tbuckley/cabot-search huggingface dataset:
Semen quality in men with disseminated testicular cancer: β-HCG associated disturbance of hypothalamic-pituitary-gonadal axis
Authors: D. de Bruin, I. J. de Jong, E. G. J. Arts, J. Nuver, W. J. Sluiter, H. J. Hoekstra, D. T. Sleijfer, J. A. Gietema
Journal: Journal of Clinical Oncology (2005)

4577 Background: At time of diagnosis, 30–60% of men with testicular cancer (TC) have impaired spermatogenesis. One factor influencing fertility is the human chorionic gonadotropin β subunit (β-hCG) secreted by the testicular tumor. It is not known whether β-hCG influences spermatogenesis directly, or through Leydig cells or by disturbance of the hypothalamic-pituitary-gonadal axis. The objective of this study is to compare in a single-center referral hospital the hormonal status (HS) between TC patients (pts) with normal and increased levels of serum β-hCG. Methods: Between 1995–2003, 107 men with stage II-IV TC cryobanked semen before chemotherapy. Of 62 men (median age 25 yrs, range 17–49) the HS at time of cryopreservation was determined. Semen quality was expressed as total motile sperm count (VCM) (106): volume (ml) x concentration (106/ml) x percentage forward motility. Pts were divided into two groups: with normal (≤5 IU/l) or increased β-hCG (>5 IU/l) levels. VCM, testosterone (T), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) levels were compared between these groups. Results: Pts with increased levels of serum β-hCG (n=41) had a lower VCM (Table). Compared to pts with a normal β-hCG (n=21), T, E2 and PRL were significantly higher in pts with an increased β-hCG, whereas LH and FSH were significantly lower. VCM correlated negatively with E2 and PRL (respectively r= -0.38, p=0.003; r= -0.35, p=0.01). No correlation was found between VCM and T (r= -0.07, p=0.61).β-hCG was positively correlated with E2 (r=0.69, p=0.001), and negatively with FSH (r= -0.37, p=0.001). Conclusions: In pts with disseminated TC and an increased β-hCG at time of cryobanking, lower sperm count is associated with increased E2 and PRL. These data show that TC pts with a β-hCG producing tumor have a disturbance of the hypothalamic-pituitary-gonadal axis. This may contribute to impaired semen quality. No significant financial relationships to disclose.
Use of restaging primary site biopsy to optimize selection of primary therapy in high stage (III/IV) squamous cancer
Authors: H. J. Wanebo, R. Rathore, K. Radie-Keane, N. Ready, A. Nadeem, P. Nigri, P. Chougule
Journal: Journal of Clinical Oncology (2008)

6042 Background: A consecutive series of neoadjuvant protocols has focused on restaging re-biopsy to select therapy of Stage III/IV squamous cancer since 1995. Patients with positive restaging biopsy have subsequent resection whereas those having a negative re-biopsy have completion chemo- radiation therapy of primary site to total dose 68–72cGy. We are currently reporting the benefit of giving induction chemotherapy prior to chemoradiation. Methods: Initial protocols (H&N 53& 67) utilized concurrent preoperative Paclitaxel (P) (60mg/M² or 40mg/M2) + Carboplatin (AUC) + RT (45G) 67(64 evaluable pts). Subsequent studies (H&N79) utilized induction chemo (P 135mg/M², C (2AUC) weekly x 6 followed by chemoradiation therapy P 40 C (1AUC) + 45 Gy (H&N79) 32 pts (13 operable). Results: Protocols, 53 & 67 induced a complete pathologic response in 70% vs. a 52% clinically determined CR permitting completion radiation with primary site preservation. Neck dissection (ND) revealed persistent disease in 37% confirming need for ND in N1–3 disease. Induction therapy followed by chemo radiation therapy (H + N #79) induced path CR of 86%. Survival OS & DFS