after 2 consecutive cycles of therapy resulted in improved outcome.
Cetuximab (Ce) + topotecan (Tc) + cisplatin (Cp) for the treatment (Tt) of advanced cervix cancer (ACC): A phase II GINECO trial
Authors: E. Kurtz, D. Besson, M. Deslandres, S. Lavau-Denes, R. Largillier, C. Roemer-Becuwe, B. Weber, P. Chinet-Charrot, D. Paraiso, E. Pujade-Lauraine
Journal: Journal of Clinical Oncology (2008)

5512 Background: Cp plus Tc has become standard chemotherapy (Cx) for ACC. Combining Cp and Tc with an EGF-R inhibitor such as Ce may increase the activity of Cx. Methods: Treatment consisted of 3-weekly cycles of Cp (50mg/m², day 1) and Tc (0.75 mg/m², day 1–3) combined with Ce (400 mg/m², I.V., day 1 of 1st cycle followed by 250 mg/m², weekly). Patients (pts) with advanced recurrent or persistent disease, squamous cell or adenocarcinoma histology, measurable lesion, performance status (PS) ECOG 0–2 and adequate major organ function including creatinine clearance > 50 mL/mn were eligible. Results: Between April 12 and July 25, 2007, 19 out of the 44 planned pts were accrued before the study was stopped early due to excessive toxicity. Median age was 49 yrs, 16% of pts had PS 2, 68% had squamous cell carcinoma, 79% had relapsing disease, and 56% had received previous combined radiotherapy and platinum-based Cx. Initial ACC stage I (n=4), IIIA (n=1), IIIB (n=6), IVA (n=2), IVB (n=5), and unknown (n=1). Pts received a median of 3 cycles (range 1–6) with G-CSF support in 55% of cases. Myelotoxicities were grade 4 neutropenia (53%), grade 4 thrombocytopenia (53%), and grade 3–4 anemia (16%). Main non-hematologic toxicities were renal (grade 2–3, 6 pts, 1 death), pulmonary embolism (grade 5, 1pt) and infections (grade 3–5, 15 events in 10 pts, 3 deaths). Infection events were febrile neutropenia (n=7), infection with or without neutropenia (n=3 and n=5 respectively). Urinary probe, venous catheter, and intestinal obstruction were the main sources of infection. Most severe toxicities occurred during cycle 1 (47%) or 2 (18%). Conclusions: Certain pt characteristics such as poor PS, underlying renal insufficiency or dilatation, previous treatment by Cp and/or pelvic RT may have contributed to the serious adverse and/or fatal events which were observed during treatment with Cp+Tc+Ce. A possible pharmacokinetic and/or pharmacodynamic interaction between study drugs cannot be excluded as phase I data in this area is not available. Precise inclusion criteria on renal function and a systematic G-CSF treatment would need to be determined before a further phase I-II trial combining either Cp-Tc-Ce or Carboplatin-Tc-Ce is undertaken. No significant financial relationships to disclose.
Inactivation of <i>BRCA2</i> cooperates with <i>Trp53</i><sup>R172H</sup> to induce invasive pancreatic ductal adenocarcinomas in mice: A mouse model of familial pancreatic cancer.
Authors: G. Feldmann, C. Karikari, M. dal Molin, S. Duringer, P. Volkmann, D. K. Bartsch, S. Bisht, J. Koorstra, P. Brossart, A. Maitra, V. Fendrich
Journal: Journal of Clinical Oncology (2011)

4128 Background: Inactivating germline mutations in BRCA2 represent the most common known genetic basis for familial pancreatic cancer (FPC), accounting for approximately 5-10% of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of BRCA2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Methods: Both BRCA2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; BRCA2f/f ("CB") mice; in addition, triple transgenic Pdx1-Cre; BRCA2f/f; LSL-Trp53R172H ("CBP") mice were generated, in order to determine the impact of p53 deregulation on BRCA2-deficient carcinogenesis. Results: Both "CB" and "CBP" mice developed non-invasive ductal precursor lesions (murine pancreatic intraepithelial neoplasia or mPanIN), although these were observed at an earlier time point (5 versus 8 months) and with higher prevalence in "CBP" mice. A minority of "CB" mice (15%) developed invasive and metastatic PDAC at a latency of 15 months or greater; in contrast, "CBP" mice of comparable age uniformly developed PDAC with variable histological features. Mortality in the absence of neoplasia in "CB" and "CBP" mice was associated with profound loss of pancreatic parenchyma, consistent with progressive elimination of BRCA2-deficient cells. Widespread DNA damage, as evidenced by overexpression of the phosphorylated histone H2AXSer139, was observed in the non-neoplastic exocrine pancreas, as well as in the mPanIN and PDAC lesions of BRCA2-deficient mice, independent of p53 status. Conclusions: Loss of BRCA2 function predisposes the exocrine pancreas to profound DNA damage and is sufficient to induce mPanIN precursor lesions as well as fully invasive cancers in a subset of cases. The frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53.
De-adoption of epidermal growth factor receptor (EGFR) inhibitors following recommendations for KRAS testing to guide treatment of metastatic colorectal cancer (mCRC).
Authors: Efrat Dotan, Tianyu Li, Michael J. Hall, Neal J. Meropol, Robert J Beck, Yu-Ning Wong
Journal: Journal of Clinical Oncology (2012)

