tbuckley/cabot-search huggingface dataset:
Preoperative (preop) radiotherapy (RT) ± 5 FU/folinic acid (FA) in T3–4 rectal cancers: results of the FFCD 9203 randomized trial
Authors: J.-P. Gerard, F. Bonnetain, T. Conroy, O. Chapet, O. Bouche, M.-T. Closon-Dejardin, M. Untereiner, B. Leduc, E. Francois, L. Bedenne
Journal: Journal of Clinical Oncology (2005)

3504 Background: The aim of this trial was to investigate a potential survival benefit of concurrent chemotherapy (CT) in a neoadjuvant schedule. Methods: Eligibility criteria were : adenocarcinoma of rectum accessible to digital examination, resectable (R0, R1) T3–4 Nx M0, < 75 years, written informed consent. Patients were randomized between RT alone (45 Gy/25 fractions/5 weeks) and RT with concurrent CT using bolus 5FU 350 mg/m2 and FA 20 mg/m2 IV days 1–5 on weeks 1 and 5. Stratification on: sex, T3/T4, low/middle rectum. Surgery was performed after a delay of 3–10 weeks. All patients had to receive 4 cycles adjuvant FU-FA cycles. Primary endpoint was 5 year overall survival (OS) and the trial was designed to test an increase in OS from 52% to 62% with RT-CT. (type 1 error: 5% and type 2 error: 20%). Results: Between 1993/2003 out of 762 included patients, 733 were eligible. Patients characteristics were well-balanced between arms: median age 63 years, T3/T4: 89%/11%. Median time to surgery 5.3 weeks. The 4 adjuvant FU-FA cycles were given to 73% of pts in both arms. Main results are given in Table below. Median follow up time: 69.3 months. Conclusions: Preop RT-CT does not increase 5 year overall survival nor sphincter preservation. No significant financial relationships to disclose.
Effect of dutasteride on tumor proliferation during the regrowth phase of intermittent androgen ablation therapy in men with advanced prostate cancer.
Authors: Daniel H. Shevrin, Gary R. MacVicar, Timothy Kuzel, Walter Michael Stadler, Borko Jovanovic, Karen Kaul, Zhou Wang
Journal: Journal of Clinical Oncology (2013)

21 Background: We have previously shown in an animal model of IAAT that blocking testosterone (T) to DHT by a 5α-reductase inhibitor (5ARI) has a more significant effect on tumor growth in a "regressed" prostate, ie previously treated with AAT, than in an "intact" prostate. It was also observed that 5ARI significantly inhibited tumor proliferation, but only early in the regrowth phase. A randomized phase II trial was done in which dut or placebo was given during the regrowth phase and a prostate biopsy was done to measure tumor proliferation. Methods: Eligible patients (pts) had metastatic, castrate-sensitive prostate cancer and had an intact prostate (no previous surgery or XRT). Treatment consisted of AAT for 8 months. Responding pts were randomized to receive dut (0.5 mg daily) or placebo during the regrowth phase. When serum T normalized, pts underwent a research biopsy of the prostate and then were resumed on AAT. Responding pts were then crossed-over to receive dut or placebo during the second regrowth phase. When T normalized, a second research biopsy was done and the pts resumed AAT. PSA levels were measured monthly to determine PSA doubling time (PSADT). Tumor proliferation was measured by Ki-67 index. Statistical analysis was by students t-test. Results: 21 pts were enrolled onto the study. 16 pts were randomized to dut vs placebo and 11 pts underwent prostate biopsies. Dut resulted in significant inhibition of tumor proliferation as measured by Ki-67 index compared to placebo (3.65 ± 1.7 vs 8.5 ± 2.3, p=0.001). PSADT during the regrowth phase was similar between the 2 groups. Dut was well tolerated without significant toxicities. Conclusions: The clincial observation of an early inhibitory effect of 5ARI on tumor proliferation during regrowth of a regressed (treated) prostate is novel and was similar to that observed in our animal xenograft model of IAAT. This suggests that using a 5ARI during the regrowth phase of IAAT and using T normalization as the trigger for resumption of AAT may result in improved efficacy of this treatment. This study was supported in part by NIH Grant P50 CA90386 (Prostate SPORE). Clinical trial information: NCT00668642.
Cardiac Effects of Sulfonylurea-Related Hypoglycemia
Authors: Timothy L. Middleton, Jencia Wong, Lynda Molyneaux, Belinda A. Brooks, Dennis K. Yue, Stephen M. Twigg, Ted Wu
Journal: Diabetes Care (2017)