were equivalent in patients having Completion Radiation by chemo Radiation or Surgery (OS 44%/54%) (DFS 54%/54%). Factors associated with persistent cancer at the primary site were high T stage (T 3 & 4) present in 94% of patients requiring resection vs. 58% in patients having a path CR. Other risk factors were location-base of tongue, larynx and mandible involvement. Conclusion: Restaging biopsy after neoadjuvant chemo radiation is superior to clinical/radiologic assessment in demonstrating a complete response to therapy and permitted completion radiation therapy and primary site organ preservation in 70%–86% of pts. Early biopsy directed surgical salvage (RO) for persistent primary tumor permits tumor eradication with survival and disease control that is equivalent to the more biologically favorable chemo radiation group. H & N Protocol (Pts) Concurrent Chemo/RT/Induction Rx-C-RT Stage III/IV Clinical Response (primary site) Path (CR%) Residual CA in Neck Survival OS/DFS C-RT (Pts) S (Pts) #53 (38) #67 (26) (64) P+C+ 45Gy 24/40 31 PR 48% 32 CR 52% 45/64 (70%) 17/46 (37%) (45) 44%/54% (18) 55%/54% #79 (30) Induction →Chem RT P + C →P+C+RT 10/20 10 PR (33%) 20 CR (67%) 26/30 (86%) 9/30 (30%) (26) 55%/45% (4) NA/NA No significant financial relationships to disclose.
Effect of AZD0530 (saracatinib) on biliary cancer cell motility and invasion.
Authors: F. Leone, C. Peraldo-Neia, G. Cavalloni, F. Colombi, M. Aglietta
Journal: Journal of Clinical Oncology (2011)

231 Background: Biliary carcinoma (BC) has a poor prognosis and limited therapeutic options. The identification of new targets is essential. Among candidates we have studied the tyrosine kinase Src, which is involved in proliferation, invasion, and migration in many tumors.It has been demonstrated that the inhibition of Src significantly reduces proliferation and metastasis development in different solid tumors, such as pancreatic and head and neck cancers. Targeting Src tyrosine kinase may be therapeuticallyuseful in cholangiocarcinoma. We explored the antitumor activity of Src inhibitor saracatinib (AZD-0530) in BC preclinical models. Methods: Four cholangiocarcinoma cell lines, TFK1, EGI-1, HuH28, and TGBC1-TKB, were treated with saracatinib and analyzed by western blot for the expression of Src and its downstream principal transducer FAK. The inhibition of proliferation was evaluated by cell titer glo assay after treatment with scalar doses of saracatinib alone or in combination with gemcitabine for 72 hours. The effect on migration of BC cells was tested by wound healing assay. Finally, we investigated the antitumor activity in EGI-1 xenografts in NOD/Shi-scidIL2rg null mice treated with saracatinib at 10 mg/kg/die. Results: Activation of Src pathaway was shown in all cell lines and saracatinib was able to inhibit its downstream molecules. Saracatinib inhibited BC cell proliferation in standard monolayer liquid culture only at very high concentration (median doses from 2.5 to 15 μM) and did not enhance the antiproliferative effect of gemcitabine. Evidence of anti-tumor activity of saracatinib was obtained in terms of migration inhibition: quantitation of the wound closure over time revealed a significant and dose-dependent inhibitory effect of saracatinib on BC cell motility. In the in vivo model, no reduction of tumor volumes was evidenced up to 14 days of treatment. Assays with prolonged treatments are ongoing. Conclusions: These results suggest that inhibition of Src kinase by saracatinib impairs the invasiveness of bile duct carcinoma. Further in vivo studies will provide information about the effect on metastasis inhibition by saracatinib. No significant financial relationships to disclose.
