tbuckley/cabot-search huggingface dataset:
CALGB 80403/ECOG 1206: A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer.
Authors: P. C. Enzinger, B. Burtness, D. Hollis, D. Niedzwiecki, D. Ilson, A. B. Benson, R. J. Mayer, R. M. Goldberg
Journal: Journal of Clinical Oncology (2010)

4006 Background: ECF (epirubicin, cisplatin, fluorouracil), IC (irinotecan, cisplatin), and FOLFOX (leucovorin, fluorouracil, oxaliplatin) are commonly used regimens for esophagogastric cancer. Cetuximab (C) improves the antitumor activity of platinum-based-therapy in head and neck and colorectal cancer. KRAS is mutated in 2% of esophageal cancers. Methods: Patients (pts) with chemonaïve, metastatic, measurable adenocarcinoma (ADC) or squamous cell carcinoma (SCC) of the esophagus (E) or GE junction (GEJ) were randomized to 3 regimens: (A) epirubicin 50 mg/m2/d1, cisplatin 60 mg/m2/d1, 5-FU 200 mg/m2/d1-21 q 21d; (B) irinotecan 65 mg/m2/d1, 8, cisplatin 35 mg/m2/d1, 8 q 21d; (C) oxaliplatin 85 mg/m2/d1, leucovorin 500 mg/m2/d1, 5-FU 500 mg/m2/d1, 5-FU 1,200 mg/m2/d1-2 q 14d. Pts were stratified by histology-ADC vs. SCC and ECOG performance status—0 and 1 vs. 2. With 64 measurable ADC pts treated per regimen, the study had a 90% power (1-sided) to detect an improvement in major response from 25% to 40%. Results: From 9.06 to 5.09, 245 pts were randomized to 3 regimens: A—82 pts, B—83 pts, C—80 pts. Pt characteristics: M/F—211/34; median age—59(30-86); PS 0/1/2—114/123/8. Tumor characteristics: ADC/SCC—222/23; primary site—E/GEJ—136/88. Conclusions: ECF-C and FOLFOX-C had response rates greater than 40% and met the criteria for further development. ECF-C had a higher response rate but FOLFOX-C was less toxic. IC-C was the least efficacious. Supported by CA31946, Bristol-Myers Squibb, Pfizer, sanofi-aventis. ECF-C IC-C FOLFOX-C Major response, ADC pts % (90% CI); N = 192 34/59 pts (58%; 46-69) 25/66 pts (38%; 29-49) 34/67 pts (51%; 40-61) Progression-free survival median (95% CI); N = 245 5.6 mos (4.3-7.2) 5.0 mos (4.0-5.9) 5.7 mos (4.9- 6.1) Overall survival median (95% CI); N = 245 10.0 mos (7.6-12.1) 8.6 mos (6.8- 12.3) 10.0 mos (8.4-11.9) Toxicity (N = 230 pts) Maximum GIII/IV heme adverse events 51% 56% 45% Maximum GIII/IV nonheme adverse events 60% 70% 64% Maximum GIII/IV overall adverse events 72% 65% 61% Grade V adverse events 6% 3% 0% Treatment modification 81% 82% 70% (p=0.0009) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, ImClone Systems, Pfizer, sanofi-aventis Roche, sanofi-aventis ImClone Systems, Pfizer, sanofi-aventis
Role of Suppressor Cells in Depression of In Vitro Lymphoproliferative Responses of Lung Cancer and Breast Cancer Patients&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: T R Jerrells, J H Dean, G L Richardson, J L McCoy, R B Herberman
Journal: JNCI Journal of the National Cancer Institute (1978)
MART-1 Is Expressed Less Frequently on Circulating Melanoma Cells in Patients Who Develop Distant Compared With Locoregional Metastases
Authors: Benjamin J. Curry, Kieda Myers, Peter Hersey
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Polymerase chain reaction (PCR) with tyrosinase and with MART-1 permits detection of small numbers of circulating melanoma cells (CMCs) in patients who have undergone surgical resection of localized disease. In a previous study, we showed that PCR with MART-1 had sensitivity and specificity similar to those of PCR with tyrosinase in terms of detection of CMCs but that PCR with MART-1 seemed to identify a different but overlapping subgroup of patients. In the current study, we examined the utility and prognostic significance of PCR with tyrosinase and with MART-1. PATIENTS AND METHODS: We analyzed the prognostic significance of the patterns of expression of tyrosinase and MART-1 in 186 patients followed sequentially before and after surgical removal of American Joint Committee on Cancer stage I, II, or III melanoma. RESULTS: PCR with tyrosinase and with MART-1 in the first 3 months after surgery identified 68.5% of 73 patients who developed recurrence in the 2-year period after surgery. Approximately 35% of patients with positive tests remained disease-free at 2-year follow-up. We found that patients with disseminated recurrence had a significantly lower incidence of MART-1–positive CMCs (16%) than of tyrosinase-positive CMCs (63%). Patients with locoregional metastases had CMCs that expressed tyrosinase and MART-1 at similar rates. These differences in expression of the markers in patients with disseminated recurrence were also associated with a much lower disease-free survival, in those who had CMCs that were positive for tyrosinase but negative for MART-1. The reverse applied in those with locoregional disease. CONCLUSION: These findings suggest that PCR with MART-1 and with tyrosinase identifies subgroups of patients who develop disseminated or locally recurrent metastases. We hypothesize that immune responses against MART-1 may reduce the establishment of disseminated metastases.
Abstract 30: Nub1l Suppresses Neddylation And Enhances Misfolded Protein Clearance In Cardiomyocytes
Authors: Huabo Su, Jie Li, Wenxia Ma, Ning Hou, Faqian Li
Journal: Circulation Research (2014)

