tbuckley/cabot-search huggingface dataset:
Loss of Apaf-1 expression and resistance to hypoxia-induced apoptosis in cervical cancer
Authors: C. Leo, L. Horn, C. Rauscher, C. E. Richter, B. Hentschel, M. Hoeckel
Journal: Journal of Clinical Oncology (2006)

5046 Background: Clinical observations suggest that intratumoral hypoxia may increase the aggressiveness of tumors through clonal selection of cancer cells that have lost their apoptotic potential. We have shown previously that patients with hypoxic cervical cancers displaying a low apoptosis rate had a significantly worse prognosis compared to all other patients. The aim of this study, therefore, was to investigate the expression of the proapoptotic protein Apaf-1 in cervical cancers and to analyze its relation to intratumoral hypoxia and apoptosis. Methods: 56 patients with cervical cancer (FIGO stage IB to IV) were subjected to pretherapeutical intratumoral pO 2 measurement with the Eppendorf electrode after informed written consent was given by each patient. The study was approved by the Ethics Committee of the University of Leipzig. Cervical cancer tissue from these patients was taken by needle core biopsy and analyzed by TUNEL assays as well as by immunohistochemistry with an anti-Apaf-1-antibody. For statistical analysis, Fisher’s exact test was used. Results: Apaf-1 was expressed in 86% of cervical cancers. The median apoptosis rate was 1.0% (range: 0.3– 3.4%). There was no direct correlation between Apaf-1 expression and intratumoral hypoxia. However, in the group of hypoxic cervical cancers (pO 2 &lt;10 mmHg) with a low apoptosis rate (&lt;1.0%), 43.8 % (95% CI: 19.8–70.1%) of tumors showed a negative Apaf-1 expression compared to only 2.5% (95% CI: 0.06–13.1%) in non-hypoxic cancers and hypoxic cancers with a high apoptosis rate (p = 0.0003, Fisher’s exact test). Conclusions: While Apaf-1 is expressed in the vast majority of cervical cancers, a significant proportion of tumors with low apoptosis rates despite intratumoral hypoxia showed a loss of Apaf-1 expression. This finding suggests a mechanism by which hypoxic cervical cancers acquire resistance to apoptosis. No significant financial relationships to disclose.
Plasma DNA: A molecular marker for the pattern of dissemination of esophageal cancer
Authors: F. Banki, J. A. Hagen, R. J. Mason, S. R. DeMeester, D. Oh, W. N. Yacoub, P. V. Danenberg, T. R. DeMeester
Journal: Journal of Clinical Oncology (2007)

21015 Background: We previously showed that free DNA is present in blood of normal subjects and that the plasma DNA level is higher in patients with esophageal cancer compared to normal subjects. These observations suggest that the plasma DNA level may be a useful molecular marker in the diagnosis of esophageal cancer. We hypothesize that lymphatic and hematogenous spread may result in different plasma DNA levels despite both representing advanced disease. Our aim was to measure and compare plasma DNA levels in normal subjects, patients with localized esophageal cancer, patients with lymph node metastases, and patients with hematogenous spread to solid organs (systemic metastases). Methods: Plasma DNA was measured using PCR in 44 normal subjects, 25 patients with localized esophageal cancer (T1–3, N0, M0), 18 patients with lymph node metastases, and 7 patients with systemic metastases. Results: The 95th percentile of plasma DNA level in normal subjects was 19 ng/ml. The median plasma DNA levels were higher in all 3 groups of patients with esophageal cancer compared to control subjects. While there was no difference between the plasma DNA level in patients with localized esophageal cancer and those with lymph node metastases (median of 5 nodes involved, range: 1–31), patients with systemic metastases had a significantly higher level of plasma DNA compared to patients with lymph node metastases and those with localized esophageal cancer. Conclusion: Plasma DNA levels are elevated in patients with esophageal cancer, whether localized or associated with lymph node metastases. In patients with systemic metastases, a significant additional increase in the plasma DNA level occurs. This suggests that measuring the plasma DNA level is a useful molecular diagnostic tool for detection of disseminated esophageal cancer. [Table: see text] No significant financial relationships to disclose.
Irinotecan (CPT-11) pharmacokinetics (PK) and neutropenia: interaction among <i>UGT1A1</i> and transporter genes
Authors: F. Innocenti, S. D. Undevia, G. L. Rosner, L. Xiao, W. Liu, P. Chen, S. Das, J. Ramirez, D. L. Kroetz, M. J. Ratain
Journal: Journal of Clinical Oncology (2005)