Effect of simvastatin on the pharmacokinetics of anastrozole
Authors: T. Bao, S. A. Slater, A. Blackford, S. C. Jeter, L. Wright, M. A. Rudek, Z. Desta, V. Stearns
Journal: Journal of Clinical Oncology (2009)

1517 Background: When used in the adjuvant setting, aromatase inhibitors (AIs) reduce the incidence of contralateral breast cancer and are therefore under investigation for primary breast cancer prevention. Statins hold promise for chemoprevention based on preclinical and epidemiological data. Adding statin to AI has the potential to enhance breast cancer prevention and to protect women from AI-related side effects. Prior to initiating a chemoprevention trial of combination therapy, we evaluated the potential for pharmacokinetic drug-drug interaction between anastrozole and simvastatin in postmenopausal women taking adjuvant anastrozole to ensure that the combination will not influence anastrozole concentration or affect its ability to reduce estrogen. Methods: Postmenopausal women with hormone receptor-positive, stage 0-III breast cancer who had been on adjuvant anastrozole (1 mg/day) for at least 30 days were prescribed 14 days of simvastatin (40 mg/day). We collected serum at baseline (anastrozole alone) and after 14 days of simvastatin initiation (combination therapy). Anastrozole and hydroxyanastrozole, its hydroxylated metabolite, concentrations were determined using liquid chromatography-tandem mass spectrometry assay. Estrogen concentrations will be determined using radio-immunoassay. Significant change in anastrozole was predetermined to be greater than a 30% decrease in concentrations. Percent changes from baseline in anastrozole and hydroxyanastrozole were evaluated using Wilcoxon signed-rank tests. Results: From December 2006 to September 2008, 11 women (10 Caucasian, 1 Black, all reported non-Hispanic with a mean age of 60 yrs [range 51–69]) were enrolled in the study. Of these women, nine had evaluable anastrozole concentrations. After 14 days of simvastatin, there were nonsignificant changes in anastrozole (median percentage difference = 10.1% [-13.5%, 38.4%], p = 0.36) and hydroxyanastrozole (median percentage difference = -3.0% [-19.1%, 11.2%], p = 0.65). Estrogen data will be available for presentation. Conclusions: Simvastatin is unlikely to alter the pharmacokinetics of anastrozole in a clinically meaningful way. Combination studies to assess chemopreventive properties of the combination are planned. [Table: see text]
Very early PSA response to abiraterone in mCRPC patients: A novel prognostic factor to predict overall survival.
Authors: Carla Cavaliere, Orazio Caffo, Cinzia Ortega, Carmine D'aniello, Sabrina Chiara Cecere, Marilena Di Napoli, Chiara Della Pepa, Anna Crispo, Francesca Maines, Fiorella Ruatta, Gelsomina Iovane, Maurizio Montella, Sandro Pignata, Gaetano Facchini
Journal: Journal of Clinical Oncology (2016)

219 Background: In the last years the therapeutic scenario of mCRPC has undergone a radical change with the approval of new drugs. AA is approved for the treatment of mCRPC after failure of ADT in whom chemotherapy (CT) is not yet clinically indicated and for treatment of mCRPC progressed on or after docetaxel (DTX) based chemotherapy. The aim of this study is to evaluate the role of early PSA decline as a marker of response for an early detection of therapy success in mCRPC patients treated with AA. Methods: We retrospectively evaluated 87 pts with mCRPC treated with AA in compassionate use in Napoli, Trento, and Candiolo, Italy. Serum PSA levels were performed after 15, 90 days and then monthly, a time course of serum PSA was obtained. The PSA flare phenomenon was evaluated, according to a confirmation value at least one week apart. The Cox proportional hazards model was used to test the effect of several variables on survival outcomes in multivariate analyses. Results: We have collected data of 87 patients between Sep 2011 and Sep 2014; 75/87 were eligible for correlation analysis. PSA decline was observed in 78.6 % (59/75) of pts. Early PSA response ( ≥ 50% from baseline at 15 days) was found in 56%(42/75) evaluated patients and confirmed in 29 of them after 90 days. In early responders patients (PSA RR ≥ 50% at 15 days), we found a significant statistical advantage in terms of PFS at 1 year, HR 0.28,95% CI 0.12-0.65, p = 0.003, and OS, HR 0.21 95% CI 0.06-0.72, p = 0.01. The median OS was 17,1 months(8,8-25,2). PFS at 1 year and OS reached statistical significance also in the evaluation at 90 days, HR: 0.23 95% CI 0.07-0.77, p = 0.02 and HR: 0.14 95% CI 0.03-0.70, p = 0.02 respectively. Our analysis showed a positive correlation between OS and duration of AA treatment, previous chemotherapy treatment, cumulative dose of docetaxel ≤ 675 mg/m² and previous hormonal therapy duration ( ≥ 2.5 months) for metastatic setting in early responders group. Conclusions: A significant proportion (78.6%) of patients achieved a rapid response in terms of decline of PSA. Early PSA RR ( ≥ 50% at 15 days after start of AA) can provide clinically meaningful information and could be considered a surrogate of longer PFS and OS.
