tbuckley/cabot-search huggingface dataset:
KRAS mutation profile in Puerto Rican patients with colorectal cancer: Trends in expression of KRAS mutation in PR between April 2009 to January 2011.
Authors: Yelitza Ruiz, Christine Miranda, Robert F. Hunter
Journal: Journal of Clinical Oncology (2012)

e14102 Background: The prevalence of a mutated KRAS gene in colorectal cancer shows ethnic variation with a range between 30-48% among the Caucasian, Asian, and European populations. The purpose of this study was to define the profile of KRAS mutation in colorectal cancer patients in Puerto Rico. Methods: Between April 2009 and January 2011, we collected the expression of KRAS gene among colorectal cancer patients in Puerto Rico. The assay was performed by a central laboratory which began to offer the test in the island in April 2009 (GENOPTIX). Data for the presence and type of mutation, age, sex, cancer histology, site of tumor, and cancer stage were collected. The site of the mutation in codon 12 and 13 were identified by the real time polymerase chain reaction (PCR). The study was approved by IRB. A total of 501 cases were available for study. SPPS version 14 was used for statistical analysis. Results: A mutated KRAS was present in 39% (n=195) of the cohort, more commonly in the 51-69 age group (55.4%; p=0.004), in females (55.4%; p=0.095), in the proximal area of colon (43.8%; p=0.017), in the codon 12 (91.2%), and 8.8% in the codon 13. The majority of mutated genes were in codon 12 (91.2%) with 12 ASP (39.5%) and 12 VAL (25.4%) most often seen. Mucinous histology was associated with 46.7% mutated KRAS, poorly differentiated tumor with 40.0% of KRAS mutation. The mutant expression of KRAS in cases with rectum carcinoma was 39.5%, where the most common mutation was 12 VAL. Conclusions: The prevalence of KRAS mutation in Puerto Rican population is similar to other reported studies. A higher prevalence of 12 VAL mutation in rectal carcinoma and a trend towards a higher mutation rate in females are different in this cohort as compared with published studies. This study was supported by NIH grant numbers G12RR-03035 &amp; 8U54MD007587-03.
Preoperative recombinant adenoviral human p53 gene combined with intensity-modulated radiation therapy in treatment of stage IV papillary thyroid carcinoma: A randomized clinical study.
Authors: Jingqiang Zhu
Journal: Journal of Clinical Oncology (2012)

5550 Background: Most of stage IV papillary thyroid carcinoma (PTC) is initially unresectable due to invading surrounding structures, and is also commonly resistant to standard radio- or chemo-therapy. P53 gene therapy could increase tumor radiosensitivity and inhibit tumor angiogenesis. This study is to evaluate the benefits of pre-operative recombinant adenoviral human p53 gene (rAd-p53) combined with intensity-modulated radiation therapy (IMRT) in treatment of stage IV PTC. Methods: Forty-six patients with historically-diagnosed stage IV PTC, satisfying the inclusion criteria, were randomly assigned into two groups: experimental group (EG) control group (CG). EG received intratumoral injection of 2-4×10 12 rAd-p53 viral particles (VP) per 3 days for 10 times and IMRT once per day for 28 days at a total dose of 65 Gy. CG received the same IMRT therapy. Once month after the combined treatment, patients were assessed for resectability. A radical surgery was performed on the patients with a resectable tumor. All the patients received standard I131 therapy 1-1.5 months after surgery or after the last IMRT. Results: EG including 25 cases, 19 females and 6 males, had a radical surgery rate of 76% (19/25), one-year survival rate of 96%, and no local recurrence and distant metastases for patients having a surgery. The tumors in six patients of EG were still unresectable. But all these six patients had a local partial response. The tissue sample analyses showed increased fibrous tissues, apoptotic cells, and increased Bax and p21 protein and mRNA levels. CG including 21 cases, 15 females and 6 males, had a radical surgery rate of 47.6% (10/21), one-year survival rate of 81.0%, and distant metastatic rate of 20% (2/10) for patients having a surgery. The local partial response rate of unresectable patients in CG was 72.7% (8/11). There were no changes in Bax and p21 protein and mRNA levels. The main side effects of rAd-p53 were self-limited fever, occurring in 24 of EG patients. Conclusions: Pre-perative rAd-p53 combinedwith IMRT in treatment of the stage IV PTC increases radical surgical rate and response rate, and improves long-term efficacy.
Association of the Severity of Alopecia With the Severity of Ichthyosis
Authors: Elana Putterman, Theodore Zaki, Leonard Milstone, Keith Choate, Leslie Castelo-Soccio
Journal: JAMA Dermatology (2019)