2006 Background: We have previously shown that UGT1A1 and ABCC2 gene polymorphisms are likely to play an important role in CPT-11 PK variability. Among several variants tested, -3156G>A in UGT1A1 and 3972C>T in ABCC2 showed the strongest phenotypic effect. However, several other ABCC2 variants have been shown to affect ABCC2 expression in vitro. The organic anion transporter polypeptide-1B1 (OATP-1B1, SLCO1B1) is involved in the liver uptake of several compounds. This study aims to evaluate the effects of ABCC2 haplotypes and SLCO1B1 genotypes on CPT-11 PK and neutropenia. Methods: We studied 65 pts previously assessed for PK and toxicity (JCO, 2004). Six SNPs in ABCC2 were genotyped [-1549G>A, -1019A>G, -24C>T, 1249G>A, intron 27 -34C>T, 3972C>T] and haplotypes were estimated. Two SNPs in SLCO1B1 [*1b (388A>G) and *5 (521T>C)] were also genotyped. Results: Twelve ABCC2 haplotypes were identified, with haplotypes 2, 3, 4, 7, and 6 having a frequency of 0.33, 0.22, 0.14, 0.12, and 0.05, respectively. Haplotype 4 was correlated with SN-38G/SN-38 AUC ratios (p<0.0001). SLCO1B1*5 genotype was correlated with SN-38G AUC (p=0.001) and CPT-11 AUC (p<0.0001). Pts with SLCO1B1*5 CT+CC genotype had a higher CPT-11 AUC compared to TT genotype (29.5±8.8 vs. 22.3±5.1 μg*h/ml, p=0.0001). SLCO1B1*1b was associated with an increased ln(ANC nadir), although with borderline significance (p=0.07). The best multivariate model for ln(ANC nadir) included UGT1A1 -3156G>A (p=0.03), SLCO1B1*1b (p=0.03), ABCC2 haplotype 4 (p=0.02), total bilirubin (p<0.0001), and gender (p=0.04) (r2=0.49, p<0.0001). Conclusions: SLCO1B1*5 appears to affect CPT-11 clearance. SLCO1B1, ABCC2 and UGT1A1 gene variants may have additive effects on neutropenia. Additional studies of the relationship of common ABCC2 and SLCO1B1 variants to CPT-11 PK and toxicity are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration FDA
Polymorphisms of transforming growth factor-β1 (TGF-β1) and recurrence in stage II and III colon cancer
Authors: A. E. Hendifar, W. Zhang, D. Y. Yang, A. E. Khoueiry, S. Iqbal, H. J. Lenz
Journal: Journal of Clinical Oncology (2005)

