tbuckley/cabot-search huggingface dataset:
KRAS and EGFR mutations in the molecular epidemiology of NSCLC: Interim analysis of S0424.
Authors: P. C. Mack, M. W. Redman, K. Chansky, S. Matsumoto, W. S. Holland, P. Lara, C. B. Ambrosone, D. R. Gandara
Journal: Journal of Clinical Oncology (2010)

7013 Background: The Intergroup molecular epidemiology study S0424 was designed to investigate relationships between tumor biology with tobacco carcinogen exposure and gender in a cohort of early stage NSCLC patients enriched for never-smokers. Each patient completed a questionnaire on smoking history and submitted tumor and blood specimens. Here we report associations between KRAS and EGFR mutational status with histology, gender, and smoking status. Methods: KRAS mutations were assessed in 549 path-confirmed tumor tissue using a cold-PCR single-strand conformational polymorphism (SSCP) approach established to distinguish at least 10 different base substitutions in codons 12 and 13. DNA sequencing was used for confirmation. Preliminary EGFR mutation analysis was conducted on 195 patients using similar methodology. Researchers are blinded to patient-level data. Results: KRAS mutations were identified in 106/549 specimens (19.3%), and were more frequent in smokers (101/495, 20%) compared to never-smokers (5/54, 9%)(p=0.047). Among female smokers, 22% (60 of 274) had KRAS mutations, nonsignificantly higher than the 16.7% rate observed in male smokers (46/275, p=0.13). KRAS mutations were more frequent in adenocarcinomas compared to other histologies (p<0.0001). Logistic regression showed that histology and smoking status, but not gender, were independent variables for KRAS mutations. 47% of KRAS mutations were codon 12 GGT→TGT (Gly→Cys), and 72% were tobacco carcinogenesis-associated G→T transversions. G→T transversions were more frequent in smokers compared to never-smokers (p=0.03). EGFR mutations were observed in 12.8% (25/195; E19del: 9; L858R: 16) and were significantly more common in never-smokers (45%) than in smokers (9%)(p<0.0001) and in patients with adenocarcinoma (p=0.04). EGFR and KRAS mutations were exclusive with the exception of 1 patient. Conclusions: S0424 is the largest prospectively designed study of gender and smoking in NSCLC to date. Smoking history and adenocarcinoma histology, but not gender, were independent variables for KRAS and EGFR mutations. Additional studies exploring tobacco-associated DNA adducts and estrogen receptor expression are ongoing. No significant financial relationships to disclose.
New college of paediatrics and child health is being set up
Authors: J. Appleyard
Journal: BMJ (1996)

Editing may ruin an obituary ED1TOR,-In common with many of Jim Raftery's friends, I was extremely disappointed by his obituary in the BM7, which, after editing, did not portray him as I knew him.'Jim's setting up of one of the first successful deputising services in general practice in the late 1960s and early '70s was an enormous achievement.Instead of receiving accolades, however, he was criticised, although all general practitioners who used the service have acknowledged its tremendous impact.Jim was perhaps better known internationally than in Britain, but despite the lack of support from the establishment his department flourished.His contribution to ambulatory monitoring was vast: he was one of the first to record an arrhythmia on a cassette recorder and also perfected the technique of monitoring blood pressure and pulmonary artery pressure.He also contributed much to the development of methods for assessing drug effects on 24 hour ambulatory blood pressure.A final, important point about Jim was the enormous support that he gave to his staff.Obituaries pose tremendous problems, for both authors and editors and for friends of the person who is being written about.The author treads a difficult path.In the BMJ most obituaries are written by a friend of the subject, yet how many of us know everything about our friends?Ask 10 friends of one person to write an obituary and you would probably get 10 quite different portraits, yet all of those friends would probably say that they knew the person well.Editors want
Regorafenib (REG) in progressive metastatic colorectal cancer (mCRC): Analysis of age subgroups in the phase III CORRECT trial.
Authors: Eric van Cutsem, Alberto Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouche, Laurent Mineur, Carlo Barone, Antoine Adenis, Guillem Argilés, Takayuki Yoshino, Heinz-Josef Lenz, Richard M. Goldberg, Daniel J. Sargent, Frank Cihon, Andrea Wagner, Dirk Laurent, Lisa Cupit, Axel Grothey
Journal: Journal of Clinical Oncology (2013)