Association of the Severity of Alopecia With the Severity of IchthyosisCongenital ichthyoses are characterized by abnormal epidermal barrier function.Scarring and nonscarring alopecia has been reported, but the pathogenesis is not well understood. 1 Clinically, it is difficult to predict which individuals are likely to experience hair loss and at what severity level. 1 The question often arises whether alopecia is extensive among patients with more severe skin disease.The primary aim of our study was to investigate the association between severity of ichthyosis and severity of alopecia.The secondary aim of our study was to characterize the severity of alopecia among patients with ichthyosis by genotype.Hair phenotype could serve as a clue in narrowing the diagnosis of ichthyosis type when access to genetic testing is limited.Patients with autosomal recessive congenital ichthyosis and alopecia are most likely to have transglutaminase-1 (TGM1) mutations; otherwise, research investigating the association between hair phenotype and ichthyosis genotype is limited.
Influence of bevacizumab on the plasma disposition of CPT 11 and its metabolites in advanced colorectal cancer patients
Authors: J. Schueller, M. Czejka, A. Kiss, E. Krexner, K. Aigner, M. Wirth
Journal: Journal of Clinical Oncology (2006)

3540 Background: The monoclonal antibody (mab) bevacizumab (BEV) inhibits VEGF, downregulates angiogenesis and lowers interstitial pressure, by which blood tissue transfer and metabolism of a drug could be modulated. CPT 11 produced survival benefit combined with BEV and undergoes complex biotransformation by different enzymatic routes: carboxylesterase hCE2 (SN 38), UGT 1 A 1 (detoxificition to SN 38 glucuronide) and CYP 3A4 (APC), the latter enzyme has been described to be reversibly inhibited by mabs. Therefore it seems worthwhile to investigate a potential influence of BEV on plasma disposition and pharmacokinetics (PK) of CPT11 and metabolites. Methods: 10 pts with advanced colorectal cancer (5 first line, 5 second line after FOLFOX) were treated by FOLFIRI schedule (with CPT 11 180 mg/m 2 1HR infusion) preceeded by BEV 5 mg/kg (90–60–30 min infusion) every 2 weeks. At cycle 1, CPT 11 was applied before BEV to allow baseline PK analysis of CPT 11 and its metabolites, at cycle 4 (i.e. after 8 weeks) determination of CPT 11 plasma conc was repeated after a 30 min infusion of BEV. Plasma samples were collected every 30 min over 4 HR and analysed by HPLC. Results: PK of CPT 11 remained unaffected by BEV, only a small decrease in cmax and AUC was found. Contrary, SN 38 formation seemed to be delayed and formation rate decreased when combined with BEV, resulting in lower cmax (-24%) and AUC (-20%). SN 38 glucuronide levels were generally found to be higher than those of SN 38, cmax and AUC reduced by 35% when BEV was preadministered. A similar effect was also observed in PK parameters of APC (about 30% reduction of cmax and AUC). Conclusion: A changed plasma disposition of all 3 metabolites - generated by 3 different enzymatic pathways - is unlikely to be caused by BEV influencing CPT 11 metabolism. The observed effect could be explained by increased blood tissue transfer, alteration of microvasculature by BEV may favour tissue uptake of the drug. [Table: see text] No significant financial relationships to disclose.
Genome-wide association analysis in host characteristics of progression to high-grade cervical intraepithelial neoplasia for women with human papilloma virus infection and normal cytology.
Authors: Chyong-Huey Lai, Angel Chao, Chiao-Yun Lin, Chu-Chun Huang, Wen-Hui Su
Journal: Journal of Clinical Oncology (2012)