OBJECTIVE To determine the effect of sulfonylurea-related hypoglycemia on cardiac repolarization and ectopy in the setting of well-controlled type 2 diabetes. RESEARCH DESIGN AND METHODS Thirty subjects with sulfonylurea-treated type 2 diabetes underwent 48 h of concurrent continuous glucose monitoring and ambulatory electrocardiography. Ventricular repolarization (QTc) and QT dynamicity were analyzed during periods of hypoglycemia (&amp;lt;3.5 mmol/L for &amp;gt;20 min) and compared with periods of euglycemia and hyperglycemia combined. Cardiac ectopy rates during hypoglycemia were compared with ectopy rates when blood glucose was 4–10 mmol/L. RESULTS Mean HbA1c was 6.9% (52 mmol/mol). Hypoglycemia was detected in 9 of 30 subjects (30%); episodes were typically nocturnal (67%) and asymptomatic (73%). Hypoglycemia-associated QTc prolongation was seen in five of nine subjects with a large variation in individual response. Higher QT dynamicity, a poor prognostic factor in cardiac disease, was seen in subjects who experienced hypoglycemia compared with subjects who did not (0.193 vs. 0.159 for the nocturnal period; P = 0.01). This finding persisted after the hypoglycemic event. The rates of ventricular and supraventricular ectopy demonstrated a nonsignificant trend toward an increase during hypoglycemia (median rate ratio 1.58 and 1.33, respectively). Similar, nonsignificant results were observed in a separate insulin-treated cohort. CONCLUSIONS Hypoglycemia, often unrecognized, is a frequent finding in well-controlled sulfonylurea-treated type 2 diabetes. It is associated with the novel finding of increased QT dynamicity and QTc prolongation in some individuals. Our findings suggest sulfonylurea-related hypoglycemia can have detrimental cardiovascular sequelae. Similar effects are also seen in the setting of insulin therapy.
Fifteen-year experience of all patients (pts) with small bowel adenocarcinoma (SBA), treated in a specialized gastrointestinal (GI) oncology unit: Royal Marsden (RM) experience.
Authors: Khurum Hayat Khan, Clare Peckitt, Francesco Sclafani, Sachin Trivedi, Vikram Kumar Jain, Susannah Jane Stanway, David Cunningham, Ian Chau
Journal: Journal of Clinical Oncology (2014)

316 Background: Small bowel adenocarcinoma (SBA) is a rare tumour with poor prognosis. There is paucity of published literature due to rarity of disease; we conducted this retrospective study to determine the clinical course and outcome along with prognostic factors in both early and later stage SBA. Methods: Clinical characteristics and outcomes of all pts treated consecutively in the GI Unit RM, 1996-2011 were recorded. The study endpoints were relapse free survival (RFS), progression free survival (PFS), and overall survival (OS), in early stage pts (G1) and in pts with advanced disease (presentation or relapse with un-resectable disease=G2). In G2 response rate (RR) to chemotherapy was determined. In both groups association to baseline prognostic factors were sought by performing Cox regression univariate analysis (UVA). Results: Eighty four pts with SBA were treated 1996-2011. A total of 48 presented with early stage disease (G1). In G1 (58.3% males; mean age, 57 years), 44/48 pts underwent R0 resection; 21 received adjuvant chemotherapy. RFS, PFS and OS in this group were 29.6 [95% confidence interval (CI) 3.3-55.9], 31.1 (CI=8.0-54.3) and 42.9 (CI=0-94.9) months (m), with median follow up of 76.4 m. Poor histological differentiation (p=0.025), abnormal CEA at presentation (P=0.082), and lymphovascular invasion (p=0.003) were prognostic of OS. G2 comprised of 36 pts with un-resectable disease along with 23 from G1 who subsequently relapsed [G2 (n=59); 52.5% males; mean age, 59 years]; 54 pts with metastatic and 5 with locally advanced disease; 78% received first-line chemotherapy. Overall RR of pts who received chemotherapy was 50%. OS and PFS were 12.8 (CI =8.4-17.2) and 8.8 (CI=5.5-12.3) m respectively; 1-year survival was 60.9% vs. 27.3% (no chemotherapy) (p=0.042). Abnormal albumin (0.041), platelet count (p=0.007) and CEA (p=0.025) were prognostic of OS in the chemotherapy group; doublet (18/41) versus triplet (23/41) chemotherapy were not prognostic (p=0.185). Conclusions: Pts with SBA and metastatic disease may derive benefit from systemic chemotherapy; prospective clinical trials are required to evaluate this further.
VEGF-D expression and EGFR mutations in non-small-cell lung carcinoma
Authors: Z. Wang, Y. Wu, A. Guo, Z. Chen, J. Su, Y. Huang
Journal: Journal of Clinical Oncology (2008)

