tbuckley/cabot-search huggingface dataset:
P3-13-10: Does Lapatinip Increase Pulmonary Toxicity When Concurrently Used with Radiation Therapy? An Experimental Study with Wistar-Albino Rats.
Authors: Bese N Senel, O Yetmen, E Guzel, C Karaca, I Coban, O Elicin, O Suzer
Journal: Cancer Research (2011)

Abstract Purpose: Lapatinib (L) is an oral receptor tyrosine kinase inhibitor which has shown activity in the treatment of metastatic breast cancer. Adjuvant usage of L is being investigated in clinical phase III trials. There is no data regarding the side effects of combination of RT and L which may be a problem when L is used in the adjuvant setting. Lung is the most radiosensitive organ to observe late effects of RT. We evaluated if concurrent administration of L has any impact for the development of radiation induced pulmonary fibrosis in rats (RIPF). Material Methods: 40 female Wistar-albino rats (WAR) were divided into 4 experimental groups (G). G1 (control) did not receive any treatment. G2 (RT) received RT to whole thoracic region. G3 (L) received L without RT. G4 (L+RT) received L with RT. A total dose of 30 Gy in 10 fractions was given to both lungs with an anterior field at 2 cm depth. L equivalent to 1500 mg/day, 60 kg adult dose, were calculated according to the mean weight of rats, orally administrated with a feeding tube twice daily including the week-ends until WAR were sacrificed. WAR were anesthetized and sacrificed 16 weeks after RT which was shown to be a sufficient period for the development of RIPF in rats. Paraffin sections (5 μm thick) of lungs were stained with hematoxylin-eosin and Masson's trichrome. A comparative analysis was performed among 4 groups by scoring the pulmonary injury between 0 and 3 according to the infiltration of inflammatory cells into the alveolar spaces, alveolar wall thickening and architectural deformation across the entire lung section. Normality distribution were tested, then one-way ANOVA followed by post hoc Holm-Sidak testing were used. Results: In G2 inflammatory cell infiltration, fibrosis with damage to lung structure and formation of small fibrous masses were observed. Alveolar septa was significantly thicker than G1 (p&amp;lt;0.05), which revealed totally normal pulmoner structure. G3 showed minimal alveolar septal thickening and infiltration of inflammatory cells into the alveolar spaces which was not significantly different than G1. Histopathological findings in G4 were similar to those in G2 and statistically different when compared with the G1 and G3(p&amp;lt;0.05). Conclusion: Study shows that addition of L to RT does not increase RIPF in rats. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-10.
Final results of the Sunbelt Melanoma Trial
Authors: K. M. McMasters, M. I. Ross, D. S. Reintgen, M. J. Edwards, R. D. Noyes, M. Urist, J. Sussman, J. Goydos, P. Beitsch, R. C. Martin, C. R. Scoggins
Journal: Journal of Clinical Oncology (2008)

9003 Background: The Sunbelt Melanoma Trial is a multicenter prospective randomized prospective trial to evaluate the role of high-dose interferon alfa-2b (IFN) or completion lymph node dissection (CLND) in patients with melanoma staged by sentinel lymph node (SLN) biopsy. Methods: Eligible patients aged 18 to 70 years with primary melanoma ≥1.0 mm Breslow thickness underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy and CLND were randomized to observation vs. high dose IFN (20 MU/m2/d i.v. x 4 wks followed by 10 MU/m2 s.q. TIW x 48 wks). In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging of the SLN by reverse transcriptase polymerase chain reaction (RT-PCR) to detect melanoma- specific mRNA (tyrosinase, MART 1, MAGE 3, gp100); patients with RT-PCR-positive SLN were randomized to observation vs. CLND vs. CLND + IFN (20 MU/m2/d i.v. x 4 wks only). Randomization was stratified for Breslow thickness and ulceration. Disease-free survival (DFS) and overall survival (OS) were the primary endpoints. Intention-to-treat and efficacy analyses were performed by Kaplan-Meier analyses and Cox Proportional Hazards Models. The final analysis was approved by the Data Safety and Monitoring Committee. Results: Patients were enrolled between 6/24/1997 and 10/31/2003. Median follow-up was 64 months. In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (HR 0.82, 95% CI: 0.47–1.40, p=0.46) or OS (HR 1.07, CI: 0.65–1.78, p=0.79) for patients randomized to IFN (N=112) vs. observation (N=106). In Protocol B there were no significant differences in DFS or OS among patients randomized to CLND (N=192, DFS: HR 0.72, CI 0.42–1.23, p=0.23; OS: HR 0.94, CI 0.55–1.59, p=0.81) or CLND + IFN (N=184; DFS: HR 0.90, CI 0.54–1.50, p=0.69; OS: HR 0.96, CI 0.56–1.63, p=0.88) vs. observation (N=180). Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS. Conclusions: This study failed to demonstrate a benefit for adjuvant high-dose IFN for patients with a single positive SLN. Among patients with melanoma cells detected in the SLN by RT-PCR analysis, there was no significant benefit to CLND or CLND + IFN. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering Oncology Biotech Schering Oncology Biotech
Correlation of HER2 and PTEN status with clinical outcome in esophageal (E), gastric (G), and gastroesophageal junction (GEJ) adenocarcinomas (ACs).
Authors: K. Linos, C. E. Sheehan, J. S. Ross
Journal: Journal of Clinical Oncology (2011)