Impact of PET staging in limited-stage SCLC.
Authors: Eric Xanthopoulos, Surbhi Grover, Michael Nino Corradetti, Annemarie Therese Fernandes, Miranda Kim, Charles B. Simone, John Paul Christodouleas, Tracey L. Evans, James Stevenson, Corey J. Langer, Smith Apisarnthanarax, Ramesh Rengan
Journal: Journal of Clinical Oncology (2012)

7098 Background: Although PET/CT has been established for the initial staging of NSCLC, it is still unproven for SCLC. This study examines clinical outcome in patients with limited-stage SCLC staged with and without PET/CT. Methods: An institutional database was reviewed to identify all patients that presented with limited-stage SCLC and treated definitively with concurrent chemoradiation. Overall survival and associations were assessed by the Kaplan-Meier approach, log-rank tests and Cox modeling. Results: From 01/04 – 08/10, 54 consecutive limited-stage SCLC patients were treated with concurrent chemoradiation at the University of Pennsylvania. 40 patients underwent PET staging; 14 underwent CT staging only; all had MR of the brain. Patient characteristics were well distributed, including age (p = 0.35), race (p = 0.21), sex (p = 0.93), dose (45 Gy, p = 0.89), and fractions per day (p = 0.89). PET-staged patients had median survival of 32 vs 15 months in patients without PET (p = 0.03). Survival rate was 57% vs 29% at 24 months. Median time to distant failure of 29 vs 11 months (p = 0.05). Median time to local failure was 41 vs 12 months (p = 0.03). Median followup was 38 months in the 19 surviving PET-staged patients and 40 in the 2 surviving non-PET patients (p = 0.59). Lack of PET-staging (OR = 0.92, p = 0.04) and race (OR = 1.02, p = 0.03) associated with increased distant failure on multivariate Cox analysis. Only PET-staging (OR = 0.93, p = 0.04) associated with increased overall survival on univariable Cox modeling. Conclusions: Median and overall survival of PET-staged SCLC patients compared favorably with those who were not. These findings are presumably due primarily to identification of CT-occult distant disease by PET. This study underscores the value of PET in staging patients with SCLC.
Prophylaxis of Graft-Versus-Host Disease (GVHD) with Pentostatin, Tacrolimus, and “Mini”-Methotrexate (MTX): A Phase I/II Controlled, Randomized Study in Unrelated Donor (UD) Transplantation.
Authors: Marcos de Lima, B. Andersson, M. Fernadez-Vina, S. Giralt, D. Couriel, E. Shpall, U. Popat, M. Qazilbash, A. Alousi, P. Cano, D. Bosque, C. Hosing, S. Qureshi, L. de Padua, M. Munsell, P. Anderlini, R. Jones, M. Westmoreland, A. Gulbis, R. Champlin
Journal: Blood (2007)
A treatment planning evaluation of protons versus IMRT in pancreatic cancer: A comparative study.
