tbuckley/cabot-search huggingface dataset:
Correlation of treatment effects on progression-free survival at 6 months (PFS-6) and overall survival (OS) in patients with newly diagnosed glioblastoma (GBM).
Authors: X. Ye, S. A. Grossman, S. Desideri, S. Piantadosi
Journal: Journal of Clinical Oncology (2011)

2008 Background: PFS-6 is commonly proposed as a primary endpoint in phase II trials to evaluate the efficacy of new therapies in patients with GBM. Two conditions must be fulfilled for validity: a strong correlation between PFS-6 and OS, and consistency in the effect of treatments on PFS-6 and OS. We examined the validity of this second condition using phase II data. Methods: OS and PFS at 6, 9, and 12 months were collected from 352 patients with newly diagnosed GBM treated in NABTT phase II trials with similar eligibility criteria and OS as the primary endpoint. 134 subjects were from historical controls (before temozolomide [TMZ]) and 218 were from 3 trials with TMZ. Treatment effects on OS compared to historical control were estimated using proportional hazards regression. Treatment effects on OS at 24 months (OS-24), PFS-6, 9, and 12 were estimated by the absolute difference in improvement of the corresponding proportions over control. Potential surrogacy of PFS-6, 9 12 for OS with respect to the effect of treatment was evaluated using rank correlation of the outcomes by bootstrap method. Results: The median age was 56 (range: 21-89), median KPS was 90 (60-100), and 80% underwent debulking surgery. Progression dates were captured in 99% of patients before death occurred. Treatment effects (percent reduction in hazard of death or OS-24) and PFS are tabulated below. The rank correlation between hazard of death (OS) and PFS-6 is -0.03 (95%CI: -0.16 to 0.11), for PFS-9 is -0.40 (95%CI:-0.51 to -0.28), and for PFS-12 is -0.21 (95%CI:-0.35 to -0.07). Similar correlations were observed between OS-24 and PFS-6, 9 or 12. Conclusions: We observe a near zero correlation between the magnitude of treatment effects on PFS-6, 9, 12 and OS. PFS-6, 9 or 12 do not appear to be valid surrogates for OS in clinical trials for newly diagnosed GBM. Improvement on treatments (95%CI) % reduction in hazard of death Absolute improvement %OS-24 %PFS-6 %PFS-9 %PFS-12 High (NABTT 0306, n=66) 49 (47-50) 28 (27-29) 23 (21-24) 27 (25-28) 21 (20-22) Median (NABTT 0304, n=85) 46 (45-48) 25 (24-26) 14 (13-15) 24 (23-26) 22 (21-23) Low (NABTT 0501, n=67) 39 (37-41) 15 (14-16) 21 (19-22) 36 (35-37) 25 (24-26)
HALT MBC: HER2 suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (LPT112515).
Authors: Nancy U. Lin, Michael A. Danso, Alice K. David, Joseph J. Muscato, Daniel Rayson, William A. Houck, Catherine Elizabeth Ellis, Michelle DeSilvio, Amanda Garofalo, Yasir M. Nagarwala, Eric Winer
Journal: Journal of Clinical Oncology (2012)

TPS658 Background: Dual blockade of HER2 with the combination of trastuzumab (T) and lapatinib (L) enhances antitumor activity in HER2-positive breast cancer (BC) preclinical models due to the complementary mechanisms of action of the 2 agents. In patients (pts) with T-treated HER2-positive metastatic BC (MBC), treatment with the combination was associated with longer progression-free (PFS) and overall survival (OS) compared with L alone. In pts with stage II/III BC, preoperative treatment with the combination plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2-positive MBC. The present study is designed to evaluate whether the addition of L improves PFS among women with HER2-positive MBC receiving T as maintenance therapy. Methods: In this open-label, Phase III study, 280 pts will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]) or T (6 mg/kg q3w) alone. Pts will receive study treatment until disease progression, death, discontinuation due to adverse events, or other reasons. The primary endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and safety. Key eligibility criteria include pts with HER2-positive MBC who have completed 12 to 24 weeks of first- or second-line treatment with T plus chemotherapy with an objective response or stable disease at time of chemotherapy discontinuation. Pts with stable brain metastases are eligible if entering the study on second-line treatment. Efficacy endpoints will be analyzed in the ITT population. A total of 193 PFS events is required to detect a 50% increase in median PFS (hazard ratio=0.67) for L plus T compared with T alone (median PFS 27 vs 18 weeks, respectively). The hypothesis will be tested using a 1-sided test with 80% power and a type I error of 0.025. The trial is currently open for accrual in the United States and Canada.
TOUCAN: A randomised phase II trial of carboplatin and gemcitabine +/- vandetanib in first line treatment of advanced urothelial cell cancer in patients who are not suitable to receive cisplatin.
Authors: Robert J. Jones, Simon J. Crabb, John D. Chester, Tony Elliott, Robert Anthony Huddart, Alison J. Birtle, Linda Evans, Jason Francis Lester, Chao Huang, Angela Claire Casbard, Tracie-Ann Madden, Gareth Griffiths
Journal: Journal of Clinical Oncology (2016)

