tbuckley/cabot-search huggingface dataset:
Impact of modern treatment strategies on second cancer incidence for patients with early stage seminoma: A population-based study in British Columbia.
Authors: Gaurav Bahl, Rima Sanjay Pathak, Jenny J. Ko, Michael Sia, Gale Bowering, Christian K. Kollmannsberger, Scott Tyldesley
Journal: Journal of Clinical Oncology (2017)

423 Background: The purpose of this study is to examine the incidence of Second Cancers (SC) in patients with Stage I or II Seminoma treated in British Columbia (BC), and compare rates between patients managed with Radiation Therapy, Chemotherapy, or Active Surveillance. Methods: Consecutive patients with Stage I or II Seminoma (n = 1549, 21167 person years) diagnosed in British Columbia between 1984 and 2013 were identified from the BC Cancer Registry and included in this study. Patients were managed with Radiation Therapy (RT; n = 663), Chemotherapy (CT; n = 259) or Active Surveillance (AS; n = 624). Data was extracted from the registry and verified by individual patient chart review. Cumulative incidence rates were computed using competing risk analysis. Age and Sex Standardized Incidence Ratios (ASIR) were calculated (compared to the Canadian population). Results: After a median follow-up of 14 years (RT group: 21.5yrs, CT group: 10yrs, AS group: 8yrs), the 15 year Overall Survival was 91.4%. Only 15 patients died from progressive Seminoma, while 46 died from second cancers. A total of 115 patients developed SCs, and the cumulative incidence (CI) of SC, at 15 years, was: 5.9% for patients who received RT, 8.6% for those who had CT, and 4.9% for patients managed with AS. The higher CI for patients treated with CT, versus RT, was not statistically significant (p = 0.08). The ASIR for RT, CT and AS groups were 1.31 (95% Confidence Intervals: 0.92- 1.86), 2.57 (1.07- 6.15; p = 0.03), and 1.38 (0.75- 2.54), respectively. Patients who underwent treatment at ages 30-44yr and 45-59yr had a significantly higher ASIRs of 4.33 (2.1- 8.9; p &lt; 0.001) and 1.8 (1.16- 2.8; p = 0.008). ASIR was not significantly different when stratified by radiation dose, field types, or year of diagnosis. Conclusions: We found no statistically significant difference in the Cumulative Incidence of Second Cancers for patients treated with Radiation Therapy versus Chemotherapy in our patient population. Longer follow-up for the CT group is required to confirm trends evident in our analysis.
Bendamustine, bortezomib, and dexamethasone (BVD) in elderly patients with relapsed/refractory multiple myeloma (RRMM): The Intergroupe Francophone du Myélome (IFM) 2009-01 protocol.
Authors: Philippe Rodon, Cyrille Hulin, Brigitte Pegourie, Mourad Tiab, Bruno Anglaret, Lotfi Benboubker, Henry Jardel, Olivier Decaux, Brigitte Kolb, Murielle Roussel, Laurent Garderet, Xavier Leleu, Olivier Fitoussi, Carine Chaleteix, Philippe Casassus, Pascal Lenain, Philippe Moreau, Marie-Odile Petillon, Claire Mathiot, Herve Avet-Loiseau
Journal: Journal of Clinical Oncology (2012)

8014 Background: Bortezomib (V) plus dexamethasone (D) is a treatment of choice of RRMM. In small series, the addition of an alkylator was beneficial. Bendamustine (B) showed a high activity in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly pts with MM progressive on or after 1 st line therapy. Methods: We conducted a phase 2 trial combining B 70 mg/m 2 D1-8, V 1.3 mg/m 2 D1-8-15-22 and D 20 mg D1-8-15-22 every 28 days. 4 cycles were administered. In responders (PR or better), 2 additional cycles were provided followed by a maintenance phase with 6 cycles given every 2 months. Inclusion criteria were progression on or after 1 prior line of therapy, measurable disease, PS ECOG &lt;3, ANC &gt; 1.5x10 9 /l, platelets &gt; 100x10 9 /l, creatinine &lt; 250 mcmol/l, AST and ALT &lt; 3xULN. Pts with prior exposure to bortezomib were excluded. Response was evaluated according to IMWG criteria. Primary end point was response at end of cycle 4, secondary objectives overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Results: The present analysis was restricted to the first 4 cycles. From 03/2010 to 07/2011, 73 pts were included, median age 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior therapy: MP in 12, MP-thalidomide in 44, lenalidomide-dexamethasone (LD) in 14, other in 3. 42 pts (57.5%) were responders at end of cycle 4 [CR: 8 (10.9%), VGPR: 9 (12.3%), PR: 25 (34.2%), SD: 10 (13.6%), progression: 11 (15%), early discontinuation: 10 (13.6%)]. 6pts/10 were in PR and 1pt/10 in VGPR at time of discontinuation. ORR was 67.1% (49/73 pts). 11 pts died (MM: 6, sepsis: 4, renal failure: 1). Adverse events grade 3-4 were neutropenia: 16 pts, thrombocytopenia: 7 pts, sepsis: 12 pts, gastro-intestinal: 8 pts, anaphylaxis: 1 pt. 2 pts had DVT. Peripheral neuropathy grade&gt;1 occurred in 9 pts, all grade 2. Treatment was stopped in 20 pts (lack of efficacy: 11, toxicity: 9). Conclusions: These results compare favorably with those achieved with VD or LD. The triplet BVD combination is very effective and tolerable in elderly pts with MM in 1 st progression.
HYPERTENSION AND THE KIDNEY
Authors: C A WATTENBERG
Journal: Annals of Internal Medicine (1946)