22149 Background: VEGF-D and EGFR are involved in pathogenesis of lung cancer. The expression of VEGF-D and somatic EGFR mutations are to be investigated. Methods: Sixty-nine primary non-small cell lung cancer and normal lung tissues adjacent to cancer were collected during operation. VEGF-D gene expression level was examined by semi-quantitative SYBR Green real-time RT-PCR with housekeeping gene ACTB as the endogenous control through the establishment of standard curves. For 55 of these patients, RT-PCR products of EGFR spanning exons 18 through 19 and KRAS spanning codons 12, 13, 59 and 61 were directly sequenced. Results: VEGF-D expression level in non-small-cell lung cancer was significantly lower than in normal control (nonparametric Mann-Whitney test, P=0.001), however, there was no difference of VEGF-D expression ratios in normal lung (42.0%) and lung cancer (53.6%). VEGF-D expression level kept no different between lung cancers with and without EGFR or KRAS gene mutation. Total EGFR mutations ratio was 43.6% (24/55), and the incidence of mutation in exons 18 through 21 showed significant difference (chi-squared test, P=0.001) with deletion mutation occurred most frequently in exon 19 and the second was L858R in exon 21. Somatic EGFR mutations occured more frequently in adenocarcinomas than in other types of histologies (Chi-squared test, P =0.001). KRAS gene mutation ratio was 12.7% (7/55). Inverse relationship between KRAS and EGFR mutations in the non-small-cell lung cancer was statistically significant (Fisher's exact test, P=0.015). Conclusions: VEGF-D plays a critical role in maintaining the structure and function of normal lung, however, the lack or decrease of VEGF-D expression is critical in tumorigenesis of non-small-cell lung cancer especially adenocarcinoma. EGFR and KRAS mutations have no impact VEGF-D expression in non-small cell lung cancer. No significant financial relationships to disclose.
Phase I/II study of dose-dense sequential chemotherapy in renal impaired patients (Pts) with transitional cell carcinoma (TCC) of the urothelium
Authors: M. D. Galsky, S. Mironov, J. Scattergood, D. Dobrzynski, N. Mitra, M. G. Boyle, D. F. Bajorin
Journal: Journal of Clinical Oncology (2005)

4529 Background: Cisplatin-based chemotherapy is standard for pts with TCC but up to 1/3 may be ineligible due to impaired renal function. We initiated a phase I/II study utilizing 4 drugs with activity in TCC and safety in renal impairment administered in a dose-dense sequential fashion. The phase I portion identified the optimal dose and schedule (Novick et al, Proc ASCO, 2000, #1423). Methods: Pts with TCC and impaired renal function [(calculated creatinine clearance (CrCl) 30–60 ml/min by Cockroft-Gault or solitary kidney)] were enrolled on two cohorts: (1) metastatic/unresectable (2) adjuvant (≥ pT3b or node + TCC of bladder or ≥pT3 or node + TCC of the renal pelvis/ureter). Treatment was administered as follows: doxorubicin (50 mg/m2) plus gemcitabine (2000 mg/m2) q2 weeks x 5 followed by paclitaxel (65 mg/m2) plus carboplatin (AUC 1.7) weekly x 12 (AG → TC). GCSF was administered between cycles of AG. Results: Thirty-eight pts have been enrolled, 24 unresectable/metastatic (M) and 14 adjuvant (A). Baseline renal impairment included solitary kidney = 15 pts, poor CrCl = 23 pts (median 48 ml/min; 33–59). Pts with risk group scores 1 or 2 comprised 54% of the M cohort (JCO 10:3173, 1999). In the M cohort, 16/24 (66%) completed all therapy and 20/24 (83%) completed ≥ 15/17 cycles. In the A cohort, 14/14 (100%) completed all therapy. There was one treatment related death (pneumonitis). Overall response rate in the M cohort is 12/24 (50%; 95% CI 31–69%) with 4/24 (17%; 95% CI 6–36%) complete responses. The 1 and 2-year survival probabilities are 60.7% (95% CI 43.5–84.6%) and 31.1% (95% CI 16.4–59.1%), respectively. In the A cohort, median survival has not been reached; at a median follow-up of 2.4 years, 8/14 patients are alive without evidence of disease. Conclusions: AG → TC is generally well tolerated in pts with TCC and renal impairment. Promising activity has been observed. Accrual continues to a target of 25 pts/cohort. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Eli Lilly
Relations of T-cell and B-cell area ratios and the number of natural killer cells (NK cells) in lymph nodes (LNs) to outcomes in patients with stage II colon cancer.
Authors: Kazutake Okada, Sotaro Sadahiro, Hiroshi Miyakita, Gota Saito, Akira Tanaka, Toshiyuki Suzuki, Shinobu Masuda
Journal: Journal of Clinical Oncology (2016)