448 Background: Whilst cisplatin combination therapy remains the standard of care for patients with advanced urothelial cancers, many patients are unsuitable for cisplatin and go on to receive carboplatin combination therapy. Although responses are frequent, overall outcomes remain poor, and there is a high unmet need for more effective first line treatment. Vandetanib is a well-tolerated, oral inhibitor of vascular and epidermal growth factor receptor tyrosine kinases, both of which are implicated in the pathogenesis of urothelial cancers. Methods: Patients with metastatic or inoperable urothelial cancer who had no prior chemotherapy and were unsuitable for cisplatin were randomly allocated to receive carboplatin (AUC 4.5, day 1) plus gemcitabine (1000mg/m 2 , days 1 and 8) plus either vandetanib (100mg od, days 1-21) (GCV) or matching placebo (GCP) in 21-day cycles up to a total of 6 cycles. Treatment allocation was double-blind. There was a planned safety review after the first 40 patients had received at least one cycle. The primary endpoint was progression free survival (PFS). Sample size (n=82) was calculated using a one-sided alpha of 0.2 and power 80% to detect a HR of 0.65 for PFS. We present the final efficacy results. The trial was coordinated by the Wales Cancer Trials Unit at Cardiff University and funded by Cancer Research UK (CRUK/09/024) and AstraZeneca. Results: Of 82 patients, 40 received GCV. 62 (76%) had a bladder primary, and 56 (68%) had poor renal function. The arms were well balanced except for age &gt; 75 (13 (16%) GCV, 23 (28%) GCP). Median PFS was 8.5 months (m) (95% CI 6.0, 9.7) and 8.8 m (5.8, 9.0) for GCV and GCP respectively (adjusted hazard ratio (HR) 0.93 (0.50, 1.71), P=0.89). Overall survival was 10.8 m (8.0, 13.0) and 13.8 m (11.1, 16.6) for GCV and GCP respectively (adjusted HR 1.38 (0.77, 2.46), P=0.24). Response rates were 50% (n=20) and 55% (n=23) for GCV and GCP. All-grade adverse events were similar but there were significantly more grade 3+ events in the GCV arm. Conclusion: Vandetanib did not improve efficacy of chemotherapy but increased toxicity in advanced urothelial cancer not suitable for cisplatin. Clinical trial information: 68146831.
Chromosome Aberrations by Conventional Karyotyping in Chronic Lymphocytic Leukemia Carrying No Aberration by Fluorescence in Situ Hybridization: Correlation with Prognostic Parameters and Clinical Features
Authors: Gian Matteo Rigolin, Francesca Cibien, Sara Martinelli, Formigaro Luca, Antonella Bardi, Lara Rizzotto, Elisa Tammiso, Elena Saccenti, Francesco Cavazzini, Maria Ciccone, Ilaria Nichele, Giovanni Pizzolo, Francesco Zaja, Renato Fanin, Piero Galieni, Alessia Dalsass, Francesca Mestichelli, Nicoletta Testa, Massimo Negrini, Antonio Cuneo
Journal: Blood (2011)
Beyond Positive Margins and Extracapsular Extension: Evaluating the Utilization and Clinical Impact of Postoperative Chemoradiotherapy in Resected Locally Advanced Head and Neck Cancer
Authors: Daniel M. Trifiletti, Andrew Smith, Nandita Mitra, Surbhi Grover, John N. Lukens, Roger B. Cohen, Paul Read, William M. Mendenhall, Alexander Lin, Samuel Swisher-McClure
Journal: Journal of Clinical Oncology (2017)