Case Reports1 October 1946HYPERTENSION AND THE KIDNEYCARL A. WATTENBERG, M.D.CARL A. WATTENBERG, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-25-4-734 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptUnilateral non-nephritic kidney disease can be the cause of hypertension, and this hypertension often can be relieved by nephrectomy. This fact has been shown definitely. Many case reports have been published since the work by Goldblatt1 and his associates, which should remove any doubt that hypertension may result from certain types of pathological unilateral renal changes. It is true that some of these cases were reported too soon following the nephrectomy, but the urologist still sees nephrectomy as a definite cure for hypertension in certain cases.Certainly there always should be a careful urological examination of all cases of hypertension...Bibliography1. GOLDBLATTLYNCHHANZALSUMMERVILLE HJRFWW: Studies on experimental hypertension. 1. The production of persistent elevation of systolic blood pressure by means of renal ischemia, Jr. Exper. Med., 1934, lix, 347-380. CrossrefGoogle Scholar2. FLOCKS RH: Clinical studies on the relationship between renal disease, renal function and arterial blood pressure, Jr. Urol., 1942, xlvii, 602-613. CrossrefGoogle Scholar3. BRAASCHWALTERSHAMMER WFWHJ: Hypertension and the surgical kidney, Jr. Am. Med. Assoc., 1940, cxv, 1837. CrossrefGoogle Scholar4. BARKERWALTERS NWW: Hypertension and chronic atrophic pyelonephritis, Jr. Am. Med. Assoc., 1940, cxv, 912. CrossrefGoogle Scholar5. BRAASCH WF: Renal disease as a factor in hypertension, Am. Jr. Surg., 1942, lvi, 209-215. CrossrefGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: St. Louis, Missouri*Received for publication July 2, 1945.From the Department of Surgery, Urological Division, Washington University School of Medicine, Barnes Hospital, St. Louis, Mo. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byPERIRENAL LYMPHANGIOMA CAUSING HYPERTENSION*JOHN E. PULASKI, M.D. 1 October 1946Volume 25, Issue 4Page: 734-741KeywordsAlbuminsBlood pressureHospital medicineHypertensionKidneysNephrectomyRenal diseasesSurgeryUrine ePublished: 1 December 2008 Issue Published: 1 October 1946 PDF downloadLoading ...
Sofosbuvir plus Peginterferon plus Ribavirin for 12 Weeks in Genotype 3 HCV Infected Patients and Treatment-Experienced Cirrhotic Patients with Genotype 2 HCV Who Did Not Achieve SVR after 16 or 24 Weeks of Sofosbuvir plus Ribavirin
Authors: K Agarwal, M Schultz, S Pianko, L Bank, J Collier, J George, M Priest, S D Ryder, B E Burman, K Cheent, M Cramp, D M Forton, B A Leggett, G C MacQuillan, A Ramji, P Richardson, M J Ryan, N Stace, A Zekry, D L Zogg, E Barnes, D M Brainard, B Massetto, F Chen, J G McHutchison, M Subramanian, E M Yoshida, G R Foster
Journal: Hepatology (2016)
A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with advanced BRAF wild-type melanoma.
Authors: Steven O'Day, Rene Gonzalez, Kevin Kim, Bartosz Chmielowski, Richard Kefford, Georgina Long, Carmen Loquai, Charles Lance Cowey, Axel Hauschild, John D. Hainsworth, Peter Hersey, Frances Boyle, T. R. Jeffry Evans, Omid Hamid, Nicole Meneses, Corina Andresen, Min Ren, James P. O'Brien, Keith Flaherty
Journal: Journal of Clinical Oncology (2013)

