tbuckley/cabot-search huggingface dataset:
Isolated polycystic liver disease genes define effectors of polycystin-1 function
Authors: Whitney Besse, Ke Dong, Jungmin Choi, Sohan Punia, Sorin V. Fedeles, Murim Choi, Anna-Rachel Gallagher, Emily B. Huang, Ashima Gulati, James Knight, Shrikant Mane, Esa Tahvanainen, Pia Tahvanainen, Simone Sanna-Cherchi, Richard P. Lifton, Terry Watnick, York P. Pei, Vicente E. Torres, Stefan Somlo
Journal: Journal of Clinical Investigation (2017)

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.
Surgical Treatment of Subungual Squamous Cell Carcinoma by Wide Excision of the Nail Unit and Skin Graft Reconstruction
Authors: Solène Topin-Ruiz, Catherine Surinach, Stéphane Dalle, Gérard Duru, Brigitte Balme, Luc Thomas
Journal: JAMA Dermatology (2017)

<h3>Importance</h3> The best surgical treatment modalities for subungual squamous cell carcinoma (SUSCC) without bone invasion need to be determined. The limited available data on Mohs micrographic surgery do not demonstrate its use as a standard procedure. A previous study in a limited series of patients has shown that wide surgical excision of the nail unit was associated with a low rate of recurrence. <h3>Objectives</h3> To confirm the efficiency of wide surgical excision of the nail unit with full-thickness skin graft reconstruction on a series of patients with SUSCC with an extended follow-up and to evaluate short- and long-term postoperative morbidity and patient satisfaction. <h3>Design, Setting, and Participants</h3> A consecutive series of 55 patients with biopsy-proven SUSCC without bone invasion treated by wide surgical excision of the nail unit followed by full-thickness skin graft reconstruction from January 1, 2000, to August 31, 2012 were included. After a minimum follow-up of 5 years, the recurrences were collected from the referring physicians. Statistical analysis was conducted from January 1 to June 30, 2016. <h3>Main Outcomes and Measures</h3> Demographic data, pathologic characteristics of tumors, postoperative follow-up, and recurrences were collected from medical records. Patients' satisfaction with surgery, quality of life, and delayed postoperative morbidity (functional outcome and sensory disorders) were assessed from a questionnaire mailed to patients and physicians. <h3>Results</h3> Among the 55 patients (23 women and 32 men; mean age, 64 years), the mean follow-up was 6.6 years (range, 5.0-11.2 years), with a minimum follow-up of 5 years. Fifty-two questionnaires (95%) were returned. Two recurrences were observed. Minor early postoperative complications, such as graft infection and delayed wound healing, were seen in 6 patients; 8 patients experienced severe pain. Late postoperative complications included hypersensitivity to mechanical shocks (39 of 51 patients [76%]), mildly increased sensitivity to cold (38 of 51 patients [75%]), loss of fine touch sensation (17 of 35 patients [49%]), and epidermal inclusion cysts (9 of 51 patients [18%]). Most patients were very satisfied with cosmetic and global outcomes of the surgery. <h3>Conclusions and Relevance</h3> Total excision of the nail unit followed by a full-thickness skin graft is a safe and efficient treatment for SUSCC without bone involvement, with satisfying cosmetic and functional outcomes.
Timeliness to treatment in patients with lung cancer at UVA Cancer Center.
Authors: Geda Tola, Hannah E Spencer, Richard Delmar Hall, Bethany J Horton, Ryan D. Gentzler
Journal: Journal of Clinical Oncology (2017)

169 Background: The current standard of care for lung cancer patients recommends initiation of treatment within 30 days of diagnosis; however, the effects of delayed treatment on prognosis have not been determined. Furthermore, it is unclear what factors lead to delayed care. Longer treatment delays have been associated with decreased survival outcomes in other cancers, but such associations have not been established for lung cancer. This study analyzed lung cancer patients at UVa Cancer Center to identify the factors associated with delayed treatment and the effect of this delay on overall survival outcomes. Methods: Lung cancer patients diagnosed from 2011 to 2014 were retrospectively analyzed using UVA Cancer Registry data. Two outcomes, diagnosis to treatment time interval, and overall survival were modeled. Multivariate analysis was used to identify the variables that affected timely care. Statistical tests were used to determine whether there were significant differences in overall survival between patients who received timely and delayed care. Results: 917 patients met the criteria for analysis. Most were stage I (47.5%) and received surgery as first line of treatment (57.7%). Median age was 66 years. The median treatment interval for this cohort was 32 days. Stage at diagnosis was major determinant for time to treatment (p = 0.0197), with stage IV patients being treated in shorter intervals (median 28 days) and stage III patients the longest (34 days). Treatment delay was not associated with overall survival (p-value 0.952) however, other covariates such as insurance type, primary treatment type and stage were (p-values &lt; 0.0001, &lt; 0.0001, &lt; 0.0001). Conclusions: Complex multidisciplinary care can lead to delays in treatment. Stage and type of primary treatment type were determinants of treatment delays and should be recognized as obstacles to timely treatment. Although delays were not associated with survival in our study, further investigation to determine the impact of delays on symptoms, quality of life, and performance status is warranted.
Secreted alkaline phosphatase defined by ms17-57 mab and ectopically expressed on the surface of GI cancer cells as a potential therapeutic target.
Authors: Runhua Feng, Ming Li, Jianpeng Gao, Xuehua Chen, Jianyu Sun, Yuling Wang, Dongqing Zhang, Zhenqing Feng, Binya Liu, Zhenggang Zhu, Mason Lu, Jeffrey Edwin Lee
Journal: Journal of Clinical Oncology (2013)