4066 Background: The determination of HER2 status is now critical for the management of E, G and GEJ AC's. Loss of expression of the PTEN tumor suppressor protein is considered to be a significant predictor of resistance to trastuzumab in the treatment of breast cancer. Methods: HER2 status was determined on 141 FFPE invasive AC's [13 E, 52 G and 76 GEJ] both by FISH (Abbott Molecular PathVysion) and IHC (Ventana Pathway and Dako HercepTeston a subset of cases) using the US FDA slide scoring criteria. PTEN expression was determined by IHC (rabbit mAB, Cell Signaling) using an automated method (Ventana) and semi-quantitative slide scoring. H&E slides were reviewed for all 44 endoscopic biopsies and 97 surgical resections included in the study, tumors were graded and staged according to the AJCC manual (7th ed). Results: While HER2 amplification/overexpression was markedly heterogeneous in both biopsy and resection specimens, extremely high correlation of FISH and IHC for HER2 status (p<0.001) was observed when the overexpressed foci were targeted for FISH examination. All (100%) IHC 2+ and 3+ cases were FISH+. Of 118 IHC 0 and 1+ cases, only 1 case (<1%) was discordant (FISH+). No cases featured HER2+ in situ carcinoma that did not also have HER2+ invasive carcinoma. HER2 status correlated with tumor site (26% GEJ vs. 8% E vs. 6% G, p=0.006), but not with grade, stage or survival. PTEN expression was lost in 70% of cases overall, and 83% (p=0.12) of HER2+ cases. PTEN loss was associated with advanced stage (p=0.005) and showed a trend toward correlation with shortened survival (p=0.09) in HER2+ cases. Conclusions: Unlike previous reports from the ToGA trial, in this series of 141 ACs there was extremely high correlation of FISH and IHC for determining HER2 status in E, G and GEJ tumors. HER2 is amplified/overexpressed in E, G and GEJ ACs, but not associated with aggressive disease in this study. PTEN expression was lost in the majority of HER2+ cases and correlated with aggressive disease. Further study of the association of PTEN with HER2 status and the interaction of PTEN with response to trastuzumab for the treatment of E, G and GEJ AC's appears warranted.
Chemo-predictive assay directs neoadjuvant chemotherapy in advanced cervical cancer.
Authors: G. Del Priore, S. R. Ding, A. Hassan Hamed, C. M. Gan, F. Nabizadeh, J. Schilder, D. Matei, F. B. Stehman
Journal: Journal of Clinical Oncology (2011)