Purpose To examine recent utilization and survival outcomes associated with use of adjuvant chemoradiotherapy (CRT) for patients with resected locally advanced head and neck cancer (LAHNC) with negative surgical margins (SM negative) and no extracapsular extension (ECE). Materials and Methods We conducted a retrospective observational cohort study using the National Cancer Database evaluating patients diagnosed in 2004 to 2012 with AJCC stage III to IVB squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx treated with definitive surgery and adjuvant radiotherapy (RT) or CRT. We identified a subset of patients with SM negative and no ECE (n = 10,870). We determined factors associated with CRT use and examined overall survival of patients receiving CRT versus RT. We further evaluated survival outcomes by number of lymph nodes involved to assess whether this was associated with benefit from CRT. Results Among patients with resected LAHNC with SM negative and no ECE, 47% received adjuvant CRT. The use of CRT varied substantially according to several factors, including patient age, contralateral/bulky neck disease, increasing number of positive lymph nodes, and lower neck disease. CRT was associated with a statistically significant improvement in overall survival compared with RT alone (hazard ratio, 0.90; 95% CI, 0.86 to 0.94; P < .001). Survival benefits of CRT versus RT alone increased in patients with multiple positive lymph nodes. Conclusion The use of adjuvant CRT in patients with resected LAHNC with SM negative and no ECE is common. Substantial practice variation as well as the survival differences observed in this study support the conduct of additional research to guide personalized treatment approaches in this setting. The number of positive lymph nodes seems to be an appropriate selection factor for further investigation of CRT in such patients.
Preclinical efficacy of growth hormone-releasing hormone antagonist MIA-602 for androgen-dependent and castration-resistant human prostate cancer.
Authors: Ferenc G. Rick, Cale D. Fahrenholtz, Maria I. Garcia, Norman L. Block, Andrew V. Schally, Kerry L. Burnstein
Journal: Journal of Clinical Oncology (2014)

221 Background: Advanced hormone-sensitive prostate cancer (PCa) responds to androgen deprivation therapy (ADT). However, therapeutic options for castration-resistant disease are limited. As growth hormone-releasing hormone receptor (GHRH-R) and ligand GHRH are regulated in an autocrine fashion in PCa, GHRH-R inhibition represents a novel approach to PCa treatment. We investigated the effects of a new, highly potent GHRH antagonist, MIA-602, on growth of androgen-dependent and castration-resistant PCa cells in vitro/in vivo. Methods: All three cell lines used in this study expressed androgen receptors (ARs). 22Rv1 cells are castration-resistant and also express clinically relevant AR splice variants. LNCaP and VCaP lines are androgen dependent models that progress to castration resistance following ADT. Protein and mRNA levels of GHRH-R and its biologically active splice variant, SV1, were evaluated in cell lines and tumors by immunoblot and real-time RT-PCR. The influence of MIA-602 on cell proliferation and tumor formation was examined. Results: GHRH-R and SV1 were present in 22Rv1, LNCaP, and VCaP. LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared to 22Rv1. However, 22Rv1 expressed higher levels of SV1. Inhibition of GHRH-R using MIA-602 decreased cell proliferation in vitro of 22Rv1, LNCaP, and VCaP PCa cell lines respectively by 70.4%, 60.7% and 20.3% (P&lt;0.05 for all). MIA-602 decreased 22Rv1 xenograft volumes in mice by 63% after 3 weeks of treatment. VCaP showed a substantial inhibition of xenograft growth following therapy with MIA-602 in vivo. MIA-602 effectively inhibited VCaP xenografts as a single agent or in combination with ADT by surgical castration. Conclusions: The effectiveness of the novel Miami class GHRH antagonist, MIA-602, in inhibiting growth of androgen-dependent and castration-resistant PCa models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists appear to be due to effects exerted through GHRH receptors on cancer cells and/or possibly by indirect mechanisms. Further investigations of GHRH antagonists for PCa treatment are warranted.
Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for advanced gastric cancer: A single center, prospective, randomized trial.
Authors: Jian-Xian Lin, Changming Huang, Chaohui Zheng, Ping Li, Jianwei Xie, Jiabin Wang, Jun Lu, Qiyue Chen, Longlong Cao, Mi Lin
Journal: Journal of Clinical Oncology (2016)