e22169 Background: There remains considerable interest in generating monoclonal antibody (mAb) directed against specific tumor targets for antigen (Ag) discovery, diagnosis and therapy. In this investigation, mAbs were generated against potentially novel Ags on the cancer cell surface using a flow cytometry-high throughput screening (FACS-HTS) strategy. Methods: Mixed live cells from four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; Sixteen highly positive hybridoma colonies were selected via FACS-HTS using a total of 20,000 colonies in sixty-seven 96-well plates against live cells (mixed human GC cells versus normal human PBMC). The purified ms17-57 and control commercial ALP mAbs were used to confirm the target Ags, which were identified as alkaline phosphatases (ALPs) expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS). Results: MS identified the Ags recognized by ms17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and Intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules (i.e. dephosphorylation). Immunohistochemical staining using ms17-57 demonstrated significantly higher staining of gastrointestinal (GI; gastric and colorectal) cancer tissues than normal (non-cancer) GI control tissues (P&lt;0.01), and confirmed binding of ms17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assay using the PALP/IALP-expressing GC cell lines demonstrated that ms17-57 inhibited cell growth by 32±8%. Transwell cell migration assay documented that ms17-57 can inhibit PALP/IALP-expressing GI cancer cell migration. Conclusions: Our findings indicate that PALP and IALP can be ectopically expressed in the extracellular matrix of GI cancers, and that ms17-57 directed against PALP/IALP identified through HTS can inhibit GI cancer cell growth and migration. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology.
Incorporating medical marijuana in clinical practice.
Authors: Stephen James Daleo, Matthew Davis, Trinh Pham, Osama Abdelghany, Andrew Putnam, Rogerio Lilenbaum
Journal: Journal of Clinical Oncology (2017)

117 Background: Medical marijuana (MM) is legal in the state of Connecticut. Regulatory issues, appropriate patient selection, and outcomes assessment have made it difficult for oncology centers to incorporate MM into clinical practice. At Smilow Cancer Hospital at Yale New Haven, a tertiary academic comprehensive cancer hospital, a multidisciplinary team was convened to propose guidelines. Based on the recommendations, the Smilow Cancer Hospital implemented a policy that outlines the use of MM in selected patients with nausea, anorexia and refractory pain. Here we describe the Smilow Experience with MM in clinical practice. Methods: Using health system-wide electronic medical record, a review of patients initiated on MM from 9/2015 to 10/2016 was conducted. Demographics, malignancy type/stage, MM indication, and preliminary data on formulation used and treatment outcomes were collected. Results: 108 cancer patients, majority evaluated by a Palliative Care physician, were initiated on MM (55.6% males/44.4% females). MM was prescribed more to patients with solid tumors compared to hematologic malignancies (91% versus 9%). The most common malignancy was gastrointestinal (34.3%), followed by lung (26.9%). Among patients with available definitive tumor staging, more had stage III or IV tumors (73.4%) compared to stage I or II tumors (26.6%). The most common indications are pain (81.8%) followed by cachexia (49.4%), and 40% of patients had more than one documented indication. Inhalation was the most common route of administration. Outcome data is limited at this juncture, though documentation indicates that more patients have reported “positive effects” from MM than “negative effects”. Conclusions: Despite legalization, the prescription of MM in cancer patients has been limited to individual practices, often outside of the context of a comprehensive cancer program. In these cases, follow up and outcomes assessment is minimal. Our review reveals that a health system-wide protocol allows patients to gain access to MM without having to leave the system. Our findings demonstrate interest among providers and patients in the potential therapeutic benefits of marijuana. Detailed data on efficacy and outcomes will be available at the time of the meeting.
Prognostic effect of eribulin-induced liver dysfunction in metastatic breast cancer.
Authors: Takayuki Kobayashi, Ippei Fukada, Kokoro Kobayashi, Tomoko Shibayama, Yoshinori Ito, Shunji Takahashi
Journal: Journal of Clinical Oncology (2014)