618 Background: In stage II colon cancer, patients with many retrieved LNs have good outcomes. We previously reported that the longest diameter of retrieved LNs correlates with the number of LNs and can be used as a prognostic factor (Int J Colorectal Dis 2015). LNs can be divided into three main regions, cortex, paracortex, and medulla, and consist mainly of T cells, B cells, NK cells, and histiocytes. We studied the relations of the T-cell, B-cell area ratios, and the number of NK cells in longest-diameter LNs to the number of retrieved LNs and outcomes. Methods: The subjects were 320 patients with stage II colon cancer who underwent curative resection. One LN with the maximum long-axis diameter was selected, and was immunostained with CD3 as a T-cell marker, CD20 as a B-cell marker, and CD56 as an NK-cell marker. Positive area ratio was determined by image analysis. The number of CD56-positive cells were examined and the mean number per 0.093 mm 2 was calculated. The relations were evaluated with the use of Spearman’s rank correlation coefficient. The cut-off values were calculated by ROC curve analysis. Results: The number of LNs was 14.8 ± 10.4 (mean ± SD). The CD3-positive area ratio was 0.39 ± 0.08. The CD20-positive area ratio was 0.42 ± 0.10. The number of CD56-positive cells was 9.9 ± 10.1. The correlation coefficients for the number of LNs with CD3-positive area ratio, CD20-positive area ratio, and the number of CD56-positive cells were respectively -0.07 (p = 0.220), 0.05 (p = 0.360), and 0.33 (p &lt; 0.001). The number of LNs positively correlated with the number of CD56-positive cells. The median follow-up period was 118 months. Patients with a CD20-positive area ratio of 0.43 or greater (n = 160) had a significantly better survival (HR, 0.64; 95%CI, 0.44-0.92; p = 0.015). Patients with 3 or more CD56-positive cells (n = 276) had a significantly better survival (HR, 0.57; 95%CI, 0.37-0.93; p = 0.017). Conclusions: A high number of NK cells in longest-diameter LNs was associated with a higher number of retrieved LNs, a longer LN diameter, and better survival. NK cells in the longest LNs may reflect the host antitumor immune response in patients with Stage II colon cancer.
Chimeric antigen receptor (CAR<sup>+</sup>) modified T cells targeting prostate specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC).
Authors: Susan F. Slovin, Xiuyan Wang, Melanie Hullings, Gabrielle Arauz, Shirley Bartido, Jason Stuart Lewis, Heiko Schöder, Pat Zanzonico, Howard I. Scher, Isabelle Riviere
Journal: Journal of Clinical Oncology (2013)

TPS3115 Background: A phase I dose-escalating study to assess safety, dose and targeting efficiency of genetically modified autologous human T cells targeted to PSMA was initiated. Preclinical models demonstrated anti-tumor activity and accumulation, migration, and persistence of these cells to tumor. The autologous PSMA-targeted T cells utilizes the P28z second generation chimeric antigen receptor following iv cyclophosphamide (Cy). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, rendering T cells sensitive to ganciclovir for immediate T cell elimination. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize these T cells Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts were dosed from 10 7 to 3 x 10 7 CAR + T cells/kg.All 7 pts received 300mg/m 2 of Cy one day before infusion. Baseline and post treatment imaging included FDG, FDHT and 18 F-FIAU PET scans. Results: Three pts in cohort 1 received 1 x 10 7 CAR + T cells/kg safely. A fourth pt received the same dose with a modified vector with higher copy number. One pt had stable disease for &gt; 6 months; a second pt has stable scans for &gt; 20 months; the third and fourth patients progressed. Of 3 pts in cohort 2, one received 1.5 x 10 7 CAR + T cells/kg and 2 received 3 x 10 7 CAR + cell/kg. All 3 had intermittent fever spikes up to 39 o C associated with increased levels of IL-4, IL-8, IP-10, sIL-2ra and IL-6 suggesting T cell activation. CAR + cells persisted in the circulation for up to 2 weeks. Scans with 18 F-FIAU labeling suggests that imaging may be cell dose dependent. Conclusions: We have shown that pts can be safely treated with an ex vivo transduction, expansion and therapeutic protocol for the generation of PSMA targeted T cells. Cytokine production suggests in vivo activation and persistence of T cells in blood for up to 2 weeks. Ongoing imaging with 18 F may be suboptimal; a second cohort of pts will be studied with 124 I-FIAU. Clinical trial information: NCTO1140373.
Establishing achievable benchmarks for quality improvement in systemic therapy for early-stage breast cancer.
Authors: Melanie Powis, Alejandro Gonzalez, Rinku Sutradhar, Katherine Enright, Nathan Taback, Christopher M. Booth, Maureen E. Trudeau, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2016)