Authors: Jerry Monroe Slater, Ted Chen-Tai Ling, Prashanth Nookala, Rachel Mifflin, Roger Grove, Anh Ly, Baldev Patyal, Jerry D. Slater, Gary Yang
Journal: Journal of Clinical Oncology (2014)

369 Background: The purpose of this study is to investigate dose distributions of proton and intensity-modulated radiation therapy (IMRT) photon treatment plans in patients with resected pancreatic adenocarcinoma, focusing specifically on dose reduction to the kidney, liver, and small bowel as organs at risk. Methods: Ten patients with pancreatic head adenocarcinoma underwent Whipple procedure between 2010 and 2013 were included in this study. Most of the patients had locally advanced disease (T 3-4 N 1 ). All patients were simulated with contrast-enhanced CT imaging. The clinical target volume (CTV) consisted of the pre-operative extent of tumor plus a 10 mm manual expansion in all directions. The planning target volume (PTV) was generated by a further expansion on the CTV ranging from 10-15 mm. A dose of 50.4 Gy given in 28 fractions was delivered to the PTV. All plans were optimized to allow 95% isodose coverage of at least 95% of the PTV. Dose-volume histograms, conformity index (CI), uniformity index (UI), homogeneity index (HI), were calculated and analyzed in order to compare plans between the two modalities. The OAR being evaluated in this study are the kidneys, liver, small bowel, and spinal cord. To determine statistical significance, ANOVA and two-tailed paired t-tests were performed for all data parameters. Results: The proton plans resulted in a lower mean kidney dose (3.17 Gy vs. 9.59 Gy, p=0.039), a lower dose delivered to 1/3 of the liver, D 1/3 , (0.25 Gy vs. 4.56 Gy, p=0.003), and a lower mean liver dose (1.83 Gy vs. 5.24 Gy, p=0.021). See table for a summary of the results. Conclusions: For patients receiving postoperative radiotherapy for pancreatic cancer, the proton plans are technically feasible and dosimetrically appealing with superior organ at risk sparing compared to IMRT photon treatment plans.[Table: see text]
Incidence, distribution, and outcomes of node positive patients at radical prostatectomy: Manitoba Prostate Center experience.
Authors: Kamaljot Singh Kaler, Tadeusz Jozef Kroczak, Premal Patel, Rebekah Rittberg, Jeffery Walter Saranchuk, Darrel E Drachenberg
Journal: Journal of Clinical Oncology (2014)

162 Background: Pelvic lymph node dissection at the time of radical retropubic prostatectomy (RRP) varies among surgeons and institutions. Differences focus on candidacy for node dissection and the limit of dissection. Standard lymph node dissection is typically above the obturator nerve to external iliac vessels. We analyzed our local experience of lymph node metastases at time of surgery. Methods: Data from the Manitoba Prostate Center were collected on consective patients undergoing RRP from January 2003 to June 2013 by two urologists with subspecialty training in oncology. Information extracted includes age, prostate-specific antigen (PSA), biochemical recurrence characteristics, and biopsy and pathological results. Results: Four hundred twenty consecutive patients comprised the data set and of whom 411 underwent a RRP and nine aborted prostatectomies. Average age of patients was 60 with an average preoperative PSA of 11. Overall lymph node metastases rate is 16.1%. Of the N1 patients, average number of positive nodes was 2.3. Average nodes removed for all patients were 13.4. Positive nodes on the right were found 53% of the time and 47% on the left. Locations of nodes are as follows: right external iliac, obturator, and hypogastric, 12%, 6%, and 19%, respectively; and for left external iliac, obturator, and hypogastric 9%, 3%, and 16%, respectively of all total nodes. One node was identified as other, and one surgeon sent packets as right pelvic and left pelvic with positive nodes 16% and 19% of all total positive nodes respectively. When looking at zones of a pelvic lymph node dissection separately, 54% are hypogastric, 13% obturator, and 33 external iliac. With an average of 37 months follow-up two patients with N1 disease died and only one from prostate cancer. Seventy nine percent had biochemical recurrence. Median time to treatment for biochemical recurrence was 4.5 months (0 to 33 months) with a median PSA of 0.28. Conclusions: This contemporary series of pelvic lymph node dissection with RRP represents high lymph node metastases (16%) relative to literature. Performing a limited pelvic lymph node dissection would under stage 54% of our patients. Despite high biochemical recurrence only one patient died of prostate cancer.
