tbuckley/cabot-search huggingface dataset:
Single institution experience of HIV-positive patients with anal carcinoma: Treatment with combined modality therapy utilizing capecitabine and mitomycin-c
Authors: T. Kasunic, M. Ajlouni, I. Wollner
Journal: Journal of Clinical Oncology (2005)

4279 Background: Although anal cancer (AC) is a relatively uncommon disease with an incidence of 7 to 9 cases per million, recent studies have shown that the relative risk of developing AC among HIV-positive MSM was 37-fold higher than in the general population. The Nigro protocol, or modifications thereof, has been the standard of care for treating AC. However, HIV-positive patients have shown a poor tolerance and response to standard combined modality therapy (CMT). Previously published Phase I and II studies have shown that capecitabine and mitomycin-c (mito) have promising activity and favorable toxicity profile in patients with gastrointestinal cancers. We report here our experience with two patients treated with CMT utilizing capecitabine. Methods: Two HIV-positive patients were treated with this protocol. Patient one was a 60 year old man diagnosed with T2N2MX squamous cell cancer of the anus. He had a CD4 count of 458 and was treated with mito 10 mg/m2 on days 1 and 28 and capecitabine daily at 1250mg/m2, with concurrent XRT. Radiation delivered to the whole pelvis consisted of 3600 cGy with a 1440 cGy boost to the primary tumor. The second patient was a 56 year old man staged as T1N0M0 and had a CD 4 count of 174 at diagnosis. He was treated with the same chemotherapy regimen, with XRT of 3600 cGy delivered to the pelvis, 2530 cGy to the inguinals and a 900 cGy boost. Results: Both patients completed treatment without interruption. Both patients experienced Grade 2 skin toxicity, and the second patient with a CD4 count < 200 developed Grade 2 cystitis. Patient one continues to show no signs of recurrence at 46 months and patient two recently completed treatment. Conclusions: Capecitabine and mito given with concurrent XRT appears to be a well tolerated regimen in HIV-positive patients with squamous cell cancer of the anus. This is consistent with findings of a case series previously presented by Adler et al. Based on the cumulative reports implementing capecitabine in this regimen, consideration should be given to the inclusion of capecitabine in future trials. No significant financial relationships to disclose.
Activity of gemcitabine in direct patient-derived xenografts and clinical outcome: Validation of an in vivo model for drug development
Authors: M. Hidalgo, I. Garrido-Laguna, M. Uson, E. De Oliveira, R. Schulick, R. H. Hruban, A. Maitra, A. Jimeno, B. Rubio-Viqueira, N. V. Rajeshkumar
Journal: Journal of Clinical Oncology (2009)

4528 Background: Novel drugs are urgently needed for pancreatic ductal adenocarcinoma (PDA). Current preclinical models may not recapitulate the biology of human cancers. Direct xenografts have the potential to better represent the biology of human cancer. We have completed a clinical trial in which surgically resected PDAs were xenografted into nude mice thus generating an in vivo platform for drug development and biomarker identification. Methods: PDAs resected at Johns Hopkins Hospital are implanted into nude mice. From November 2005 to December 2008, 240 patients were consented, 236 operated, 102 were resectable PDAs thus fulfilling the inclusion criteria. 104 patients had other histologies and 34 were unresectable PDAs. Xenografted tumors were treated with gemcitabine and the activity in the xenograft correlated with patient clinical outcome. Results: Out of these 102 cases, 77 were xenografted, 53 were engrafted and reached the treatment phase. 35 out of the 53 originator patients were clinically treated with gemcitabine. The median overall survival of resected patients was 646 days (similar to 660 days from CONKO-001 trial). Patients whose carcinomas engrafted had a shorter median overall survival (319 vs. 728 days, p=0.002), probably reflecting a more aggressive tumor biology in the engrafted group. The response rate of gemcitabine in xenografts based on RECIST criteria was 8% (similar to response rate to gemcitabine in phase III trial by Moore et al.). In the adjuvant setting, the median disease free survival (DFS) was significantly longer in those patients predicted as sensitive by the xenograft model (568 vs. 286 days, p=0.037). In the metastatic setting, the median time to progression (TTP) was longer in those patients predicted as sensitive by the model (126 vs. 73 days) though this difference was not statistically significant. Overall the correlation between gemcitabine activity in this model and clinical outcome as measured by DFS was 0.71 in the subgroup of patients whose xenografts had a TGI lower than -10%. Conclusions: This preclinical model predicts gemcitabine outcome in the clinic in the adjuvant setting. Further studies to analyze the causes of shorter survival in patients whose PDA engrafted are warranted. No significant financial relationships to disclose.
Clinical trial of the novel structure proteasome inhibitor NPI-0052 in patients with relapsed and relapsed/refractory multiple myeloma (r/r MM)
Authors: C. C. Hofmeister, P. Richardson, T. Zimmerman, M. A. Spear, M. A. Palladino, A. M. Longenecker, G. F. Cropp, G. K. Lloyd, A. L. Hannah, K. Anderson
Journal: Journal of Clinical Oncology (2009)