3636 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival (OS) and progression-free survival vs placebo (Pla) in patients (pts) with mCRC whose disease progressed on other standard therapies. The most frequent REG-related grade ≥3 adverse events (AEs) of interest were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation. We explored whether the impact of REG in pts aged ≥65 years differed from that in younger patients. Methods: Pts with mCRC progressing following all other available therapies were randomized 2:1 to receive REG 160 mg once daily (n=505) or Pla (n=255) for the first 3 weeks of each 4-week cycle. The dose could be modified to manage AEs. The primary endpoint was OS. We report efficacy, safety, and dosing data from REG recipients by age. Results: The REG treatment group included 309 pts &lt;65 years (307 evaluable for safety) and 196 pts ≥65 years (193 evaluable for safety). The OS hazard ratio (REG/Pla) was 0.72 (95% confidence interval [CI] 0.56–0.91) in pts &lt;65 years and 0.86 (95% CI 0.61–1.19) in pts ≥65 years (interaction p-value = 0.405). Median OS was 6.7 vs 5 months for REG vs Pla in pts &lt;65 years, and 6.0 vs 5.6 months, respectively, in pts ≥65 years. Most pts experienced drug-related AEs (&lt;65 years: 93.8%; ≥65 years: 91.7%). The rates of grade ≥3 REG-related AEs of interest and dose modifications are shown in the Table. In pts &lt;65 years vs ≥65 years, median (interquartile range [IQR]) duration of REG was 7.6 weeks (6.6–15.4) vs 7.1 weeks (5.1–17.2), median (IQR) daily REG dose was 160.0 mg (134.6–160.0) vs 160.0 mg (137.5–160.0), and median (IQR) proportion of planned REG dose was 83.3% (65.7–100.0) vs 78.6% (66.7–100.0), respectively. Conclusions: In the CORRECT trial, REG demonstrated an OS benefit in pts &lt;65 years and ≥65 years. Safety and tolerability of REG appeared to be similar in both age subgroups. Clinical trial information: NCT01103323. [Table: see text]
Changes in the Chemical Speciation of Arsenic Following Ingestion by Man
Authors: Eric A. Crecelius
Journal: Environmental Health Perspectives (1977)

The concentrations of four chemical species of arsenic in urine were observed with time, after ingestion of three different chemical species of arsenic. The arsenic-rich substances ingested, including arsenite-rich wine, arsenate-rich drinking water, and crab meat which contained organo-arsenic compounds. After ingestion of arsenite-rich wine, approximately 10% of the arsenic was excreted as arsenite, but the majority of the arsenic was methylated to methylarsonic acid and dimethylarsinic acid and excreted. After ingestion of arsenate-rich water, elevated levels of both arsenate and dimethylarsinic acid were observed. When crab meat was ingested, none of these four arsenic species were observed at elevated levels until the urine was heated in 2N NaOH. After the hot base digestion, high levels of dimethylarsinic acid were detected in these samples. The apparent biological half-lives were on the order of 10 hr for inorganic arsenic and 30 hr for the methylated arsenic forms.
P1313 : WTX101–201 : Phase 2 study of bis-choline tetrathiomolybdate in newly diagnosed wilson disease patients
Authors: K.H. Weiss, F. Askari, P. Ferenci, A. Czlonkowska, J. Bronstein, M. Schilsky, D. Clark, J. Hansson
Journal: Journal of Hepatology (2015)
The Mechanism of Induction of Ovarian Tumors in the Mouse by 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracene. II. Experiments on Ovarian Tumor Induction in Organ Culture
Authors: J. W. Jull, D. J. Streeter, L. Sutherland, B. Carrick
Journal: JNCI Journal of the National Cancer Institute (1966)