e15517 Background: Neoadjuvant chemotherapy is a treatment option for locally advanced cervical cancer. Short induction times and early responses are associated with improved outcomes. Selecting treatment based on in-vitro chemoresponse assessment of individual patients’ tumors may be clinically useful. Methods: Retrospective database review of a commercially available assay (ChemoFx) and a subset chart review. Results: In a convenient sample from Jan 2009-Sept 2010, 539 cervical cancer specimens were submitted for ChemoFx testing (Precision Therapeutics, Pittsburgh). The assay was successful in 328 (60.9%) of the specimens. 119 assay terminations occurred due to failure to pass a quality assurance step (i.e. insufficient epithelial cells to test), while only 5 specimens could not be tested due to contamination (bacterial, fungal, or yeast). A heat map indicated that the carbo/paclitaxel combination is usually an active regimen and docetaxel is not. In our practice, from Feb 2008 to present, 10 patients (Stage IB2-IIB) were treated with neoadjuvant chemo. Among the 10 neoadjuvant patients, 80% responded (1 pathologic CR) to initial empiric chemo (i.e. platinum-based doublets) and had definitive surgery; 2 patients did not respond and were changed to chemoresponse assay-indicated drugs. Both went on to respond. All patients are currently disease free or responding on treatment. Median PFS-12 months (range 4-24). Conclusions: Cervical cancers specimens submitted for in vitro chemoresesponse testing are rarely contaminated and often provide clinically-impactful results. We have found a clinical application for its use in locally advanced cervical cancer.
Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis
Authors: Emma Guttman-Yassky, Benjamin Ungar, Kunal Malik, Daniel Dickstein, Maria Suprun, Yeriel D. Estrada, Hui Xu, Xiangyu Peng, Margeaux Oliva, Dan Todd, Tord Labuda, Mayte Suarez-Farinas, Robert Bissonnette
Journal: Journal of Allergy and Clinical Immunology (2017)

Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The "plaque model" has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis.We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics.We enrolled 30 patients with mild-to-moderate AD in a randomized, double-blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT-PCR and immunohistochemistry) were evaluated.TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL-13, IL-22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers.We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.
Evaluation of the Japanese opioid conversion ratio for switching to methadone for cancer pain control.
Authors: Yoshinobu Matsuda, Sachiko Okayama, Yoshito Yoshikawa, Yoshio Kobayashi
Journal: Journal of Clinical Oncology (2016)

196 Background: In Japan, oral administration of methadone was approved for patients with cancer pain in March 2013. As methadone exhibits complex pharmacokinetics with individual differences and rare but serious adverse effects, methadone is only prescribed as a fourth-line drug by cancer pain specialists, who must start methadone according to the following table and must not increase methadone dose within 7 days. Aims: To assess the validity of the Japanese opioid conversion ratio. Methods: The clinical characteristics of 60 patients who were prescribed oral methadone between April 2013 and March 2016 were analyzed. Results: The switch from other opioids to methadone was initiated due to refractory pain in the stop-and-go switching. According to the table in Japan, the starting dose of methadone ranged from 15-45mg/day, depending on the previous opioid dose. Fifty cases (11 outpatients, 39 inpatients) were successfully switched to methadone; although 10 cases subsequently exhibited rapid progression of illness and failed due to oral difficulty during the course of dose titration. At the outset, the average oral morphine equivalent daily dose before methadone administration was 155mg (range, 40-660mg) and the starting methadone dose was 10 mg in 2 cases (extremely old age and multi-drug taking), 15 mg in 35 cases, 30 mg in 11 cases and 45 mg in 2 cases. Upon completion of the dose titration according to the Japanese definition, the methadone dose was the same as the starting dose in 21 cases, and was decreased or increased from the starting dose in 5 and 24 cases, respectively. Conclusions: TheJapanese opioid conversion ratio might be better corrected in the near future. For example, it is good to be able to start with 10mg or 20 mg because minute changes might lead the performance of low dose titration in some cases. It should be possible to increase the dose of methadone after 3 or 4 days from the later change based upon the pain severity. [Table: see text]
Paclitaxel hypersensitivity reactions: Prevalence and outcomes.
Authors: Y. Lin, L. C. Hartmann, H. D. Gunderson
Journal: Journal of Clinical Oncology (2010)