8505 Background: NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities of the 20S proteasome. NPI-0052 has a non-peptide based structure that appears to result in a unique proteasome inhibition (PI), signal transduction and safety profile. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including MM resistant to bortezomib (BZ) and other agents. Methods: This phase I dose escalation study of NPI-0052 was conducted in patients (pts) with r/r MM, including after BZ and/or lenalidomide. Pts were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated utilizing a combination of accelerated titration and 3+3 designs. PI and PK were assayed after the 1 st and 3 rd doses. Results: 17 patients have been treated at doses ranging from 0.025 mg/m 2 to 0.6 mg/m 2 without reaching a MTD. One patient experienced reversible creatinine elevation associated with progression of light chain nephropathy at 0.075 mg/m 2 . Drug- related adverse events have consisted principally of mild-to-moderate fatigue, nausea and diarrhea. In this study at dose levels 0.75 and 0.15 mg/m 2 , the half-life = 0.5 - 5.0 min; clearance = 4.8 ± 5.2 L/min and Vz = 22.6 ± 44.2 L. PI in whole blood demonstrates dose-dependent chymotrypsin-like inhibition up to 26% at 0.075 mg/m 2 . Of note, 2 patients remained on study for over 6 months and one year with stable disease and no significant toxicity. Importantly, NPI-0052 does not appear to induce peripheral neuropathy or myelosuppression. Conclusions: NPI-0052 was well tolerated in this study with escalation continuing to a recommended phase II dose (RP2D) for r/r MM. The RP2D (0.7 - 0.8 mg/m 2 ), PI and safety profiles of NPI-0052 have been defined in other diagnoses, and appear unique from BZ in spite of up to 100% proteasome inhibition. In this study, NPI-0052 has effects on PD, PK and may potentially confer clinical benefit at doses which are well below the MTD determined in the other trials. Additional trials in MM are being initiated, including with lenalidomide. [Table: see text]
NEUROPHARMACOLOGY OF PERIPHERAL NERVE
Authors: JAMES E.P. TOMAN
Journal: Pharmacological Reviews (1952)

1. Some basic properties of peripheral nerve are discussed, together with notes their measurement and on some typical effects of drugs.

2. The actions of a variety of drugs on peripheral nerve are described.

3. A suggested empirical scheme is presented for the tentative classification drugs acting on peripheral nerve.

4. Interrelationships between drugs in several categories of mechanism of action discussed, with particular attention to the contradictory actions of presumed chemical mediators and blocking agents.