Ovarian tissue was found in 93% of ovariectomized IF × C57 mice grafted 40 weeks before with ovaries maintained for 48 hours in organ culture. One microscopic granulosa cell tumor was found among the 40 mice so treated. Normal follicles or corpora lutea were in 20 mice and 29 showed evidence of estrogen or estrogen and progesterone secretion. No ovarian tumors occurred among 103 mice grafted with ovaries incubated with medium containing 0.4 or 6.0 μg/ml 7,12-dimethylbenz[a]anthracene (DMBA) for 48 hours or 0.4 μg/ml DMBA with either 4.0 μg/ml of progesterone, testosterone, or corticosterone. There was ovarian tissue in 15 of 18 mice grafted with ovaries incubated for 48 hours in medium containing 0.4 μg/ml of DMBA and 4.0 μg/ml of 11-deoxycorticosterone. Three macroscopic and 1 microscopic granulosa cell tumors were found in this group. Normal follicles and corpora lutea were absent from all but 2 of the ovaries incubated in media containing DMBA, and evidence for estrogen and progesterone secretion was much reduced. All the granulosa cell tumors were associated with evidence of ovarian steroid secretion.
Sunitinib blocks tumoral growth on an orthotopic model of human testicular germ cell tumors
Authors: J. Piulats, W. Castillo, X. Garcia del Muro, A. Vidal, E. Condom, O. Casanovas, G. Capellà, A. Villanueva, F. Viñals, J. R. Germà Lluch
Journal: Journal of Clinical Oncology (2008)

16070 Background: Germ cell tumors (GCTs) of the testis are highly curable, but patients refractory to cisplatin (CDDP) based chemotherapy have a poor prognosis. Several studies support an important role of angiogenesis in GCT, suggesting anti-angiogenic treatment as a good alternative. Sunitinib is an oral multitarget tyrosine kinase receptor with antiangiogenic and antitumoral activities. We evaluate the effect of sunitinib, CDDP or the combination of both compounds on tumoral growth using an orthotopic model of human testicular GCTs (Piulats et al., AACR 2006; abstract 2760). Methods: Mice were implanted with 4 different tumors: a yolk sac without prior exposure to CDDP; a choriocarcinoma from a CDDP-resistant patient; and finally both a choriocarcinoma without prior exposure to CDDP and its CDDP refractory variant induced in mice by a continous CDDP exposure. Mice were treated with sunitinib (40 mg/kg, daily for 15 days), CDDP (2 mg/kg three times at 5-day interval) or combination of both. Animals were sacrificed once tumors in vehicle-treated mice affected the well being of the animals and tumors were analyzed. Results: We observed a significant block of tumoral volume, decreased circulating αFP and βHCG serum levels, and longer survival after sunitinib treatment for all GCTs analyzed. Tumor disappeared when mice were treated combining CDDP and sunitinib. Moreover, in the model of CDDP refractory induced choriocarcinoma, sunitinib clearly blocked tumoral growth. Sunitinib treatment inhibited VEGFR1,2 and 3, Flt-3 and PDGFRα, levels in absence of any effect on EGFR or PDGFRβ levels. Conclusions: Sunitinib may play a role in the treatment of CDDP-resistant patients that warrants further investigation. No significant financial relationships to disclose.
Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties
Authors: Ramindhu Galgamuwa, Kristine Hardy, Jane E. Dahlstrom, Anneke C. Blackburn, Elize Wium, Melissa Rooke, Jean Y. Cappello, Padmaja Tummala, Hardip R. Patel, Aaron Chuah, Luyang Tian, Linda McMorrow, Philip G. Board, Angelo Theodoratos
Journal: Journal of the American Society of Nephrology (2016)

Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin.
Referral patterns and adjuvant chemotherapy use in patients with stage II colon cancer
Authors: C. L. Aitelli, H. M. Kirkpatrick, H. Qin, W. E. Lichliter, C. R. Becerra, A. D. McCollum
Journal: Journal of Clinical Oncology (2008)