e14021 Background: KRAS mutation status is a predictive biomarker for resistance to EGFR antibodies among mCRC pts, and is recommended for use by ASCO and the FDA. Little is known about the uptake of clinical recommendations in oncology practice. We sought to study the effect of ASCO and FDA guidelines on the use of EGFR antibodies among a commercially insured population. Methods: The LifeLink Health Plan Claims Database (formerly the PharMetrics Patient-Centric Database) was used to create a cohort of &gt;18 yo mCRC pts treated between 2004-2010. We identified treatment and diagnosis using ICD-9 or HCPCS (J) codes. We defined 1st line therapy as any chemotherapy +/- bevacizumab given after the pt had a claim for mCRC, excluding pts treated with EGFR antibodies in the 1 st line. 2 nd line therapy was defined as the initiation of a new chemotherapy agent (irinotecan/oxaliplatin) +/- EGFR antibody. We examined pts in two-month time intervals and calculated the fraction of pts in each interval who received EGFR antibody at any point beyond their 1 st line treatment. Chi 2 tests were used to compare treatment rates at the time points shown in the Table. Results: 5099 pts received 2 nd line therapy of which 2603 pts received an EGFR antibody. Median age was 61 years, with 57% males. 59% received an EGFR antibody as a single agent. The remainder received this in combination with one or more of the following agents: fluorouracil 13.5%, irinotecan 36.7%, oxaliplatin 3.9%, and bevacizumab 6.1%. Rates of EGFR antibody use are outlined in the Table. Conclusions: The utilization of EGFR antibodies for mCRC treatment decreased following the presentation of clinical trial data, publication of ASCO guidelines and FDA label change. These data suggest that oncologists respond rapidly to new evidence and professional guidelines, and readily accept the use of predictive biomarkers in clinical practice. [Table: see text]
Feasibility of intensity-modulated radiation therapy (IMRT) with PET-defined simultaneous integrated boost (SIB) for distal rectal adenocarcinoma (DRA).
Authors: V. Valakh, A. V. Kirichenko, J. Betler, B. Leicher, E. D. Werts, D. Medich, D. S. Parda
Journal: Journal of Clinical Oncology (2011)

550 Background: PET/CT guided preoperative IMRT is being used with increasing frequency in standard practice but reports of methods, efficacy, and toxicity are limited. We report the AGH experience from 2007-2010 of IMRT with SIB for DRA. Methods: 22 pts with stage IB–IV DRA (8 with anal canal involvement) were treated with preoperative concurrent IMRT with SIB, 5FU-based chemotherapy. 15 received weekly oxaliplatin. All had PET/CT simulation. The planned target volume included PET-avid primary tumor and LNs with median margins of 3mm (range, 0–13), in a median of 24 fx (range, 20–28), a median dose of 2.25 Gy/fx (range, 1.9–2.4 Gy) to a median total dose of 53.3 Gy (range, 50.6–57.2 Gy). Clinical target volume included non PET-avid 1st echelon LNs with a median dose of 2.0 Gy/fx (range, 1.6–2.3 Gy) to a total median dose of 47 Gy (range, 40.7–54.04 Gy). Median follow-up was 18 mos (range, 4–35). Late toxicities were scored using CTCAE v. 3.0. Results: 17 of 22 patients (TNM stages IB (3), IIA (3), IIB (1), IIIA (2), IIIB (7), IV (1)) were treated curatively. The remaining 5 pts were treated palliatively. The median length of time from completion of radiation to surgery was 81 days (range, 48–398). 5 pts did not have surgery due to advanced metastatic disease (3), death (1) or biopsy proven complete response (CR) (1). R0 resection was accomplished in 15 of 17 surgical pts including 13/14 curative and 2/3 palliative cases. R1 resection occurred in 2 pts; 1 with stage IIIB and 1 with stage IV. No pts had R2 resection. 6 pts (5 with T2 lesions and 1 with a T4 lesion) had a pathologic CR. 2 of 3 non-surgical pts with metastatic disease had LRF at 5 and 11 mos. 9/22 pts had no late toxicity, 9/22 ≤ grade 2 and 4/22 had grade 3 late toxicity. No patients with T2 tumors had grade 3 late toxicity, and this appeared to be related to lower GTV. Kaplan-Meier freedom from grade 3late toxicity was 85% at 18 mos. Conclusions: IMRT with SIB is an accurate targeting technique in pts with DRA that showed a pathologic CR in 100% of T2 lesions. Advanced T stage and larger GTV were possible risk factors for grade 3 late toxicity. [Table: see text] No significant financial relationships to disclose.
9q32-q33.1 amplification as a prognostic factor for overall survival in metastatic germ cell tumors.
Authors: J. M. Piulats, A. Vidal, M. Nadal, A. Pisa, J. R. Germa-Lluch, E. Condom, A. Villanueva, X. Garcia del Muro
Journal: Journal of Clinical Oncology (2011)