3634 Background: The biologic effects of the TGF-β signaling pathway are context dependant and range from inhibiting cell growth to inducing differentiation, apoptosis, cell migration, adhesion and extra-cellular matrix deposition. Recent studies indicate that TGF-β1 serum levels and variants in TGF-β receptors may be associated with outcome and prognosis in colorectal cancer. A common polymorphism of TGF-β1 (T29C), the CC genotype, is associated with higher TGF-β1 serum levels. We hypothesized the inheritance of this polymorphism may help predict recurrence in stage II and III colon cancer. Methods: A retrospective study was designed to examine molecular determinants of recurrence in stage II or III colon cancer patients who received adjuvant chemotherapy. Between 1/94–9/02 specimens were obtained from about 98 patients receiving adjuvant 5-fluorouracil based chemotherapy for stage II or III colon cancer at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) or the Los Angeles County/University of Southern California Medical Center (LAC/USC). DNA was extracted from peripheral blood and the genotypes were analyzed using the fluorogenic 5’-nuclease assay. TGF-β1 polymorphisms data were available in 42 patients in the preliminary analysis. Results: There were 22 women and 20 men with median age of 61 (range 28–85) years. Twenty-five patients had stage II disease and 17 had stage III disease. The median follow-up was 4.8 years. Eleven patients had developed recurrence. The probability of 5-year recurrence was 0.28 (±0.09 SE). We found that patients carrying C/C genotype (n=9) tended to have a higher risk of recurrence (p<0.001 logrank test), comparing to those carrying T/T (n=11) or T/C genotypes (n=22), independent of N-stage. Conclusions: The TGF-β signaling pathway plays a significant role in colon cancer development and progression. These results indicate that TGF-β1 may be an important predictor of recurrence in stage II and III colon cancer. A larger prospective study of TGF-β1 and recurrence in patients with stage II or III colon cancer is warranted to better characterize the association. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron, Response Genetics, Gentec Roche, Pfizer, Lilly Oncology, Sanofi NCI, NIH
Prospective Observational Cohort Study of Second-Line Chemotherapy Administration After the First-Line Platinum-Based Chemotherapy for Patients with Advanced Nsclc in Japan (Sapphire Study): Update Analysis
Authors: Y. Goto, K. Yoh, Y. Naito, K. Kishi, Y. Ohashi, H. Kunitoh
Journal: Annals of Oncology (2014)
P-210 Detection of epithelial-mesenchymal transition in colorectal cancer in consideration of intratumor heterogeneity
Authors: Y. Muto, K. Suzuki, K. Ichida, Y. Takayama, T. Fukui, N. Kakizawa, F. Watanabe, T. Kato, M. Saito, F. Konishi, T. Rikiyama
Journal: Annals of Oncology (2015)
Prospective control trial of cancer ultrastaging in the left colon with sentinel lymph node
Authors: R. Hernando, X. Serra, J. Bombardó, A. Casalots, E. Mena, J. Martín, F. Junquera, C. Pericay, S. Navarro
Journal: Journal of Clinical Oncology (2007)

14547 Background: The use of the sentinel node lymph (SNL) in connection with colorectal cancer is a subject in which there has been some controversy. Methods: Prospective control trial of 60 patients with left colon cancer stage II. Methylene Blue® or Nanocoll® had been used to identify the SNL. The standard pathologic examination with hematoxylin and eosin (H&amp;E) had been compared with the study of SNL with H&amp;E and Cytokeratine CAM 5.2. Results: Identification of the SNL: 100%, 2.4 SNL detected in each patient. Nodal disease (N+) was found in 19 patients (31.7%), and 41 patients (68.3%) were classified as node-negative (N0). Hidden micrometastasis in the SNL were found in 9.7% (4/41) patients considered as N0 by conventional histopathology. However, in 17.7% (7/41) patients considered as N0 we found large cell clusters, contatining up to 10 tumor cells, falling short of the AJCC on cancer criteria, and were considered to have high- risk disease. Having applied both the SNL study and the standard pathologic examination the number of patients N+ has increased to 38.3% (23 patients), ultrastaging: 6.6% (p= ns). If the patients with large cell clusters in the SNL had been considered as N+ the number of N+ patients would have increased to 50%(30 patients), ultrastaging 18,3%(p=0,001). Conclusions: The combined nodal study (H&amp;E + SNL) increased 6.6% the staging in our group, and it let to identify a group of patietnts N0 with high-risk tumor progression. If the large cell clusters in the SNL were considered as micrometastases disease the ultrastaging would have been 18.3%.The implications of large cell clusters prognosis is yet, unknown. No significant financial relationships to disclose.
A comparison of delusional disorders in women and men
Authors: M Rudden, J Sweeney, A Frances, M Gilmore
Journal: American Journal of Psychiatry (1983)

The authors compared delusional disorders in men and women and found that women have more frequent erotic and heterosexual delusions, more affective symptoms, and more interpersonal precipitants and that men have more delusions with a homosexual theme. Perhaps because of these differences in delusional content and affective symptoms, delusional women are more difficult to diagnose within the DSM-III nomenclature than are delusional men. The authors discuss these findings from psychodynamic, ethologic, and sociocultural perspectives and suggest ways of improving DSM-III to make it more representative of female patients.
Does positron emission tomography (PET) improve our ability to detect residual neck node (NN) disease in patients with squamous cell head and neck cancer (SCHNC) after definitive chemoradiotherapy?
Authors: A. Tan, D. J. Adelstein, R. M. Esclamado, L. A. Rybicki, J. P. Saxton, B. G. Wood, R. R. Lorenz, M. Strome, M. A. Carroll
Journal: Journal of Clinical Oncology (2006)