17515 Background: Little is known about the rate of use of adjuvant chemotherapy in stage II colon cancer and about referral patterns that give patients access to this treatment. We studied patients from a tertiary referral center with stage II colon cancer to determine the factors associated with referral to medical oncology and adjuvant chemotherapy administration. Methods: We searched the tumor registry at Baylor University Medical Center Dallas to identify patients with stage II colon cancer who underwent resection between 1995- 2003. Pathologic stage was confirmed and referral information and patient characteristics were recorded from individual chart review. The rates of referral to medical oncology and adjuvant chemotherapy use were calculated and potential predictive variables including age, sex, insurance status, bowel obstruction at diagnosis, co-morbidity score, tumor grade and T stage were analyzed using univariate and multivariate techniques. Results: We identified 287 patients with stage II colon cancer, of which only one hundred and sixty patients (56%) were referred to a medical oncologist. Only poorly differentiated histology was a significant predictor of referral using multivariate analysis. Using univariate analysis, age younger than 50, private insurance status and poorly differentiated histology were significant predictors of referral. Eighty patients (28%) received adjuvant chemotherapy. Age younger than 50, private insurance status, lower co-morbidity score, higher T stage, and poor tumor differentiation were significant predictors of adjuvant chemotherapy use in univariate and multivariate analysis. Conclusions: During 1995–2003 just over half of patients at this large tertiary referral center with resected stage II colon cancer were referred to medical oncology, potentially limiting patient discussion and access to the full spectrum of cancer care options. Adjuvant chemotherapy was used frequently for the patients who were referred to medical oncology. In addition to accepted high-risk features such as T stage and tumor grade, patient age and co-morbidity score were significant predictors for the use of adjuvant treatment. No significant financial relationships to disclose.
A multicenter phase II trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer.
Authors: T. Ioka, M. Ikeda, Y. Ito, N. Yonemoto, M. Nagase, K. Yamao, H. Miyakawa, K. Sato, T. Sato, T. Okusaka
Journal: Journal of Clinical Oncology (2010)

4058 Background: The aim of this trial was to evaluate the efficacy and toxicity of S-1 and concurrent radiotherapy for locally advanced pancreatic cancer (PC). Methods: Locally advanced PC patients with histologically or cytologically confirmed adenocarcinoma who had no history of prior chemotherapy were enrolled in this study. S-1 was administered orally at doses of 80 mg/m2 bid on the day of irradiation during radiotherapy. Radiation therapy was delivered through three or more fields at a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. A maintenance dose of S-1 (80 mg/m2/day for 28 consecutive days, followed by a 14-day rest period) was then administered until the appearance of evidence of disease progression or of unacceptable toxicity. The primary efficacy endpoint was survival and the secondary endpoints were progression-free survival, response rate, response of CA19-9, and the safety endpoint was toxicity. Results: The study completed accrual of 61 patients enrolled at 20 institutions between July 06 and November 07. Among the 59 evaluable patients, 16 achieved a partial response (27.1%; 95% confidence interval [CI], 17.4 to 39.6%) with a median survival duration of 19.4 months (range, 9.8 to 32.6, 95%CI, 13.9-25.1 months). The median progression-free survival, overall survival and 1-year survival in the 60 evaluable patients were 9.7 months (95% CI, 6.9–11.6 months), 16.0 months (95% CI, 13.5–21.3 months) and 71.7% (95%CI, 59.2-81.5%), respectively. The serum CA19-9 level was reduced by more than 50% as compared to the pretreatment level in 34 (81%) of the 42 patients who had shown a pretreatment level of 100 U/mL or greater. The major grade 3-4 toxicities were leukopenia in 6 patients (10%) and anorexia in 4 patients (7%), and the other toxicities were also generally transient, with the exception of one treatment-related death due to perforation of the duodenum and biliary tract. Conclusions: S-1 with concurrent radiotherapy exerted extremely favorable activity with mild toxicity in patients with locally advanced PC, which we propose to confirm in a prospective randomized controlled study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, Taiho Pharmaceutical Lilly, Taiho Pharmaceutical
XmAb Fc engineered anti-CD19 monoclonal antibodies with enhanced <i>in vitro</i> efficacy against multiple lymphoma cell lines
Authors: E. Zhukovsky, S. Chu, M. Bernett, S. Karki, W. Dang, P. Hammond, C. Edler, N. Polder, C. Chan, J. Jacinto, J. Desjarlais
Journal: Journal of Clinical Oncology (2007)