Protein modification by ubiquitin (Ub) or Ub-like proteins such as NEDD8 (neddylation) constitutes a fundamental regulatory mechanism of protein function. In contrast to well-recognized role of Ub in protein degradation, little is known about the role of NEDD8 in protein quality control. We have previously revealed that CM-restricted inactivation of deneddylation, a process that removes NEDD8 from modified proteins, accumulates neddylated proteins and impairs proteasomal and autophagic proteolysis. Here we report that proteasome inhibitors, simulated ischemia/reperfusion and H2O2 significantly increase NEDD8 conjugates in cardiomyocytes (CMs). Immunoprecipitation analysis reveals mixed modification of these proteins by Ub and NEDD8. Expression of NEDD8 but not the conjugation-deficient mutant increases neddylated proteins and accumulates a proteasome surrogate substrate GFPu in a dose-dependent manner, suggesting that excessive neddylation disrupts proteasomal proteolysis. We further targets to NUB1L, a UBL (Ub-like domain)-UBA (Ub associating domain) family protein that was shown to negatively regulate neddylation. NUB1L expression markedly reduces free NEDD8 by promoting its degradation, and abrogates proteasome inhibition-induced neddylation in CMs. Suppression of neddylation by NUB1L expression enhances GFPu degradation at baseline, and attenuates GFPu accumulation upon sI/R and H2O2 treatment. Furthermore, NUB1L expression promotes, while down-regulation of NUB1L impairs, the clearance of a bona fide misfolded protein in CMs. NUB1L expression also ameliorates proteotoxic stress- and sI/R-induced CM injury. Finally, increased NEDD8 conjugates are evident in the mouse hearts of a number of cardiac disease models as well as in human failing hearts. Together, our findings suggest that excessive neddylation disrupts protein quality control and that antagonizing neddylation by NUB1L promotes misfolded protein degradation. Targeting neddylation/NUB1L could be a novel therapeutic strategy for prevention and treatment of insufficient protein quality control-associated cardiac disease.
Immune Response to Inactivated Syngeneic Mammary Adenocarcinoma Cells. II. Parameters of Immunogenicity in DBA/2 Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: F DeLustro, J S Haskill
Journal: JNCI Journal of the National Cancer Institute (1980)