5526 Background: Management of the neck in patients undergoing non-operative treatment for SCHNC is controversial. This study details our experience using the neck exam, computerized tomography (CT), and PET to clinically evaluate patients for residual NN disease after definitive chemoradiotherapy. Methods: We retrospectively reviewed all patients with SCHNC with NN involvement at presentation, who were treated with definitive concurrent chemoradiotherapy using fluorouracil and cisplatin. Clinical restaging by neck exam, CT, and PET was accomplished 8–12 weeks after completion of treatment. Residual palpable nodes on exam, residual nodes larger than 1 centimeter, or with central necrosis on CT, or any residual hypermetabolic lymph nodes on PET were considered to be clinical evidence of residual NN disease. Persistent NN disease was confirmed only if pathologic involvement was identified at the time of neck dissection, or if regional recurrence developed. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy (Acc) were calculated for all three clinical assessment tools. Results: The study included 43 patients with 64 positive necks at diagnosis, followed for a median of 11.5 (range 3.9–43.3) months. All but two patients are alive. Planned neck dissection was performed in 26 necks after chemoradiotherapy, and was positive in four. Recurrent primary site or NN disease prompted a delayed neck dissection in eight necks, which was positive in three. The utility of these clinical assessment tools and combinations thereof are detailed in the table . Conclusions: Residual NN disease after definitive chemoradiotherapy was infrequent and not well predicted by PET. A positive PET in this setting is of little utility. Although a negative PET was highly predictive for control of neck disease after chemoradiotherapy, it added little to the clinical neck exam and the CT. [Table: see text] No significant financial relationships to disclose.
Second Japan-SWOG common arm analysis of paclitaxel/carboplatin in advanced stage non-small cell lung cancer (NSCLC): A model for testing population-related pharmacogenomics
Authors: J. Crowley, K. Furuse, M. Kawahara, M. Fukushima, T. Kawaguchi, S. Williamson, P. N. Lara, P. C. Mack, D. R. Gandara
Journal: Journal of Clinical Oncology (2006)

7050 Background: Whether results of clinical trials performed outside the United States (US) can be fully extrapolated to US populations remains in question due to potential differences in trial designs, study-specific criteria, patient demographics, and population-related pharmacogenomics. The first of these comparisons, FACS-S0003 has been presented (Gandara, PASCO, 2004). Here we present the second comparative analysis. Methods: We prospectively designed &amp; conducted 3 separate phase III trials in advanced NSCLC linked by a “common arm” with identical eligibility, staging, response &amp; toxicity criteria, to: 1) determine similarities &amp; differences in patient demographics &amp; outcomes in cooperative group trials in Japan (in this analysis, the Japan Multinational Trial Organization LC03) &amp; the US (SWOG 0003), 2) provide the basis for global standardization in clinical trials in NSCLC, and 3) facilitate regulatory changes needed for joint Japan-US studies. We performed a planned comparative analysis of the paclitaxel/carboplatin arms from LC03 &amp; S0003, which had identical doses and schedules of paclitaxel dose (225mg/m 2 ) and carboplatin (AUC 6). Conclusions: 1) This common arm analysis, as in our prior FACS-S003 report, shows great similarities in patient demographics between the LC03 and S0003. 2) Variable toxicities may be due to population-related pharmacogenomics (increased neutropenia &amp; febrile neutropenia in LC03), and could be explained by polymorphisms in cytochrome P450 for paclitaxel metabolism (ongoing analysis). 3) Survival is increased in LC03. 4) Future joint Japan-US clinical trials should assess possible pharmacogenomic differences in drug disposition. [Table: see text] No significant financial relationships to disclose.
Lenalidomide, bendamustine, and rituximab as first-line therapy for patients &gt; 65 years with mantle cell lymphoma: The Nordic Lymphoma Group MCL4 (LENA-BERIT) trial.
Authors: M. Jerkeman, A. Kolstad, A. Laurell, R. Räty, K. Gr∅nbæk, C. Geisler
Journal: Journal of Clinical Oncology (2010)