9026 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. Melanoma responses in the phase I study led to this multicenter phase II trial of lenvatinib in separate cohorts of BRAF mutant and BRAF wild-type (wt) melanoma to provide an estimate of efficacy and to identify molecular correlates of clinical benefit. Primary analyses of clinical outcomes for the BRAF wt cohort are reported here; the BRAF mutant cohort will be presented at a later date. Methods: Eligible patients (pts) had stage IV or unresectable stage III BRAF wt melanoma with ≥1 prior treatment (26/96 [27%] pts received ≥3 treatments) and no prior VEGF-targeted therapy. Lenvatinib 24 mg once daily with dose reduction for toxicity was administered until disease progression or unmanageable toxicities. Primary endpoint was response rate by independent review (IRR) using RECIST 1.1. Archival tumor tissue and baseline and posttreatment serum samples were collected for molecular analysis. Results: 93 pts were treated (median [m] age: 64 y; male: 69%; 95% AJCC stage IV). Confirmed partial responses (PRs) were observed in 8 pts (9%) with a clinical benefit rate (CR+PR+durable SD ≥23 wks) of 32% by IRR. mPFS was 3.7 mos (95% CI, 2.5-4.0) by IRR and mOS was 9.5 mos (95% CI, 8.3-12.9); 46% pts required dose reduction for management of toxicity; 12% were withdrawn from therapy due to toxicity. Treatment-related adverse events reported in ≥20% pts included hypertension 59% (34% Gr 3/4), fatigue 58% (16% Gr 3/4), nausea 44% (3% Gr 3/4), diarrhea 43% (2% Gr 3/4), decreased appetite 38%, vomiting 29% (2% Gr 3), dysphonia 27%, and proteinuria and headache 26% each (4% and 1% Gr 3/4). Serum biomarker analysis showed baseline levels of serum angiogenic factors, such as angiopoietin-2, correlated with OS. More extensive biomarker analyses are reported in an accompanying abstract. Conclusions: Lenvatinib administered to pts with advanced BRAF wt melanoma was associated with frequent but manageable toxicity. Clinical benefit was seen in some pts. Predictive biomarkers for response to lenvatinib, such as the serum level of angiogenic factors, may be useful for future clinical trials. Clinical trial information: NCT01136967.
Association of specific gene expression profiles with a pathologic complete response to neoadjuvant therapy in esophageal adenocarcinoma.
Authors: Patrick James McLaren, Anthony P Barnes, Willy Z Terrell, Gina M. Vaccaro, Jack Wiedrick, John G. Hunter, James P. Dolan
Journal: Journal of Clinical Oncology (2017)

51 Background: Predicting prognosis in esophageal cancer remains an unrealized goal despite studies linking constellations of genes to therapeutic response. In this study, we analyzed specific predictor genes expressed in tumor specimens from our institutional repository. Our aim was to determine if specific gene expression profiles are associated with pathologic complete response (pCR) after neoadjuvant chemo-radiotherapy (CRT). Methods: We investigated eleven genes identified from prior studies (CCL28, SPARC, S100A2, SPRR3, SIRT2, NOV, PERP, PAPSS2, DCK, DKK3, ALDH1) that have significant association with esophageal cancer progression. Patients with esophageal adenocarcinoma treated with neoadjuvant CRT followed by esophagectomy at our institution between January 2011 and July 2015 were included. Quantitative real-time polymerase chain reaction was conducted on pre-treatment biopsy specimens to determine gene expression. Patients were classified into two groups: 1) pCR and, 2) no or poor response (NR) after CRT based on final pathology report. An omnibus test using Mahalanobis distance was applied to evaluate overall genetic expression differences between groups. Log-rank tests compared the differential expression of individual genes. Results: 29 patients (11 pCR and 18 NR) were analyzed. Overall, gene expression profiles were significantly different between pCR and NR patients (p &lt; 0.01). In particular, CCL28 was over-expressed in pCR (Log-HR: 1.53, 95%CI: 0.46-2.59, p = 0.005), and DKK3-was under-expressed in pCR patients (Log-HR: -1.03 95%CI: -1.97, -0.10, p = 0.031). Conclusions: Esophageal adenocarcinoma patients with a pCR after neoadjuvant therapy have genetic profiles that are significantly different from typical NR profiles. In our population, the genes CCL28 and DKK3 are potential predictors of treatment response.
Abstract P182: Risk for Hypertension Extends Across Generations in the Community: a Multi-generational Cohort Study
Authors: Teemu Niiranen, Elizabeth McCabe, Martin Larson, Neal Lakdawala, Ramachandran Vasan, Susan Cheng
Journal: Circulation (2017)