55 Background: Laparoscopic-assisted distal gastrectomy (LADG) is rapidly gaining popularity. However, there is limited evidence regarding the safety for advanced gastric cancer (AGC). We therefore conducted a single center, prospective, randomized study comparing LADG with open distal gastrectomy (ODG) for AGC to evaluate the safety of this trial with respect to morbidity and mortality. Methods: The eligible criteria were pathologically-proven adenocarcinoma, 18 to 75 years of age, no history of other cancer, chemotherapy, or radiotherapy, preoperative stage T2-4aN0-3M0 with R0 resection. The primary end point was to determine whether there is a difference in overall survival between LADG and ODG groups. The morbidity and mortality were compared to evaluate the safety of this trial. Results: A total of 192 patients were randomized (96 cases in LADG Group; 96 patients in ODG Group) between July 1, 2011 and August 31, 2014. There were no significant differences between the two groups in the clinicopathological characteristics. Median number of retrieved lymph nodes per patient was 36, and the mean number of retrieved lymph nodes in LADG Group was more than that in ODG Group (39.8±11.1 vs. 35.4±14.8 per case, P = 0.021). The number of transfused units per patient and times to resumption of activities, resumption of soft diet, and post-operative stay were similar in the two groups; while the operation time, blood loss, and times to first flatus were significantly lower in the LATG Group (P &lt; 0.05, respectively). The post-operative complication rates of the LADG and ODG groups were 19.8% (24/96) and 16.7% (16/96), respectively (P = 0.575). The postoperative mortality was 0% (0/96) and 1.0% (1/96) in the LADG and ODG groups (P = 0.316), respectively. Conclusions: There was no significance difference in the morbidity and mortality between LADG and ODG groups. A well-designed phase III multicenter, prospective, randomized trial comparing surgical outcomes and oncologic safety between laparoscopic and open gastrectomy for AGC can be carried out. Clinical trial information: ChiCTR-TRC-11001340.
Biomarkers in pancreatic neuroendocrine tumors.
Authors: Angela Tatiana Alistar, Richard Warner, Erin Moshier, Michelle Kim, Randall F. Holcombe
Journal: Journal of Clinical Oncology (2012)

166 Background: This study was designed to determine the role of Chromogranin A (CGA) and serotonin as prognostic biomarkers in relation with cytoreductive surgery for pancreatic neuroendocrine tumors (PNETs).The role of CGA and serotonin as biomarkers for PNETs is not fully established. Clinicians use CGA to monitor progression of disease and response to treatment; however this hasn’t been fully validated. There is no definitive data for serotonin as prognostic biomarker in PNETs. Methods: A retrospective study of patients with PNETs seen at Mount Sinai from 1980 to 2011 was performed. All patients (142) that have had CGA and serotonin concentrations measured at least once were evaluated. Data relating to diagnosis, therapies and survival outcome were noted Results: We evaluated the probability of survival post cytoreductive surgery among patients characterized by their postoperative CGA and serotonin values. 27 patients have had CGA level measured early post-op (0 to 3 months) and 30 patients have had CGA measurement late post-op (3-12 months). We identified no correlation between survival and a normal CGA early post-op (p = 0.5895). We identified a trend (p=0.1369) towards increase in survival for patients with a normal CGA late post-op with a probability in survival of 92.86% vs 65.12% at 3 years and median months to death of 80.265 for normal CGA vs 50.39 months for high CGA late post-op. For the 22 patients that had both a CGA early and late post-op the probability of survival by their change from early to late post- surgery CgA values was not statistically significant (p=0.2903). Serotonin did not correlate with survival in any of the 3 analyses: early post op, late postop or change in serotonin level. Conclusions: The role of CGA as a predictive or prospective biomarker for PNETs is worth prospective investigation. Our study shows that late post-op CGA may predict clinical outocome while CGA early postop and serotonin early, late and change post op did not have value in predicting survival.
Randomized phase III trial of neoadjuvant chemotherapy (NAC) with methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by radical cystectomy (RC) compared with RC alone for invasive bladder cancer (BC): Japan Clinical Oncology Group Study, JCOG0209.
Authors: Hiroshi Kitamura, Taiji Tsukamoto, Naoya Masumori, Taro Shibata, Futoshi Kunieda, Hiroyuki Fujimoto, Yoshihiko Hirao, Yasuo Kitamura, Yoshihiko Tomita, Kenichi Tobisu, Masashi Niwakawa, Seiji Naito, Masatoshi Eto, Yoshiyuki Kakehi
Journal: Journal of Clinical Oncology (2013)