3021 Background: CD19 is a pan-B cell surface receptor that is expressed from early stages of pre-B cell development through terminal differentiation into plasma cells. It is an attractive immunotherapy target for cancers of lymphoid origin since it is also expressed on the vast majority of Non-Hodgkin Lymphoma (NHL) cells as well as some leukemias. Despite major improvements in response rates and progression free survival the majority of NHL patients will relapse under the current combination chemotherapy with anti-CD20. Thus salvage regimens with new non-cross resistant antibody therapies are warranted. Methods: We employ our XmAb antibody engineering technology to increase the affinity of IgG antibodies for Fc gamma receptors (FcγR), improve the effector function of antibodies, and significantly increases their antitumor potency; we also we humanize and affinity mature such antibodies. Results: The XmAb technology was applied to a humanized anti-CD19 antibody to engineer a variant with significantly enhanced (10- to 100-fold) antibody-dependent cell-mediated cytotoxicity (ADCC). The resulting XmAb CD19 variant was assayed for ADCC against multiple cell lines representative of follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), B-cell acute lymphoblastic leukemia (B-ALL), mantle cell lymphoma (MCL), hairy cell leukemia (HCL), chronic myelogenous leukemia (CML), and Burkitt’s lymphoma (BL). The ADCC activity of the XmAb CD19 was in striking contrast to a wild type IgG1 version of the antibody that mediates little ADCC. Moreover, ADCC potency and efficacy of the anti-CD19 Fc variant antibody were superior to that of rituximab: CLL - 10- and 1.5-fold higher, ALL - 10- and 100-fold higher, and HCL - 6- and 1.2-fold higher, respectively. Further, we observed no correlation between ADCC and antigen expression based on the measured cell surface density of CD19 for these cell lines. Conclusions: The increased affinity for FcγRs exhibited by the anti-CD19 Fc variant antibody overcomes much of the dependence of cytotoxicity on surface antigen density. Our data suggest that the anti-CD19 Fc variant antibody engineered for increased effector function could be a promising next-generation NHL immunotherapeutic. No significant financial relationships to disclose.
Abstract 14668: Balloon Angioplasty versus Implantation of Nitinol Stents in Small Diameter Vessel and Intermediate Length Superficial Femoral Artery Lesions
Authors: Jun Nakazato, Seiichi Hiramori, Yusuke Tomoi, Atsushi Tosaka, Yoshimitsu Soga, Hiroyoshi Yokoi, Masashi Iwabuchi, Masakiyo Nobuyoshi
Journal: Circulation (2012)

Background: Self-expanding nitinol stents have proven superior primary patency than balloon angioplasty in superficial femoral artery (SFA) lesions. However, the effective therapy for small diameter and diffuse long SFA lesion is unknown.

Methods: This study was a single center, retrospective observational study. From January 2004 to December 2011, 171 limbs with less than 4mm diameter vessels and more than 40mm length SFA stenosis or occlusion lesions were treated by balloon angioplasty (BA) or stenting (ST). Patency was assessed by duplex ultrasound or angiography. And outcomes were compared between groups by the Kaplan-Meier and log-rank methods.

Results: ST group was 86 limbs and BA group was 85 limbs. Patients characteristics were not significant difference except ABI (ST group=0.6, BA group=0.7, P=0.01). The mean total lesion length was 92mm for ST group and 63mm for BA group (P<0.0001). The vessel diameter was 4.2mm for ST group and 3.9mm for BA group (P<0.001). A higher percentage of ST group was chronic total occlusion lesion when compared to BA group (43% ST group vs 11% BA group; P<0.0001). At 1 year, the primary patency rate was similar ST group and BA group (59% versus 65%; P=0.43). There was no significant difference in MACE for up to 1 year (P=0.39).

Conclusions: The results of our study suggest that stent placement in the small vessel and intermediate length SFA lesions dose not increase the patency rate when compared with balloon angioplasty.

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High resolution cholangioscopic electrohydraulic lithotripsy for fragmentation and extraction of impacted cystic duct stones
Authors: Nauzer Forbes, Takuya Ishikawa, Rachid Mohamed
Journal: Endoscopy (2016)

A 29-year-old woman presented with right-sided abdominal pain and jaundice. The patient was postpartum but otherwise healthy. Her total bilirubin level was 74 µmol/L. Abdominal ultrasound revealed a 9-mm dilated proximal common bile duct (CBD), a suspected CBD stone and a distended gallbladder with gallstones. The patient underwent endoscopic retrograde cholangiopancreatography (ERCP); however, no obvious filling defects were seen in the CBD. A convex filling defect was seen protruding from the cystic duct confluence, with proximal dilatation and an absence of gallbladder filling ([Fig. 1]). Sphincterotomy was performed, and but the stones could not be extracted by means of balloon sweeps. A plastic biliary stent was placed and the patient underwent laparoscopic cholecystectomy. Intraoperative choledochoscopy revealed an impacted stone at the cystic duct confluence. Despite attempts to extract the stone with three wire baskets and two Fogarty catheters, the stone could not be removed.