263 Background: Setting realistic targets for performance on quality indicators (QI) is a consistent challenge in quality improvement. The purpose of this study was to utilize administrative data to define achievable targets for QI in the early stage breast cancer (EBC) population in relation to systemic therapy (ST) delivery based on best performers. Methods: Deterministically linked administrative healthcare databases were used to identify EBC cases diagnosed 2006 – 2010 in Ontario, Canada. Panel of previously established QIs for systemic therapy was applied to patients who met eligibility criteria for the individual indicators. Institutions with less than 10 eligible patients for a specific indicator were excluded. An empiric benchmark was defined as the proportion of patients meeting the indicator from institutions accounting for the top decile of eligible patients. Results: We identified 28,303 EBC patients who received surgery of which 12,252 received adjuvant chemotherapy. Benchmark results are summarized in Table. Conclusions: Many institutions fell considerably below the benchmark. Further analysis of institution-level drivers of high quality care is required to help characterize high performing institutions. [Table: see text]
High Incidence of Radiation Induced Cavernous Hemangioma (RICH) in Long Term Survivors Who Underwent BMT with Radiation Therapy During Childhood or Adolescence.
Authors: Takashi Koike, Noriharu Yanagimachi, Hiromasa Yabe, Miharu Yabe, Tsuyoshi Morimoto, Takashi Shimizu, Hiroyuki Ishiguro, Hiromitsu Takakura, Kiyoshi Ando, Shunichi Kato
Journal: Blood (2009)
Differential expression of DNA repair machinery genes in normal bronchial tissue and non-small cell lung cancer (NSCLC)
Authors: G. Selvaggi, S. Saviozzi, P. Ceppi, M. Volante, M. Iacono, S. Novello, M. Longo, R. Calogero, M. Papotti, G. V. Scagliotti
Journal: Journal of Clinical Oncology (2008)

22017 Background: Genes involved in DNA repair and/or replication have been recently investigated as predictive markers of response to chemotherapy in NSCLC. However, few data on the expression of these genes in NSCLC tumor samples versus corresponding normal lung are currently available. Aim of this study was to evaluate differential mRNA levels of 22 DNA repair genes belonging to 5 different DNA repair pathways: direct (DR), base excision (BER), nucleotide excision (NER), double strand break (DSBR) and post-replicative (PRR) repair. In addition, 6 genes involved in DNA replication (REP) and 2 telomere maintenance (TM) genes were also investigated. Methods: Total RNA was extracted from fresh snap-frozen tumors and corresponding normal tissues from 50 consecutive chemo-naive resected NSCLC patients. Transcript levels were quantified by Real-Time PCR (TaqMan), fold changes were calculated with the 2-ΔΔCt method and statistical significance assessed by Wilcoxon's test. POLR2A and 18SrRNA were used as reference genes and normal specimens as calibrators. Results: A significant overexpression in 13 out of 22 (60%) DNA repair and in 7 out of 8 (88%) REP and TM genes was detected (all p<0.0001). Three out of 22 (14%) DNA repair genes were instead significantly down-expressed. Interestingly, among DNA repair pathway, DSB genes were those with the highest overexpression rate, and high transcript levels were significantly associated with tumor grade and male gender. BRCA1, BRCA2, XRCC3, XRCC5, uracil-DNA glycosilase, thymidylate synthase and topoisomerase DNA IIIß (TOPIIIß) genes were correlated with poor prognosis at univariate, while at multivariate analysis only TOPIIIß (p=0.02) and tumor grade (p=0.04) were retained as independent prognostic markers adjusting for major clinico-pathological parameters. Conclusion: This pivotal study shows that the overexpression of DNA repair genes in lung tumors are correlated with a more aggressive phenotype. Moreover, DNA repair genes (TOPIIIß especially) should be further investigated as candidate prognostic markers in NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, Eli Lilly, Janssen Cilag, Millennium, sanofi-aventis