Detection of low-frequency FGFR3 mutations in the urine of patients with bladder cancer using next-generation deep sequencing.
Authors: John M. Millholland, Shuqiang Li, Cecilia A. Fernandez, Anthony P. Shuber
Journal: Journal of Clinical Oncology (2012)

59 Background: FGFR3 mutations have been identified in ~60-70% of low-stage, non-invasive tumors. Our group and others have developed assays to detect FGFR3 mutations in the urine of bladder cancer patients. However, urine-based assays have been limited by the technical ability to detect rare events in a dilute medium where there is a high background of normal DNA. In these assays, FGFR3 mutations are generally found in ~30% of the urine samples, which is &lt; 50% concordance with the expected detection in tissue. We have now developed an ultra-deep amplicon sequencing technique that increases FGFR3 mutation detection in urine to ~67%, close to the expected detection frequency if every mutation found in tissue could be detected in urine. Methods: Amplicons were designed against FGFR3 exons 7, 10, and 15 using PCR primers containing the adapter sequences for unidirectional sequencing. Primary amplification was performed from DNA isolated from 4 ml of urine. The resulting PCR products were used as template for emulsion PCR and these were then sequenced using the Roche 454 GS Junior. Samples were analyzed for total DNA reads per sample and number of mutant sequencing reads to determine percent mutation. Results: Urine samples from 43 patients with bladder cancer were analyzed by both our previously described qPCR method and the new ultra-deep sequencing approach. Using ultra-deep amplicon sequencing, 24 out of 43 (55.8%) were positive for FGFR3 mutations, while only 5 out of 43 (11.6%) were positive for mutations by qPCR. The urine samples from the 15 newly identified mutations using deep sequencing contained FGFR3 mutations as low as 0.05% mutant DNA. The sensitivity achieved using deep sequencing was 91% concordant with the FGFR3 mutations observed in tissue. Conclusions: We have developed a highly sensitive non-invasive urine based assay that can detect FGFR3 mutant DNA when present at &lt; 1% of the sample and is &gt; 90% concordance with the mutations found in tumor tissues. To our knowledge, this is the first practical application of next generation sequencing technology for diagnostic use.
Multicenter phase II study of combination therapy with paclitaxel, cisplatin, and S-1 for adavanced gastric cancer (OGSG0703).
Authors: R. Kawabata, H. Imamura, T. Kishimoto, Y. Kimura, M. Goto, S. Iijima, K. Fujitani, M. Oshita, S. Ueda, T. Shimokawa, H. Takiuchi, T. Tsujinaka, H. Furukawa
Journal: Journal of Clinical Oncology (2011)

e14654 Background: A multicenter phaseII study was conducted to evaluate the efficacy and safety of a combination regimen (PCS) with paclitaxel, cisplatin, and S-1 in patients with advanced gastric cancer in an outpatient setting. Methods: Patients with previously untreated metastatic or recurrent gastric cancer received intravenous paclitaxel at 70 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 15, plus oral S-1 at 40 mg/m2 b.i.d. on days 1 to 21,followed by 2 weeks off, in a 35-day cycle. Results: A total of 52 patients were enrolled in this study, among whom 49 were assessable for efficacy and 51 assessable for toxicity. The overall response rate was 46.9% (95% CI: 32.5-61.7%). The median progression-free survival and median overall survival were 5.4 months (95% CI:4.1-7.0) and 11.5 months (95% CI:7.3-16.1), respectively. Frequent grade 3/4 toxic effects included neutropenia (51%), leucopenia (25%), anemia (20%), hyponatremia (16%), anorexia (14%), and fatigue (10%). There was no treatment-related death. Conclusions: In this study, the predicted response rate was not achieved employing this combination regimen with paclitaxel, cisplatin, and S-1, although it was found to be well- tolerated.