5109 Background: Although it is well accepted that persistent human papillomavirus (HPV) is necessary for carcinogenesis of cervical neoplasms, the molecular mechanism for progression is unclear. HPV testing is widely used for cervical cancer screening. The hazard ratio of developing cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) in baseline HPV-positive/normal cytology women is 30-50 fold as compared with HPV-negative/normal cytoloy women. HPV positivity would cause substantial anxiety. It is important to identify a prognostic profile for predicting progression. Methods: We collected blood samples from women aged ≥ 30 years in a population-based nested cohort study enrolling women with HPV infection (n = 871) or HPV-negative (n = 902) with normal cytology in 2004-2009 for prospective follow-up. To identify the host genetic characteristics associated with cervical carcinogenesis, a genome-wide association study (analyzing 530,194 SNPs) was conducted in 23 cases who developed CIN2+ and 62 viral type- and age-matched controls who were HPV-positive at baseline without developing CIN throughout the follow-up period. Results: One SNP with significant P values (rs16969682; P=4.58 x 10 -5 , OR=5.9, 95% CI=2.52-13.96) located in SEC14-like 1 (SEC14L1) gene localized to chromosome 17 was identified with association between progression to CIN2+ and controls without CIN throughout follow-up. SEC14L1 belongs to the widely-expressed SEC14-superfamily. This superfamily consists of &gt; 500 members that are involved in biological functions including membrane trafficking and phospolipid metabolism. Furthermore, using T-cell based cDNA screening, SEC14L-1a is identified as a regulator of HIV-1 replication. Conclusions: The potential role of SEC14L1 in host-viral interaction will be further elucidated. Additional statistically significant SNPs including rs16969682 will be validated on cases with CIN2+ (n = 250) and normal controls (normal cytology/HPV-negative at baseline without acquisition of HPV or abnormal cytology/histology during follow-up, n = 500).
Phase III study on larynx preservation comparing induction chemotherapy and radiotherapy versus alternating chemoradiotherapy in resectable hypopharynx and larynx cancers. EORTC protocol 24954–22950
Authors: J. Lefebvre, J. Horiot, F. Rolland, M. Tesselaar, C. R. Leemans, L. Geoffrois, P. Hupperets, D. Lacombe, J. Bogaerts, J. Bernier
Journal: Journal of Clinical Oncology (2007)