249 Background: Cisplatin-based NAC for patients (pts) with invasive BC is considered to provide a 5–8% overall survival (OS) advantage, although several studies failed to prove the survival benefit of NAC. Methods: Eligibility criteria included histologically proven urothelial carcinoma, invasive (T2-4aN0M0) bladder cancer within 8 weeks from TURBT, PS 0-1, age 20 to 75 years old. Patients were randomized to receive either 2 cycles of neoadjuvant MVAC followed by RC (NAC arm) or RC alone (RC arm). MVAC comprised M (30 mg/m 2 ) on days 1, 15, and 22; V (3 mg/m 2 ) on days 2, 15, and 22; A (30 mg/m 2 ) on day 2; C (70 mg/m 2 ) on day 2. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), the surgery-related complication rate, adverse events during NAC, the rate of no residual tumor in the RC specimens (pT0), and quality of life. The sample size was 180 pts in each arm with a one-sided alpha of 5% and a power of 80% to detect a difference in 5-year OS from 45% in the RC arm to 57% in the NAC arm. Results: From March 2003 to March 2009, 130 pts were randomized to the NAC arm (n=64) and RC arm (n=66). The patient registration was terminated early because of slow accrual. At the second interim analysis conducted after the completion of patient accrual, the OS of the NAC arm was better than that of the RC arm (median, 102 and 81 months, respectively), although the difference was not statistically significant (HR, 0.65; multiplicity adjusted 99.99%CI, 0.19 - 2.18; one-sided log-rank p = 0.07). Considering the current situation in which NAC with gemcitabine and cisplatin (GC) is widely used in clinical practice, the Data and Safety Monitoring Committee recommended early publication of the results. The median PFS times in the RC arm and NAC arm were 78 and 99 months, respectively (p=0.04). No differences in perioperative complications, other than lymph leakage, were observed between the groups. pT0 in the NAC arm and RC arm was 34 % vs. 9 %, respectively (p&lt;0.01). Conclusions: Although NAC with GC is widely used for invasive BC, NAC with MVAC can still be considered promising. Clinical trial information: 000000093.
Different Modes of Visual Integration in the Lateral Geniculate Nucleus Revealed by Single-Cell-Initiated Transsynaptic Tracing
Authors: Santiago B. Rompani, Fiona E. Müllner, Adrian Wanner, Chi Zhang, Chiara N. Roth, Keisuke Yonehara, Botond Roska
Journal: Neuron (2017)

The thalamus receives sensory input from different circuits in the periphery. How these sensory channels are integrated at the level of single thalamic cells is not well understood. We performed targeted single-cell-initiated transsynaptic tracing to label the retinal ganglion cells that provide input to individual principal cells in the mouse lateral geniculate nucleus (LGN). We identified three modes of sensory integration by single LGN cells. In the first, 1-5 ganglion cells of mostly the same type converged from one eye, indicating a relay mode. In the second, 6-36 ganglion cells of different types converged from one eye, revealing a combination mode. In the third, up to 91 ganglion cells converged from both eyes, revealing a binocular combination mode in which functionally specialized ipsilateral inputs joined broadly distributed contralateral inputs. Thus, the LGN employs at least three modes of visual input integration, each exhibiting different degrees of specialization.
Comparison of zoledronic acid retention in bone of multiple myeloma and breast cancer patients: Consequences for efficacy?
Authors: K. Søe, J. Delaisse, E. H. Jakobsen, H. B. Jørgensen, T. Plesner
Journal: Journal of Clinical Oncology (2010)

TPS137 Background: Zoledronic acid (ZA) is a potent amino-containing bisphosphonate (BP), and monthly infusions of ZA are widely used for prevention of skeletal events in breast cancer (BC) and multiple myeloma (MM). ZA has strong affinity for bone where it accumulates and inhibits osteoclastic bone resorption. The degree of retention of BP in bone was shown to depend on the level of bone turnover of the patient, as evaluated through the bone resorption maker NTX (Cremers et al. 2005 JBMR, 9, 1543-7). It is also well-accepted that the radiolabeled BP used as a probe for bone scintigraphy is less effective in labeling affected sites of bone from MM compared to BC patients. Thus, the binding to bone and retention of ZA, like the binding of radiolabeled BP used as tracer for bone scintigraphy, may be less in MM. Our aim is to determine whether the degree of retention of ZA in bone differs between MM and BC and if there is a difference in efficacy as determined by bone markers. This may have implications for the dosing and duration of treatment with ZA. Methods: The trial is an investigator-initiated phase II single-center trial enrolling 30 MM patients and 30 BC patients with metastasis to bone all scheduled for treatment with ZA. Each patient group is split into two subgroups: group 1: 10 BP-naive patients (no oral or iv BP) and group 2: 20 patients that have received at least six previous courses of ZA treatment. Inclusion criteria: postmenopausal women and men from the age of 50 years diagnosed with BC and metastasis to bone or MM scheduled for treatment with ZA. Study plan: bone scintigrafi analysis is performed prior to the infusion of ZA for later comparison. Just prior to infusion a fasting serum sample is taken. After infusion the total 48h urine is collected. 14 days later a final fasting blood sample is taken. Primary endpoint: the amount of ZA in the 48h urine samples from which the retention of ZA in the body is calculated. This value will be compared with the effect of ZA on the bone resorption marker, CTX, and the bone formation marker BAP (determined before and after infusion). In addition, the efficacy of the first compared to after multiple ZA treatments (minimum six) will be investigated. Expected end of recruitment: summer 2011. No significant financial relationships to disclose.