5. The applicability of modern peripheral nerve methodology to brain neuropharmacology is noted.

6. Some speculations are presented on the continuity between resting and active functions in nerve.
E4201: Randomized phase II study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with locally advanced, unresectable, pancreatic cancer (LAPC): Quality-of-life (QOL) analysis
Authors: H. R. Cardenes, M. Powell, P. J. Loehrer, L. I. Wagner, D. F. Cella, J. Brell, R. K. Ramanathan, C. H. Crane, S. R. Alberts, A. B. Benson
Journal: Journal of Clinical Oncology (2009)

4627 Background: E4201 compared radiation and gemcitabine (RT+Gem) versus Gem alone in LAPC. The primary endpoint was overall survival; secondary objectives included: objective response rate (RR), progression-free survival (PFS), toxicity and QOL. We previously reported that RT+Gem was associated with improved overall survival compared with Gem alone [median survival time, 11 months and 9.2 months, respectively; p=0.034], without impact in RR or PFS. (ASCO 2008, abstract # 4506). We now report on QOL as measured by the Hep subscale from the FACT-Hepatobiliary [FACT-Hep] between both arms. Methods: Eligible patients had LAPC adenocarcinoma, PS &lt;2, without prior therapy. They were randomized to Arm A: Gem alone (1,000 mg/m2/week x 3, every 4 weeks, 7 cycles), or Arm B: RT (50.4Gy/28 fractions) plus Gem (600 mg/m2/weekly x 6) followed by 5 cycles of Gem alone (1,000 mg/m2/weekly x 3 every 4 wks). The FACT-Hep was administered at baseline (before starting induction), 6 weeks (immediately after completing induction), week 16 (Arm A) or week 15 (Arm B) mid-consolidation, and at 9 months. Results: From April, 2003 to December, 2005, 74 patients were enrolled, 71 were eligible [37 Arm A; 34 Arm B]. Grade ≥3 was reported in 80% and 82.4% in ARM A and B, respectively (p=1.00). Grade IV toxicities, mainly gastrointestinal and hematologic, were more common in ARM B (41.2% vs 5.7%, p=&lt;0.0001). QOL compliance declined over time, most commonly attributable to either patients or staff choosing not to complete or administer the instrument due to declining health (96%, 69%, 60%, and 40% at baseline, week 6, 15/16 weeks and 9 months, respectively). Within Arm B, QoL scores dropped significantly from baseline to 6 weeks. By week 15, QoL scores for patients on Arm B rebounded to levels similar to baseline. Two-sided Wilcoxon rank sum tests failed to suggest differences in median FACT-Hep subscale score between treatment arms at any of the four time-points (alpha = 0.10). Conclusions: RT+Gem is associated with an overall survival benefit without apparent long term adverse impact on QOL when compared with Gem alone. No significant financial relationships to disclose.
European Collaborative Study of Treatment Outcomes in 347 Patients with Systemic AL Amyloidosis with Mayo Stage III Disease
Authors: Ashutosh Wechalekar, Stefan O Schonland, Efstathios Kastritis, Philip N Hawkins, Meletios A. Dimopoulos, Paola Russo, Thirusha Lane, Andrea Foli, Darren Foard, Paolo Milani, Lisa Rannigan, Ute Hegenbart, Julian D Gillmore, Giampaolo Merlini, Giovanni Palladini
Journal: Blood (2011)
Cancer risk in patients with chronic lymphocytic thyroiditis
Authors: S. Krishnamurthy, S. Kumar, A. Naik, V. Deshmane
Journal: Journal of Clinical Oncology (2008)