Background: Hypertension is a major risk factor for cardiovascular disease, and parental hypertension is known to predict high blood pressure (BP) in children. However, the extent to which risk for hypertension is conferred across multiple generations, notwithstanding the impact of environmental factors, is unclear. Our objective was therefore to evaluate the degree to which risk for hypertension extends across multiple generations. Methods: We studied three generations of Framingham Heart Study participants with objectively ascertained, uniform BP measurements performed at serial examinations spanning 5 decades: First Generation cohort (1948-2005), Second Generation cohort (1971-2008), and Third Generation cohort (2002-2005). We examined the simultaneous associations of early-onset hypertension (prior to age 55 years) in parents or grandparents with normotension (BP &lt;120/80; reference), prehypertension (BP 120-139/80-89 mmHg), and hypertension (BP ≥140/90 mmHg, or use of antihypertensive medication) in the Third Generation cohort. We estimated odds ratios (OR) and 95% confidence intervals (CI) for prehypertension and hypertension per additional parent or grandparent with early-onset hypertension using multinomial logistic regression adjusting for standard environmental factors. Results: Our final dataset for analyses included BP measurements collected from 2280 First Generation participants (i.e., grandparents), 3122 Second Generation participants (i.e., parents), and 3608 Third Generation participants (mean age 39 years, 53% women). In Third Generation participants, risk for elevated BP was conferred simultaneously by both parental (OR for prehypertension 1.72 [CI, 1.42-2.08]; OR for hypertension 2.22 [CI, 1.72-2.86]) and grandparental (OR for prehypertension 1.24 [CI, 1.05-1.46]; OR for hypertension 1.38 [CI, 1.11-1.73]) early-onset hypertension. In a secondary analysis with a subset of 3319 Third Generation participants with all covariates available, results were also similar in models additionally adjusting for physical activity and daily dietary intake of sodium. Conclusions: A predisposition for developing hypertension is conferred from grandparents to grandchildren, even after adjusting for parental history of hypertension and lifestyle factors. Additional studies are warranted to elucidate how identifying transgenerational risk for early-onset hypertension can improve the care of individuals at risk. Our results also suggest that when assessing an individual’s risk for hypertension, more accurate risk stratification could be achieved by considering both parental and grandparental history of hypertension.
A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic<i>BRAF</i>-Mutant Colorectal Cancer
Authors: Robin M.J.M. van Geel, Josep Tabernero, Elena Elez, Johanna C. Bendell, Anna Spreafico, Martin Schuler, Takayuki Yoshino, Jean-Pierre Delord, Yasuhide Yamada, Martijn P. Lolkema, Jason E. Faris, Ferry A.L.M. Eskens, Sunil Sharma, Rona Yaeger, Heinz-Josef Lenz, Zev A. Wainberg, Emin Avsar, Arkendu Chatterjee, Savina Jaeger, Eugene Tan, Kati Maharry, Tim Demuth, Jan H.M. Schellens
Journal: Cancer Discovery (2017)

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610-9. ©2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539.
<i>PIK3CA</i> mutations in colorectal and endometrial cancer with double somatic mismatch repair mutations compared to Lynch syndrome.
Authors: Stacey Shiovitz, Emily Turner, Mallory Beightol, Angela Jacobson, Theodore Gooley, Stephen J Salipante, Sigurdis Haraldsdottir, Jonathan F. Tait, William M. Grady, Edward H. Lin, Albert De La Chapelle, David E. Cohn, Paul J. Goodfellow, Mark Arnold, Heather Hampel, Colin C. Pritchard
Journal: Journal of Clinical Oncology (2015)