e16518 Background: Paclitaxel is an effective and commonly used chemotherapeutic. Severe hypersensitivity reactions (HSRs) to this drug are characterized by a combination of erythroderma, chest/back pain, dyspnea, and hyper- or hypotension. The frequency of HSRs is not well characterized for a general oncology population; and management is not standardized, including the approach to retreatment. With this retrospective analysis, we sought to identify the prevalence of paclitaxel HSRs and characterize the outcome of these patients, especially after retreatment. Methods: All cancer patients who received paclitaxel at Mayo Clinic Rochester from January to December 2008 were identified by electronic query of chemotherapy records. Medical records of these patients were manually reviewed to identify those who had HSRs. Treatment and outcome following the reactions were assessed by review of treatment records. Results: Of the 460 patients who received paclitaxel in 2008, 47 (10.2%) had a hypersensitivity reaction, with a female predominance (women: 40 of 327, 12.2%; men: 7 of 133, 5.3%). The most common malignancies for paclitaxel administration and percent of HSRs were breast (137; 12.4%), gynecologic (129; 13.2%) and lung (94; 5.3%). The prevalence among the remaining patients was 8%. By infusion type, the prevalence was 8.5% (14 of 165) for 1 hour IV infusion, 11.3% (32 of 284) for 3 hour IV infusion, and 9.1% (1 of 11) for IP administration. Regarding outcome, 39 of the 47 patients with HSRs received further paclitaxel without incident, most (37) on the same day after diphenhydramine (32) or diphenhydramine and dexamethasone (4) administration and symptom resolution. One patient was switched to 24 hour IV infusion, 4 patients were given alternative chemotherapy agents, and 3 stopped therapy altogether. Conclusions: Paclitaxel HSRs occur fairly commonly, especially in women. The large majority of patients are able to tolerate retreatment without a desensitization procedure. No significant financial relationships to disclose.
Importance of tumor location and histology in long term survivors (LTS) of non small cell lung cancer (NSCLC) treated without surgery
Authors: E. D. Johnson, J. M. Hanneken, S. Taylor, S. Liu, J. J. Lee, D. J. Stewart, I. I. Wistuba, S. M. Lippman, D. D. Karp
Journal: Journal of Clinical Oncology (2008)

17524 Background: The prognostic spectrum for NSCLC ranges from weeks to years and depends on stage, age, sex, and performance status. We have undertaken to identify additional characteristics of LTS treated non-surgically. Methods: We analyzed the records of 14,764 NSCLC pts from the MDACC tumor registry who were evaluated between 1991–2001 to find LTS treated with chemotherapy (C) and/or radiation (R) only. We excluded all pts who had pneumonectomy, lobectomy, segmental or wedge resection. LTS was defined as survival 36 months or greater. LTS were analyzed by tumor location, histological subtypes, smoking status, the presence of pleural effusion and/or emphysema. Results: Only 5,114/14,764 (34.6%) received initial treatment at MDACC; 1,925/5,114 (37.6%) had surgery. The remaining 3,189 (62.4%) had C, R, or combined modality treatment. LTS pts totaled 294/3,189 (9.2%). Median age was 62, females represented 44% of LTS. Median survival for LTS was 5.2 yrs. The LTS clinical stages were IA/IB, 16%, IIA/IIB, 2%, IIIA/IIIB 52%, IV 30%. Upper lobe lesions made up 64% of LTS cases (p<0.001). The ratio of upper lobe to lower lobe lesions was 4:1. The ratio is even more pronounced for stages III & IV. Pleural effusion was present in only 13% of LTS and had significant negative survival effect (univariate log-rank test). 91% were either current or former smokers, 9% never smoked. Squamous histology subtype was over-represented in the LTS compared to adenocarcinoma (p <0.02). NSC/non-specified histology (NOS) comprised 18% of pts. Conclusion: LTS of NSCLC treated non- surgically are significantly more likely to have upper lobe lesions and squamous histology. As pathways for different histologies emerge, decreasing the number of pts labeled NOS appears to be desirable. No significant financial relationships to disclose.
Intensity-modulated radiation therapy (IMRT) for anal cancer: Results from a multi-institutional retrospective cohort study.
Authors: Jason Andrew Call, Brendan M Prendergast, Lindsay G Jensen, Celine B Ord, Karyn A. Goodman, Rojymon Jacob, Loren K. Mell, Charles R. Thomas, Salma Jabbour, Robert C. Miller
Journal: Journal of Clinical Oncology (2012)