4652 Background: Germ cell tumors (GCTs) are the most common malignancy in young men. Recently, our group has reported the development of human nonseminoma (NSE) after orthotopic nude mice implantation and demonstrated acquisition of specific chromosomal imbalances after becoming cisplatin (CDDP) resistant in vivo (Piulats et al, ASCO 2009; abstr e16143). Gain of 9q32-q33.1 was present in 3 of 4 tumors explored and contains genes that could be related to CDDP resistance. Methods: To gain insight into the clinical relevance of these results we next investigate the gains at 9q32-q33.1 by FISH analysis in a retrospective cohort of 75 male patients with metastatic CGTs treated at our hospital from August 1989 to November 2004. NSE represents 84% of the tumors analyzed and 32% were resistant to CDDP based chemotherapy. Four patients with extragonadal GCTs were included. Forty-four patients were considered good prognosis, 14 intermediate and 16 bad according to the IGCCCG prognostic classification. Results: 9q32-q33.1 amplification was identified in 18 out 75 (24%) cases. This amplification was present in 37.5% of resistant and 17.6% of sensitive cases (p=0.06). Overall survival (OS) analysis showed that amplification at 9q32-q33.1 is associated with an increased risk of death in patients with GCTs (HR=2.84; 95% CI 1.14-7.09; p=0.033). In the group of patients with NSE (n=63) the risk of death was increased (HR=3.03; 95% CI 1.18-7.76; p=0.026). The higher risk of death was identified among the group of patients with NSE and good/intermediate prognosis (HR=5.16; 95% CI 1.47-18.12; p=0.014), whereas risk was not modified in patients with bad prognosis disease. When progression-free survival was evaluated, the same pattern was found. Conclusions: We have identified amplification at 9q32-q33.1 as a prognostic factor for OS in metastatic NSE GCTs, being to date the only molecular prognostic marker in this disease.
Surgery for solitary pulmonary metastasis after curative gastrectomy for gastric cancer: Contribution to the long-term survival.
Authors: Shigeya Hayashi, Kenki Segami, Taiichi Kawabe, Toru Aoyama, Yousuke Makuuchi, Takanobu Yamada, Tsutomu Sato, Takashi Oshima, Yasushi Rino, Munetaka Masuda, Takashi Ogata, Haruhiko Cho, Takaki Yoshikawa
Journal: Journal of Clinical Oncology (2015)

102 Background: Surgical resection is rarely indicated for pulmonary recurrence after curative gastrectomy for gastric cancer because most tumors recurred as multiple nodules or carcinomatous lymphangitis / pleuritis and prognosis is extremely poor. However, some investigators reported a sporadic case developing a solitary pulmonary metastasis which was surgically resected and resulted in a relatively favorable clinical outcome. The present study aimed to clarify contribution of surgery for solitary pulmonary recurrence to the long-term survival. Methods: We performed a systematic review of the literature by searching the words of “stomach”, “neoplasms”, “lung”, and “metastasis” in the Pubmed and Japanese ICHUSHI database, and analyzed the cases reporting on resection of solitary pulmonary metastasis after curative gastrectomy for gastric cancer together with our cases treated at our hospital. Overall survival was estimated by Kaplan-Meier method. Results: A total of 45 patients, 42 from a systematic review and 3 from our cases, were examined. Median age (range) was 67 years (31–84 years). Primary gastric cancer had the following characteristics; histologically differentiated type in 30 patients, undifferentiated type in 2, and unknown in 13 patients and tumor depth of T1 in 3, T2 in 6, T3 in 13, T4 in 9, and unknown in 6. Surgery for the primary gastric cancer was total gastrectomy in 30 patients and distal one in 15. The median (range) disease-free survival (DFS) between initial gastric resection and the detection of pulmonary metastasis was 28.0 months (5-128 months). Surgery for pulmonary tumor was lobectomies in 20 patients, segmentectomies in 3, wedge resections in 18, and unknown in 4. Only 4 patients received adjuvant chemotherapy after pulmonary resection. The median (range) follow-up period after pulmonary surgery was 20 months (3-98 months). The overall survival after pulmonary resection was 86% at 1-year, 62% at 3-year, and 56% at 5-year with the median (range) survival time of 67 months (3-98 months). Conclusions: Surgery for solitary pulmonary recurrence could contribute to the long-term survival.