LBA6016 Background: Final analysis of a larynx preservation study comparing sequential induction chemotherapy and radiotherapy (XRT) versus alternating chemoradiotherapy in treating resectable hypopharynx and larynx cancers. Methods: Patients (pts) with untreated, resectable T3-T4 larynx or T2-T3-T4 hypopharynx, N0-N2, M0 squamous cell carcinoma (SCC) were randomized in this prospective Phase III trial. Pts received in the control arm (SEQ) 2 cycles of cisplatin/5-FU (CF), followed in case of response by 2 additional cycles of CF, followed on day 80 by XRT (70 Gy / 35 fractions / 7 weeks), or in the experimental arm a CF cycle in weeks 1, 4, 7 and 10, alternated with XRT (20 Gy / 10 fractions) during the three 2-week intervals (ALT). Pts had surgery and postoperative XRT in case of non- response. The primary endpoint was survival with a functional larynx (FLS), with events including local relapse, laryngectomy, tracheotomy, gastrostomy, feeding tube, and death. With 450 patients and 3 yrs minimum followup per pt, this trial was planned to provide 80% power to detect a difference of 11% (from 28% to 39%) in this endpoint at 3 years by 2-sided Logrank test (Type I error 5%). Results: The trial enrolled 450 pts (224 to SEQ, 226 to ALT) from July 1996 to May 2004. Median followup is 6.5 years (yrs). 76 pts discontinued treatment for toxicity (34 on SEQ, 42 on ALT). Hazard ratio (HR) for FLS was 0.84 (95% CI 0.67–1.05, p=0.12) with medians 1.6 yrs on SEQ and 2.3 yrs on ALT. OS (medians of 4.4 and 5.2 yrs) and PFS (medians of 3.0 and 3.1 yrs) were similar for SEQ and ALT, respectively. At 3 yrs, cumulative incidence of larynx events was 46% on SEQ and 38% on ALT (HR 0.79, p=0.09). Grade 3/4 mucositis was seen in 32% of pts who received RTX on SEQ, and 21% on ALT. Late severe edema and/or fibrosis was observed in 16% of pts in SEQ and 11% in ALT. Conclusion: A 8% difference in larynx function preservation rate at 3 yrs favoring ALT did not translate into statistically significant differences. ALT, as a form of chemoradiation, did not lead to increased incidence and severity of mucositis. There were no relevant long-term sequelae in either arm. No significant financial relationships to disclose.
Role of surgery in the management of carcinoma larynx and hypopharynx
Authors: B. T. Varghese
Journal: Journal of Clinical Oncology (2007)

16528 Background: With the advent of chemoradiation the role of surgery in management of cancer of larynx and hypopharynx has come down considerably. Aim: To evaluate the overall outcome of surgery for carcinoma of the larynx and hypopharynx, with a view to establish its role in management of cancer of larynx and hypopharynx. Patients and Methods: All patients who have undergone laryngectomy at the Division of Surgical Oncology RCC from June 1995 to Dec 2005 were included in the study which retrospectively recorded the age and sex distribution TNM staging, the indications and types of laryngectomy, and reconstructive options used. The influence of preoperative chemotherapy, radiotherapy, and tracheostomy, systemic illness like diabetes melletus and COPD on the surgical outcome was assessed. Results: The ages of the patient ranged from 23 years to 75 years with a mean ± s.d of 55 ± 9.5 years. Out of a total of 167 cases, 123 (74%) cases had salvage surgery for failed chemo RT/Radical RT and 44 (26%) had primary surgical treatment. Conservation surgery was undertaken in 4 cases, Near total laryngectomy/laryngopharyngectomy (NTL/NTLP) was done in 14, Total laryngopharyngo esophagectomy (TLPE) with gastric pull up was done in 5 and total laryngectomy (TL) or TL with partial or subtotal pharyngectomy was done in 142 cases. 62 (37 %) patients had postoperative leaks, 5 leaks persisted to form pharyngocutaneous fistulae. 2 were repaired and in 2 cases speech prosthesis insertion was possible due its anatomical position. 1 patient refused further surgical closure after a previously failed repair. Fifty-six (34%) patients recurred locoregionally. Four (2.3%) patients developed second primary and 5 (2.9%) had distant metastasis. Wound infection, previous radiation and diabetes melletes were the predominant predisposing factors for the leaks and wound related complications were the commonest cause for prolongation of postoperative hospital stay. Seventy-nine patients were alive at the time of study. Conclusions: Hypopharyngeal cancers warrant a closer follow up after an organ preservation protocol, to detect recurrence at the earliest and plan for an effective salvage surgery. No significant financial relationships to disclose.
Abstract 13416: Phospholipase cβ1b Depletes Sarcoplasmic Reticulum Calcium Content and Causes Cardiac Contractile Dysfunction
Authors: David R Grubb, Gillian Y Ma, Jieting Luo, Nicola Cooley, Hongwei Qian, Helen Kiriazis, Xiao-Ming Gao, Paul Gregorevic, Xiao-Jun Du, Elizabeth A Woodcock
Journal: Circulation (2013)