3550 Background: Double somatic mutations in mismatch repair (MMR) genes have recently been described in a high proportion of colorectal and endometrial cancers with microsatellite instability (MSI) not attributable to MLH1 hypermethylation or germline mutation. We sought to define the molecular phenotype of this new tumor subtype. Methods: We identified patients with double somatic colorectal and endometrial tumors from two Ohio-based prospective Lynch syndrome screening studies who had abnormal tumor testing (MSI and/or by immunohistochemistry (IHC) without coexistent MLH1 methylation), but normal germline MMR testing. We determined the frequency of PIK3CA, BRAF, KRAS, NRAS, and PTEN mutations in double somatic tumors by targeted next-generation sequencing and compared the mutation frequencies to tumors of other MSI sub-groups: Lynch syndrome, MLH1 hypermethylation, and microsatellite stable (MSS) tumors. The frequencies were compared among groups with a logistic regression model. Results: We found that 28/35 (80%) of double somatic tumors had PIK3CA mutations compared to 6/21 (29%) in Lynch syndrome tumors, 4/13 (31%) in MLH1 hypermethylated tumors, and 17/90 (19%) in MSS tumors, p < 0.0001. Among double somatic cases, a PIK3CA mutation was observed in 100% (13/13) of endometrial tumors and 68% (15/22) of colorectal tumors. These frequencies were significantly higher than all other case groups when analyzing by tumor type (colorectal p < 0.0001, endometrial p = 0.02). As expected, BRAF V600 mutations were frequent in MLH1 hypermethylated tumors (8/13) and not detected in any double somatic or Lynch tumors (p < 0.0001). No substantive differences were observed for KRAS, NRAS, or PTEN. Conclusions: PIK3CA mutations are present in the majority of double somatic colorectal and endometrial cancers at frequencies significantly higher than those observed in other MSI sub-groups. PIK3CA mutation status may improve identification of Lynch syndrome by tumor-based screening and better define an emerging molecular entity in colorectal and endometrial cancers.
Mobilization and elimination of FLT3-ITD<sup>+</sup> acute myelogenous leukemia (AML) stem/progenitor cells by plerixafor, G-CSF, and sorafenib: Phase I trial results in relapsed/refractory AML patients.
Authors: Michael Andreeff, Gautam Borthakur, Zhihong Zeng, Mary A. Kelly, Rui-Yu Wang, Teresa J. McQueen, Yihua Qiu, Duncan Mak, Jan Andreas Burger, Naval Guastad Daver, Naveen Pemmaraju, Tapan M. Kadia, Elias Jabbour, Sherry Pierce, Farhad Ravandi, Guillermo Garcia-Manero, Susan Mary O'Brien, Jorge E. Cortes, Hagop M. Kantarjian, Marina Konopleva
Journal: Journal of Clinical Oncology (2014)

7033 Background: FLT3-ITD mutant AML is associated with poor prognosis. Our group identified sorafenib (S) as potent inhibitor of FLT3-ITD AML. We demonstrated increased preclinical activity of S when combined with the CXCR4 inhibitor plerixafor (P) and G-CSF (G). Here, we report clinical and translational data testing this concept in patients with R/R FLT3-ITD AML, including patients refractory to FLT3-ITD inhibitors. Methods: G (10 mg/kg) and P (240 mg/kg) were given s.c. QOD on days 1 through 13, and S (400 to 800 mg) was given on days 1 through 28 (one cycle). Stem cell, adhesion markers, and phospho-proteins were serially assessed by FACS and CyTOF mass cytometry. Results: Of 33 patients enrolled, 28 received treatment and 21 were evaluable for toxicity and disease response. Two CRp, four CR and eight PR were achieved, resulting in 62% overall response rate, 28% CR/CRp, and 33% PR. Responses included 3 patients refractory to FLT3inhibitors.Two patients achieved long-lasting molecular remissions. There was no treatment-related mortality. Side effects included hyperleukocytosis, hand foot syndrome, hypertension, diarrhea. Striking mobilization was observed : 30-fold increase in WBC, 40-fold in absolute blasts and increases in circulating LSC : > 100-fold CD34+, CD34+/38-, CD34+/38-/123+ (LSC), CXCR4+, VLA-4+, and CD44. Serial FISH analyses demonstrated preferential mobilization of leukemic versus non-leukemic cells and FACS/CyTOF mobilization of primitive LSC, positive for pAKT, pmTOR, pSYK, p4EP1, ERK, and pSTAT5. Conclusions: Combination of G-CSF and plerixafor is safe and superior to plerixafor in mobilizing leukemic blasts and LSC in heavily pretreated FLT3-ITD AML patients. Overall response rate was 62%, including 28% CR/CRp. Mobilized LSC displayed increased MAPK/AKT/STAT signaling. This is the first clinical study of G-CSF and plerixafor for the mobilization of leukemic cells, which was aimed at removing these cells from their protective bone marrow microenvironment. The encouraging clinical responses provide proof-of-concept, and can be further improved by more potent FLT3 and CXCR inhibitors.