17028 Background: To study the Cancer risk in patients with chronic lymphocytic thyroiditis. Methods: The study included 290 patients diagnosed as Hashimotos thyroiditis at our institute over a six year period. Diagnosis was established by FNAC, Anti-thyroglobulin and Anti-microsomal antibody estimation. 163 of 290 patients underwent surgery, for suspicious lesions, remaining treated conservatively. Comparison of the incidence of malignancy in Hashimotos thyroiditis was studied from correlation with clinical findings, FNAC, and histopathology. Sensitivity of identifying malignancy by clinical finding/FNAC and final histopathology was compared. Results: Among 290 patients in our study, 163 patients (56.21%) underwent surgery and 55 (33.7%) patients were found to be harboring malignancy. Of the 47 patients with FNAC positive lesions, only 28 specimens showed malignancy with a sensitivity of 59%. Among 116 FNAC negative lesions 27 specimens harbored malignancy with a specificity of 93%. Conclusions: Hashimotos thyroiditis has a varied presentation. FNAC will not be able to diagnose HT in all the patients. Incidence of malignancy in HT was found to be high, 33.7% of patients undergoing surgery in our study, FNAC was inaccurate in identifying these lesions, indicating the importance of surgery in identifying these suspicious lesions in patients with Hashimotos thyroiditis. We had 33.7% incidence of malignancy in patients undergoing surgery in our study. Every case of Hashimotos thyroiditis should be evaluated based on clinical suspicion and treated by surgery if indicated. No significant financial relationships to disclose.
Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib (IM).
Authors: B. Nguyen, F. Grabellus, M. Hoiczyk, G. Taeger, M. H. Schuler, S. Bauer
Journal: Journal of Clinical Oncology (2010)

10047 Background: Long-term complete remissions remain a rare exception in patients with metastatic GIST. The value of surgical resection of metastatic disease to improve survival remains unknown, and data from a prospective trial will still take years to mature. Hence, identification of patients who might benefit from metastasectomy remains a challenge in clinical practice. Methods: We analyzed our GIST data base (n=209) for overall survival (OS) in patients with metastatic disease (n=117) who underwent metastasectomy at any time of their treatment (n=65). Covariates included perioperative treatment with IM, status of resection, location of metastases and PDGFR/KIT mutational status. Results: Median follow-up (FU) from time to diagnosis and time from first IM doses was 3.4 years and 3.2 years, respectively. 65 patients underwent metastasectomy, with 46 pts (71%) receiving perioperative IM with a median FU of 4 years. Median OS for all patients undergoing metastastectomy was 8 years, as compared to 4 years in pts with metastatic disease not undergoing metastasectomy (p=0.01). Median OS was not reached in 24 pts with macroscopically complete resection (R0=20, and R1 n=4), and 69% of pts are alive after 8 years. In comparison, OS of pts with incomplete resections (R2) was 4 years (p=0.02). Median OS for patients with KIT exon 11 mutation undergoing metastasectomy (n=20) was 6.3 years. Patients with hepatic (± peritoneal) metastases showed a better survival than those with peritoneal metastases only (p=0.02). Conclusions: These findings implicate a possible long-term benefit from R0/R1 metastasectomy in patients with metastatic GIST. In contrast, incomplete resection, including debulking surgery, appears not to be beneficial. However, confounding by selection bias cannot be excluded in this hypothesis-generating, retrospective analysis. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GIST
A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN).
Authors: Jordi Giralt, Andre Fortin, Ricard Mesia, Heikki Minn, Michael Henke, Alejandro Yunes Ancona, Anthony Cmelak, Avi B. Markowitz, Sebastien J. Hotte, Simron Singh, Anthony T. C. Chan, Marco Carlo Merlano, Alicia Zhang, Kelly S. Oliner, Ari M. Vanderwalde
Journal: Journal of Clinical Oncology (2012)