Phospholipase Cβ1b (PLCβ1b) is the immediate effector of Gq and Gq-coupled receptors (α1-adrenergic-, endothelin- and angiotensin II- receptors). Dilated atria from humans, mice and sheep show heig...
Herpes simplex virus type 1 epidemiology in Africa: Systematic review, meta-analyses, and meta-regressions
Authors: Manale Harfouche, Hiam Chemaitelly, Laith J. Abu-Raddad
Journal: Journal of Infection (2019)

ObjectiveTo assess herpes simplex virus type 1 (HSV-1) epidemiology in Africa.MethodsThis systematic review was conducted per the Cochrane Collaboration guidelines. Findings were reported following the PRISMA guidelines. Research questions were addressed using random-effects meta-analyses and meta-regressions.ResultsForty-three overall (and 69 stratified) HSV-1 seroprevalence measures, and 18 and eight proportions of HSV-1 viral detection in genital ulcer disease (GUD) and in genital herpes, respectively, were extracted from 37 reports. Pooled mean seroprevalence was 67.1% (95% confidence interval (CI): 54.7–78.5%) in children, and 96.2% (95% CI: 95.0–97.3%) in adults. Across age groups, pooled mean was 44.4% (95% CI: 29.9–59.3%) in ≤5 years-old, 85.6% (95% CI: 81.0–89.6%) in 6–15 years-old, 93.3% (95% CI: 89.2–96.6%) in 16–25 years-old, and 93.8% (95% CI: 84.6–99.4%) in >25 years-old. Age explained 78.8% of seroprevalence variation. Pooled mean proportion of HSV-1 detection was 0.4% (95% CI: 0.0–1.5%) in GUD, and 1.2% (95% CI: 0.0–4.0%) in genital herpes.ConclusionsHSV-1 is universally prevalent in Africa, at higher levels than other regions, with no evidence for declines in seroprevalence in recent decades. Nearly every person acquires the infection in childhood through oral-to-oral transmission, before sexual debut. Sexual oral-to-genital and genital-to-genital transmission appear very limited.
Polatuzumab Vedotin: First Global Approval
Authors: Emma D. Deeks
Journal: Drugs (2019)

Polatuzumab vedotin (polatuzumab vedotin-piiq; Polivy™) is an antibody-drug conjugate comprising a monoclonal antibody against CD79b (a B cell receptor component) covalently conjugated to the anti-mitotic cytotoxic agent monomethyl auristatin (MMAE) via a cleavable linker. After binding to CD79b on the B-cell surface, polatuzumab vedotin is internalized and the linker is cleaved, releasing MMAE into the cell, where it inhibits division and induces apoptosis. Polatuzumab vedotin is being developed by Genentech (a subsidiary of Roche) for the treatment of haematological malignancies. In June 2019, the US FDA granted accelerated approval to polatuzumab vedotin, in combination with bendamustine plus rituximab, for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received at least two prior therapies. Use of the compound in combination with bendamustine plus rituximab is also under regulatory review for relapsed/refractory DLBCL in the EU and is in ongoing phase 1b/2 development in this setting or relapsed/refractory follicular lymphoma (FL) in several countries. Various other polatuzumab vedotin combination therapy regimens are also in phase 1b/2 development for relapsed/refractory non-Hodgkin lymphoma (NHL) [including DLBCL and FL] or in phase 2 or 3 development for previously untreated DLBCL, while polatuzumab vedotin monotherapy has been in phase 1 development for relapsed/refractory B-cell NHL in Japan. This article summarizes the milestones in the development of polatuzumab vedotin leading to this first approval for its use in combination with bendamustine plus rituximab for relapsed/refractory DLBCL.
VEGF-A and COX-2 expression correlate with platinum resistance in ovarian cancers
Authors: K. Engels, P. Moll, P. Harter, A. Du Bois, A. Fisseler-Eckhoff, F. Kommoss, M. Kaufmann, S. Loibl
Journal: Journal of Clinical Oncology (2006)