With the use of the DBA/2 mammary adenocarcinoma (T1699), the early events that occurred after a single sc injection of untreated or inactivated tumor cells in the syngeneic host were investigated. Examination of the vascularization of the site of sensitization revealed that by day 3, injection of irradiated T1699 tumor cells (XR-T1699) induced the same high level of blood vessel formation as did untreated T1699 tumor cells (T1699u). Whereas the former then decreased, the latter peaked at day 5 and gradually tapered off. Inoculation sites of mitomycin C-treated T1699 tumor cells (T1699m) were poorly vascularized at all times and stimulated a predominantly granulocyte host cell response that peaked at day 1. XR-T1699 caused a peak granulomatous response at day 5, which was distinguished by increased levels of mononuclear cell infiltration. XR-T1699 showed much longer survival and replicating potential than did T1699m in vivo. However, an increased dose of radiation to 30 krads did not significantly reduce the ability of the XR-T1699 immunization to induce anti-T1699 antibody synthesis and protection against subsequent tumor cell challenge. Surgical excision of the XR-T1699 granuloma at day 3 prevented immunization as indicated by the lack of significant antibody-dependent cellular cytotoxicity (ADCC) activity in the sera of these mice and by their inability to reject a subsequent challenge with T1699u However, removal at day 5 did not decrease the ADCC titer below levels seen in XR-T1699-sensitized mice that were not surgically treated and did not alter the ability of those mice to reject a T1699u challenge.
Independent Examination of Patients Hospitalized Against Their Will
Authors: IRWIN N. PERR
Journal: American Journal of Psychiatry (1974)

The justification for legal commitment of the mentally ill has come under increasing public and professional scrutiny. While there have been few abuses or errors, certain types of problems are more likely to be reflected in unmerited hospitalization. This paper reviews nine hospitalizations in which an independent psychiatric review was requested by a private attorney. In three of the nine cases, mandatory hospitalization was not justified. Problem cases involved individuals with a history of mental illness, domestic or marital disputes, and organic mental illness—particularly those related to aging. Another factor to be kept in mind is that examination at a later date may reflect the marked improvement that has occurred clinically rather than the symptom picture at the time of hospitalization.
Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors
Authors: Dejan Juric, Rodrigo Dienstmann, Andres Cervantes, Manuel Hidalgo, Wells Messersmith, George R. Blumenschein, Josep Tabernero, Desamparados Roda, Antonio Calles, Antonio Jimeno, Xiaodong Wang, Sandra Sanabria Bohórquez, Cecilia Leddy, Catherine Littman, Amy V. Kapp, David S. Shames, Elicia Penuel, Lukas C. Amler, Andrea Pirzkall, José Baselga
Journal: Clinical Cancer Research (2015)

Abstract Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1–30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. Results: No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non–small cell lung cancer (n = 3). Conclusions: MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer. Clin Cancer Res; 21(11); 2462–70. ©2015 AACR.
Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer: a multicenter German randomized trial.
Authors: M Wolf, K Havemann, R Holle, C Gropp, P Drings, K Hans, M Schroeder, M Heim, M Dommes, S Mende
Journal: Journal of Clinical Oncology (1987)