5502 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor. We evaluated the safety and efficacy in pts receiving CRT alone or CRT plus pmab (PCRT) as 1st‑line treatment of LASCCHN (sponsored and funded by Amgen Inc.). Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites excluding the nasopharynx were randomized 2:3 to open-label CRT or PCRT. CRT included cisplatin 100 mg/m 2 for 3 cycles during standard fractionation radiotherapy (RT). PCRT included pmab 9.0 mg/kg + cisplatin 75 mg/m 2 , both administered with RT as in the CRT arm. The primary endpoint was local regional control (LRC) rate at 2 years; key secondary endpoints included PFS, OS, and safety. Preplanned HPV subset analysis, as determined by p16 immunohistochemistry, was performed on available samples. Results: Of 150 treated pts (87 pts PCRT, 63 pts CRT), 87% were men; median (range) age was 57 (39-77) years; ECOG PS 0: 68%. Of 99 pts with tumor evaluable for HPV, 42% were HPV+. Overall, the 2-year LRC rate (95% CI) was 61% (50%-71%) for PCRT and 68% (54%-78%) for CRT. PFS events occurred in 40% of the PCRT and 35% of CRT arm (HR [95% CI] 1.15 [0.68-1.96]; p=0.61). Death occurred in 36% of the PCRT arm vs 24% of the CRT arm (HR [95% Cl] for OS 1.63 [0.88-3.02]; p=0.12). Disease progression was the cause of death in 22% of PCRT pts and 10% of CRT pts. There were no differences in outcome by tumor HPV status. No difference in fatal adverse events (AEs) was seen between arms. Grade 3+ AEs occurred in 85% vs 68% of pts (PCRT vs CRT). Differences in grade 3+ toxicity between treatment arms (PCRT, CRT) were most pronounced for mucosal inflammation (55%, 24%), radiation skin injury (28%, 13%), dysphagia (40%, 27%), and rash (11%, 0%). RT delays of &gt;10 days occurred in 16% of the PCRT arm and 3% of the CRT arm. Median cisplatin cumulative dose received was 223.1 mg/m 2 in the PCRT arm and 296.9 mg/m 2 in the CRT arm, reflective of differences in planned dose. Conclusions: The addition of pmab to CRT did not show an increase in efficacy and was associated with increased toxicity. Further results of HPV biomarker analysis will be presented.
Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer
Authors: F. Fabbri, M. Montanari, G. Cruciani, D. Amadori, W. Zoli
Journal: Journal of Clinical Oncology (2009)

e16026 Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m 2 ) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (&gt; 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of &gt;10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. No significant financial relationships to disclose.
Comparison of HER2 extra cellular domain (ECD) serum level at the time of metastasis with HER2 status modification between primary breast cancers and their respective metastases
Authors: J. Thery, J. Picquenot, M. Cornic, C. Lamarche, V. Raillot, S. Laberge-Le-couteulx, C. Veyret, J. Basuyau, E. Blot
Journal: Journal of Clinical Oncology (2008)

1030 Background: Modification of HER2 level of expression/amplification between primary breast cancer and late metastasis was reported as a rare event. We investigated the usefulness of HER2 ECD serum level assessment at the time of metastasis to identify modification of HER2 status in the metastatic tissue. Methods: We performed a retrospective comparison of HER2 level of expression/amplification on paraffin-embedded tissues from 69 patients of both primary breast cancers and their distant metastasis using immunohistochemistry (IHC) (CB11, Ventana) and chromogenic in situ hybridization (CISH) (Zymed). For 60 patients, frozen serum at time of metastasis was available and HER 2 ECD serum level was measured with an Elisa commercial kit (Oncogene Science); we used 15ng/ml as cut-off value. Results: Among the 69 primary tumors, 9 were HER2 positive, 7 on IHC and 7 on CISH (but 2 of these were only 2+ on IHC). There were 13 metastatic HER2 positive lesions (7 on IHC, 9 on CISH and 3 positive using both methods), resulting in a clinically relevant modification of HER2 status in 8 patients: 6 patients became HER2 positive and 2 patients became HER2 negative on metastatic samples. Among the 60 patients with available frozen serum at the time of metastasis, 16 had elevated HER2 ECD serum level, 7 (54%) of them having a HER2+ metastatic tissue on either IHC or CISH out of the 13 HER2+ metastatic samples whereas in 47 HER2 negative ones, 9 (19%) had an elevated HER2 ECD serum level (p=0.012, Pearson chi-square). Specificity of HER2 ECD serum level was 81% and sensitivity was 54% with a negative predictive value of 86%. Conclusions: In this retrospective series, clinically relevant HER2 status of metastatic tissue was modified in 12% of patients. Elevated HER2 ECD serum level at the time of metastasis was significantly linked with metastatic tissue HER2 overexpression/amplification suggesting its potential utility to select patients for whom metastasis biopsy could change therapeutic strategy. No significant financial relationships to disclose.