e18567 Background: Mantle cell lymphoma is a disease of the elderly, with a median age of 70 years. Younger patients may be treated with potentially curative treatment including high dose chemotherapy. (Geisler CH. Blood. 2008;12:2687-93.) For elderly patients, however, no standard therapy has been defined. In a randomized comparison between R-CHOP and R-bendamustine (R-B) by the German StiL Group, R-B was associated with less toxicity and improved outcome, making R-B the preferable first-line therapy. (Rummel, M.J, American Society of Hematology. 2009: New Orleans, Abstract 405.) Lenalidomide is another active agent in MCL, with a response rate of 53% in relapsed/refractory MCL. (Wiernik, P.H, J Clin Oncol. 2008;26:4952-7.) In the current trial, we investigate if the addition of lenalidomide to R-B may enhance efficacy, with manageable toxicity, for the older population of MCL patients. Methods: In phase I, the MTD of lenalidomide will be determined, starting with 5 mg/day given up to 25 mg/day in sequential dose escalation by a 3+3 design. Additional subjects are enrolled at the MTD on the phase II portion, up to a total number of 60 patients. Lenalidomide, bendamustine and rituximab are given in 6 cycles/28 days. Lenalidomide D1-21, bendamustine 90 mg/m2 D1-2 and rituximab 375 mg/m2 D1. The maintenance phase, consists of lenalidomide 25 mg/day, D1-21, for 7 cycles. Eligibility criteria are age > 65 years, or ≤ 65 years, unable to tolerate high dose chemotherapy, with untreated mantle cell lymphoma, stage II-IV. Results: The trial was commenced in October 2009, and will recruit patients from an initial 17 centres in Sweden, Norway and Denmark. Centres in Finland will be activated at a later stage. The planned study duration is 2 years. Conclusions: A prolongation of median PFS with 6 months compared to the R-B arm in the StiL study is considered clinically significant, meriting further study of the LBR regimen in a phase III setting. In a preliminary analysis of the STiL study, the median PFS for patients with MCL in the R-B arm is 30 months, indicating that a median PFS of ≥ 36 months with the LBR regimen would be a clinically significant improvement. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene
Long-term follow-up of metastatic renal cancer patients undergoing reduced-intensity allografting
Authors: M. Bregni, M. Bernardi, P. Servida, A. Pescarollo, R. Crocchiolo, E. Treppiedi, P. Corradini, F. Ciceri, J. Peccatori
Journal: Journal of Clinical Oncology (2009)

7037 Background: Stem cell transplantation from a HLA-compatible sibling donor is an adoptive immunotherapy for cytokine-refractory, metastatic clear-cell renal cell cancer (RCC). However, the recent introduction of targeted therapy compounds has reduced the interest in this therapeutic strategy. We have reanalyzed our series with the aim to assess long-term benefit from allografting. Methods: Twenty-five RCC patients (Table) received a reduced-intensity allograft from an HLA-identical sibling donor after a thiotepa, fludarabine, and cyclophosphamide conditioning regimen, and a cyclosporine-based GVHD prophylaxis. Allogeneic peripheral blood hematopoietic cells were collected by apheresis after filgrastim treatment of the donor. Results: Best response to allograft was evaluable in 24 patients: 1 complete remission, 4 partial remissions, 12 minor response or stable disease, 7 progressive disease. Six patients died because of transplant related mortality (TRM) at day +12, +71, +86, +151, +259, +478. Cause of death was infection in four cases, GVHD in one case, and acute renal failure in one case. Fourteen patients died for progressive disease at median 415 (36–958) days from transplant. One-year survival was 48%, and 5-yr survival was 20%. At a median observation time of 65 months, 5 patients are alive, one in CR, one in PR, and three with stable disease. At multivariate analysis, CRP value before transplant, number of CD34+ infused cells and disease status at +90 significantly correlated with survival. Survival of patients at favourable/intermediate-risk according to the MSKCC score that underwent allografting was better in comparison to the survival predicted by historical controls. Conclusions: Transplantation is able to induce long-term disease control in a fraction (20%) of relapsed RCC patients. Identifying patients who could benefit from allografting, and incorporating molecularly targeted drugs in the transplant regimen, could further decrease progression and prolong overall survival. [Table: see text] No significant financial relationships to disclose.