e14555 Background: This study was done to assess the toxicity and efficacy of IMRT for anal cancer in a multi-institutional setting. Methods: Records of 152 total patients (pts) were reviewed retrospectively. Data on disease control and toxicity were collected as well as pt and treatment characteristics. Acute (&lt;6 months) and late (&gt;6 months) severe toxicity (grade &gt;3) were recorded at each institution. Four were excluded for either presence of metastatic disease (2) or stage TX (2). There was data for late toxicity on 120 pts. Results: T stage was T1 in 28, T2 in 79, T3 in 29 and T4 in 12 pts. N stage was N0 in 77, N1 in 40, N2 in 19 and N3 in 12 pts. The median age was 56 yrs and median follow-up was 26.8 months. Cumulative IMRT dose was 51.25 Gy (median) (range: 4.32-61.2 Gy) in a median of 28 fractions (2-34). Chemotherapy was given in all but 2 pts and the most common regimen was 5- fluorouracil plus mitomycin-C. The median total elapsed treatment time was 40 days. Local control at 3 yrs was 87% and was significantly worse for patients with T3-4 disease (79% vs 90% at 3 years; p=0.04). There was no correlation between dose and local control. Regional control, distant control and overall survival were 97%, 91%, and 87% at 3 yrs, respectively. Nodal status was associated with regional and distal control as well as overall survival (p&lt;0.01 for each). The most common acute severe toxicity was hematologic (41%). Severe acute GI, skin or other toxicity was 11%, 20% and 1% respectively. There were two grade 5 toxicities (hematologic and GI). Severe late toxicity was limited to skin (1%) and GI (3%). Conclusions: IMRT resulted in excellent local control in this multi-institutional cohort of pts. Although T stage did predict for worse local control, most pts with T3-4 disease were controlled with IMRT. Nodal status predicts for regional and distal control as well as overall survival. Severe toxicity was acceptable with this technique.
Use of the essential autophagy protein beclin 1 to regulate DNA damage response and predict response to chemoradiation in rectal cancer.
Authors: David Tougeron, Jae Myung Park, Koichi Okamoto, Shengbing Huang, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2014)

492 Background: Beclin 1 interacts with its cofactor UVRAG to promote autophagy, a cellular degradation process induced by cellular stress. While cells with defective autophagy are prone to genomic instability, it is unknown whether Beclin 1 and/or UVRAG can regulate DNA damage/repair. Methods: Colorectal cancer cell lines (HT-29, DLD1) with Beclin 1 or UVRAG siRNA were irradiated ± 5-FU. DNA damage (pATM, pH2Ax, 53BP1, RAD51), cell death (annexin V, caspase-3, clonogenic survival), and centrosome number (γ-tubulin staining), were determined. Beclin 1 protein expression was analyzed in pretreatment endoscopic biopsies from 96 rectal carcinoma patients who received radiation + 5-FU followed by surgery. Results: Beclin 1 or UVRAG knockdown was shown to enhance DNA double-strand breaks (DSBs) and cell death induced by radiation ± 5-FU. Suppression of either gene increased the percentage of irradiated cells with nuclear foci expressing 53BP1 (nonhomologous end joining), but not RAD51 (homologous recombination). Beclin 1 was shown to regulate UVRAG, and a UVRAG deletion mutant defective in Beclin 1 binding decreased protection against radiation-induced DSBs. Knockdown of Beclin 1 or UVRAG increased centrosome number in irradiated cells. While autophagy inhibition by ATG5 or LC3 siRNA enhanced radiation-induced DSBs, they did not alter centrosome number suggesting independence from autophagy. In rectal carcinomas, high vs low level Beclin 1 expression was detected in 56 (58.3%) and 40 (41.7%) tumors, respectively. Pre-treatment Beclin 1 was not associated with clinicopathological variables. However, high vs low Beclin 1 predicted a significantly reduced pathological response (macroscopic vs. microscopic or no residual tumor) to chemoradiation (high: 14.2% vs. low: 40%; p = 0.017). High vs low Beclin 1 was independently associated with poorer overall survival (HR, 4.30; 95% CI, 1.42-16.47; p = 0.009). Conclusions: Beclin 1 and UVRAG confer protection against radiation-induced DNA damage and maintain centrosome stability. The ability of Beclin 1 overexpression to confer resistance to chemoradiation, suggests its potential utility as a predictive biomarker in rectal cancer.