A total of 144 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin/etoposide (PE) or ifosfamide/etoposide (IE) combination chemotherapy. PE consisted of cisplatin, 80 mg/m2, intravenously (IV) on day 1, and etoposide, 150 mg/m2, IV on days 3 through 5. IE consisted of ifosfamide, 1,500 mg/m2, IV on days 1 through 5, and etoposide, 120 mg/m2, IV on days 3 through 5. Six cycles were administered in 3-week intervals. Nonresponders were switched immediately to CAV, consisting of cyclophosphamide, 600 mg/m2, IV on days 1 and 2, Adriamycin (Adria Laboratories, Columbus, OH), 50 mg/m2, IV on day 1, and vincristine, 2 mg, IV on day 1. Patients obtaining complete remission (CR) received prophylactic cranial irradiation with 30 Gy. After completion of chemotherapy, patients with limited disease received chest irradiation with 45 Gy. No maintenance therapy was given to patients in CR. Minimum follow-up was 2 years. Of the 141 patients evaluable, the overall response rate was 65% in PE therapy and 68% in IE therapy. The CR rate was 32% v 20% for all patients, 50% v 24% for limited disease, and 22% v 18% for extensive disease, all in favor of PE therapy. Median survival for all patients was 11.6 months v 9.4 months, for limited disease 14.8 months v 11.0 months, and for extensive disease 8.9 months v 7.5 months, all preferring PE therapy. The 2-year survival rate was higher in PE therapy than in IE therapy for all patients (12% v 9%) and for limited disease (23% v 10%), but not for extensive disease (5% v 9%). Median progression-free survival was 7.5 months v 6.0 months for all patients, 12.2 months v 8.8 months for limited disease, and 5.9 months v 4.4 months for extensive disease, all in favor of PE. Relapse in the area of the primary tumor was found less often after PE than after IE therapy (25% v 38%). Response to second-line CAV was seen in 30% of patients with prior PE and 43% with prior IE therapy, but was usually short lasting, and only one patient achieved CR. Toxicity included three lethal complications. Nausea, vomiting, diarrhea, and skin lesions occurred more often after PE than after IE therapy. These results suggest that PE is superior to IE chemotherapy in limited-stage, but not in extensive-stage SCLC, and that CAV is cross-resistant to PE, as well as to IE in the majority of patients.
Survival outcomes of non small cell lung cancer (NSCLC) patients who are suitable for radical treatment at initial presentation
Authors: Masood Ahmad Khalil, Joyce Barclay
Journal: European Respiratory Journal (2011)

Background: Lung cancer survival continues to remain poor despite the availability of better diagnostic & management strategies; as most patients have advanced disease at presentation with poor performance status (PS) & coexisting morbidities. All patients with limited disease bulk & good PS should be offered radical treatment to improve overall outcomes.

Aims: To assess the number of NSCLC patients who were suitable for treatment & determine the reasons for either not receiving or completing treatment. To compare outcomes of those who completed treatment with those who did not.

Methods: Retrospective study of all (136) newly diagnosed NSCLC (Jun 2008-May 2009). 9 were excluded (insufficient data).

Results: Of the 127 patients, 93% aged >/= 60, 52% females, 95 were not suitable and 32 were suitable for treatment. 28 received treatment (8 surgical resection, 8 radical radiotherapy, 12 chemo-radiotherapy) and 4 either did not receive or complete treatment (1 refused treatment, 1 deteriorated while receiving radical radiotherapy, 1 recurrent chest infections with deterioration, 1 treatment related side effects).

View this table:

Table 1





Conclusion: Although, carefully selected patients who received treatment showed better survival, a good number of suitable patients (12%) either did not receive or complete treatment resulting in poor prognosis. Holistic approach is required in dealing with this unfortunate group.
Treatment of severe lithium-induced polyuria with amiloride
Authors: T R Kosten, J N Forrest
Journal: American Journal of Psychiatry (1986)