5062 Background: Regulators of angiogenesis such as VEGF-A and cell cycle such as p53 and COX-2 influence tumor behavior and response to chemotherapy. Methods: 114 patients with primary ovarian cancer treated in Frankfurt or Wiesbaden between 1999 and 2004 were examined. Primary surgery was followed by a platinum and taxane based chemotherapy in all patients. Expression of i-NOS, COX-2, VEGF-A, HIF-1 alpha was analyzed immunohistochemically using tissue micro arrays of primary tumor samples. Results were scored according to staining intensity and percentage of positive tumor cells resulting in an immune-reactive score (IRS) from 0 to 12. Vascularity was assessed using the Chalkley-Grid method after highlighting vessels with CD34 antibodies in whole tissue sections. These results were correlated with classical prognostic factors and survival. Non-parametric correlations were done using Spearman’s rho, correlations were significant at the 0,05 level (2-tailed). Results: The median age at the time of surgery was 63y (33–89y). The majority of the patients (85%) had advanced disease (FIGO III-IV). Tumor grading was G1 in 2%, G2 in 37%, and G3 in 61%. Expressions were as follows: i-NOS 60% positive (IRS ≥4); COX-2 50% positive (IRS ≥5); VEGF-A 50% strong (IRS ≥8), 32% moderate (IRS 4–7), 18% weak (IRS ≤4); HIF-1 alpha 37% positive (IRS ≥3), p53 33% weak (IRS ≤4), 67% strong (IRS &gt;4); vascularity 41% low (≤5), 52% moderate (6–9), 7% high (&gt;9). I-NOS correlated positively with COX-2 (p = 0,03), VEGF-A (p = 0,05), and p53 (p = 0,01). Grading correlated positively with HIF-1 alpha (p = 0,02) and vascularity (p = 0,01). Up to now none of the new parameters did show correlations with recurrence free survival (median follow-up 36 months). Platinum resistant tumors (time from primary diagnosis to relapse &lt;12 months) were significantly more often negative for VEGF-A (p = 0,005) and COX-2 (p = 0,02). Conclusions: I-NOS correlates with markers of angiogenesis and cell cycle regulation. VEGF-A and COX-2 expression might predict platinum resistance in ovarian cancers. No significant financial relationships to disclose.
Pollen exposure weakens innate defense against respiratory viruses
Authors: Stefanie Gilles, Cornelia Blume, Maria Wimmer, Athanasios Damialis, Laura Meulenbroek, Mehmet Gökkaya, Carolin Bergougnan, Selina Eisenbart, Nicklas Sundell, Magnus Lindh, Lars‐Magnus Andersson, Åslög Dahl, Adam Chaker, Franziska Kolek, Sabrina Wagner, Avidan U. Neumann, Cezmi A. Akdis, Johan Garssen, Johan Westin, Belinda van't Land, Donna E. Davies, Claudia Traidl‐Hoffmann
Journal: Allergy (2019)

Hundreds of plant species release their pollen into the air every year during early spring. During that period, pollen allergic as well as non-allergic patients frequently present to doctors with severe respiratory tract infections. Our objective was therefore to assess whether pollen may interfere with antiviral immunity.We combined data from real-life human exposure cohorts, a mouse model and human cell culture to test our hypothesis.Pollen significantly diminished interferon-λ and pro-inflammatory chemokine responses of airway epithelia to rhinovirus and viral mimics and decreased nuclear translocation of interferon regulatory factors. In mice infected with respiratory syncytial virus, co-exposure to pollen caused attenuated antiviral gene expression and increased pulmonary viral titers. In non-allergic human volunteers, nasal symptoms were positively correlated with airborne birch pollen abundance, and nasal birch pollen challenge led to downregulation of type I and -III interferons in nasal mucosa. In a large patient cohort, numbers of rhinoviruspositive cases were correlated with airborne birch pollen concentrations.The ability of pollen to suppress innate antiviral immunity, independent of allergy, suggests that high-risk population groups should avoid extensive outdoor activities when pollen and respiratory virus seasons coincide.