One of the major side effects of lithium is nephrogenic diabetes insipidus. The established treatment for the disorder is thiazide diuretics, which are associated with hypokalemia and reduced lithium excretion, predisposing the patient to lithium toxicity. Amiloride is a new diuretic that reduces lithium-induced polyuria in animals without affecting lithium or potassium levels. The authors found that 10-20 mg/day of amiloride given to eight patients who had become hypokalemic while being treated with hydrochlorothiazide for lithium-induced nephrogenic diabetes insipidus increased renal concentrating ability and reduced polyuria. They conclude that amiloride can be useful in treating lithium-induced nephrogenic diabetes insipidus and merits future randomized clinical trials.
Durable Remission After Aggressive Chemotherapy for Very Late Post–Kidney Transplant Lymphoproliferation: A Report of 16 Cases Observed in a Single Center
Authors: M-F. Mamzer-Bruneel, C. Lomé, E. Morelon, V. Levy, P. Bourquelot, F. Jacobs, A. Gessain, E. Mac Intyre, N. Brousse, H. Kreis, O. Hermine
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Posttransplant lymphoproliferative diseases (PTLDs) represent a group of potentially lethal lymphoid proliferations that may complicate the course of solid organ transplantation. Although early-onset PTLDs frequently have a favorable outcome, late-onset PTLDs behave more alike aggressive lymphoma. We report a monocentric retrospective study that focused on PTLDs occurring later than 1 year after kidney transplantation (very late–onset PTLDs) to define their incidence, clinical presentation, pathologic features, and outcome. We particularly emphasized the follow-up of patients treated with conventional chemotherapy. PATIENTS AND METHODS: The medical histories of all patients who developed very late–onset PTLD in our institution were reviewed, and diagnostic biopsy materials were retrospectively studied. RESULTS: Very late–onset PTLDs were diagnosed in 16 (1.1%) of 1,421 patients. Mean (± SD) time to tumor onset was 103.93 ± 70.88 months. Most tumors were Epstein-Barr virus–related monomorphic large-cell PTLDs of B phenotype. Ten patients received conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone regimen). Two of them died within 2 months, two achieved partial remission, and six achieved definitive complete remission. Overall median survival time was 13 months and rose to 27 months in the treated group. The main cause of mortality was sepsis. None of the treated patients experienced rejection despite withdrawal of immunosuppressive treatment. CONCLUSION: Despite characteristics of aggressive lymphoma, very late–onset PTLDs after renal transplantation may respond to conventional chemotherapy. However, because a high rate of infectious complications occurred, new therapeutic strategies, such as combinations of anti-CD20 monoclonal antibodies and lower doses of chemotherapy, are warranted.
Treatment of metastatic breast cancer with alternative vinorelbine and gemcitabine
Authors: D. L. Stanculeanu, A. Cringeanu, L. N. Minea, R. M. Anghel, N. Gutulescu
Journal: Journal of Clinical Oncology (2004)

800 Background: In Romania, most breast cancer cases are locally advanced or metastatic. Single agent therapy with gemcitabine or vinorelbine showed good tolerability and efficacy in advanced breast cancer. Methods: to evaluate safety profile and efficacy of alternatively gemcitabine and vinorelbine regimen in pretreated metastatic breast cancer. 32 patients were included between October 2001 -October 2002. All patients had prior chemotherapy with antracicline or taxane. They had progression or recurrence within 6 month of prior treatment. They had measurable or evaluable disease. Median age was 52 years. Performance status was ECOG 0–2. Metastatic sites: liver -9 patients, lung -8 patients, bone -17 patients, soft tissue -6 patients. Treatment schedule: Gemcitabine 1000 mg/m2 given on day 1, 15, 29, 43, 57, etc and vinorelbine 25 mg/m2 given on day 8, 22, 36, 50, etc. until disease progression; the median duration of administration was six month. Results: The treatment was well tolerated. Grade 1–2 myelosuppression was commonly observed; grade 3–4 neutropenia - 4 patients (12.5%), never complicated with septicaemia, grade 3 anemia - 2 patients (6.25%), grade 3 trombocitopenia -1 patient (3.12%). Grade 2 neurotoxicity was observed in 3 patients (9.37%). Grade 1–2 gastrointestinal toxicity (nausea/emesis) occurred in 13 patients (40.62%). Malaise or flu-like syndrome were mild and occurred in 9 patients (28.12%). No treatment-related death was observed with gemcitabine -vinorelbine alternative regimen. No patients required dose reduction. One patient was not evaluable for tumor response. Overall response rate was 31.25% (2 patients (6.25%) complete response, 8 patients (25%) partial response); 12 patients had stable disease (37.5%) and 9 patients progressive disease (31.25%). The median time to progression was 8,3 month. Conclusion: Our results suggest that gemcitabine and vinorelbine alternative administration has an acceptable efficacy and a favorable safety profile. No significant financial relationships to disclose.