1043 Background: Eribulin is a non-taxane, microtubule dynamics inhibitor with a survival benefit for patients with metastatic breast cancer. Although eribulin is well tolerated in patients with heavily pretreated disease, eribulin-induced liver dysfunction (EILD) occasionally occurs in clinical practice, which may results in treatment discontinuation, with subsequent poor disease control. We conducted a retrospective study to clarify the effect of EILD in patients. Methods: The medical records of 157 metastatic breast cancer patients treated with eribulin between Jul 2011 and Nov 2013 at Cancer Institute Hospital were retrospectively analyzed. EILD was defined as 1) an increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >3 times the upper limit of normal, and/or 2) starting liver-supporting oral drug therapy such as ursodeoxycholic acid and glycyron. Fatty liver was defined as a decrease in the liver-to-spleen attenuation ratio on computed tomography to <0.9. Results: The median age was 56 years, median treatment duration was 4.0 months, and mean body mass index (BMI) was 22.9. EILD occured in 42 (27%) patients, including one patient in whom eribulin treatment was stopped due to EILD. The patients with EILD had significantly higher BMI than the remaining 115 patients (25.4 vs. 22.1, p<0.0001), with no difference in the relative dose intensity of eribulin between the two groups (1.21 vs. 1.15 mg/body/week, p=0.36). Interestingly, the patients with EILD had significantly longer progression-free survival (PFS) than the other patients (p=0.018). Furthermore, among 78 patients without liver metastases, 18 with EILD showed significantly longer PFS than the other 60 patients (p=0.0035). During eribulin treatment, 17 (11%) patients developed fatty liver, and their mean BMI was 27.1. Eleven of 17 patients had EILD. Conclusions: Although EILD and fatty liver occurred with relatively higher frequency in clinical practice, most of the patients had no severe side effects. We found the paradoxical results showing positive correlation between EILD and PFS, especially in patients without liver metastases. Further studies are needed to confirm our findings in another cohort of patients.
Timing of surgical antimicrobial prophylaxis: a phase 3 randomised controlled trial
Authors: Walter P Weber, Edin Mujagic, Marcel Zwahlen, Marcel Bundi, Henry Hoffmann, Savas D Soysal, Marko Kraljević, Tarik Delko, Marco von Strauss, Lukas Iselin, Richard X Sousa Da Silva, Jasmin Zeindler, Rachel Rosenthal, Heidi Misteli, Christoph Kindler, Peter Müller, Ramon Saccilotto, Andrea Kopp Lugli, Mark Kaufmann, Lorenz Gürke, Urs von Holzen, Daniel Oertli, Evelin Bucheli-Laffer, Julia Landin, Andreas F Widmer, Christoph A Fux, Walter R Marti
Journal: The Lancet Infectious Diseases (2017)
Sleep apnoea and risk of post-operative infection: beyond cardiovascular impact
Authors: Miguel Ángel Martínez-García, Eusebi Chiner
Journal: European Respiratory Journal (2017)

Recent decades have seen the publication of numerous studies on the association between excessive sleep disordered breathing (SDB), particularly sleep apnoea, and an increase in cardiovascular morbidity and mortality. These studies have used a wide range of methodologies and criteria for patient inclusion. The results have been diverse, depending on the type of cardiovascular event or risk factor investigated, the patients' cardiovascular risk, the severity or type of the SDB, and the analysis of the primary and secondary prevention of cardiovascular events [1]. Sleep apnoea impacts negatively on different diseases beyond the cardiovascular sphere <http://ow.ly/ZdOC309KHXD>
Whole body retention in relation to rate of bone resorption after intravenous bisphosphonate (pamidronate) in patients with breast cancer and bone metastases
Authors: S. Cremers, L. Van Zuylen, H. Gelderblom, C. Seynaeve, H.-J. Guchelaar, H. Pols, P. Vermeij, C. Van der Rijt, S. Papapoulos
Journal: Journal of Clinical Oncology (2004)

881 Background: Bisphosphonates (BPs) given i.v. every 3 to 4 weeks are effective in the management of metastatic bone disease from breast cancer but responses among patients vary and it is not known whether current dose and dose intervals are appropriate for an individual patient. An influence of PK of BP on its antiresorptive action may contribute to this variation. To test this hypothesis we determined the skeletal retention of intravenous pamidronate and its association to the rate of bone resorption in patients with bone metastases from breast cancer. Methods: In a cross-sectional study, 24 hr urinary excretion of pamidronate and NTx were measured in 40 patients with bone metastases from breast cancer at the beginning, after 3–6 months or after 1 year of treatment with iv pamidronate 90 mg every 3–4 weeks. Results: Skeletal retention (= dose –amount excreted into urine) varied between 12–98% (mean 62%) of the administered dose but there were no differences in retention between patients receiving pamidronate for the first time or after three to six months or after one year of treatment. Retention of pamidronate was related to the prevalent rate of bone resorption in previously untreated patients whereas no such relationship was found in previously treated patients. The rate of bone resorption normalized in nearly all patients, whereas mean NTx levels tended to increase again before the next dose. Rate of bone resorption appeared to be related to the amount of pamidronate retained by the skeleton. Conclusions: During 1 year of treatment with i.v. pamidronate, skeletal retention of the BP does not change, indicating no saturation of skeletal binding sites with treatment. The variability in retention among patients can be attributed to the number of potential binding sites. This is related, however, to bone resorption only before start of pamidronate treatment. The apparent relationships between the amount of BP retained by the body and the effect could have implications for therapeutic regimens in patients with bone metastases from breast cancer. No significant financial relationships to disclose.
Strategies for Increasing Pancreatic Tumor Immunogenicity
Authors: Burles A. Johnson, Mark Yarchoan, Valerie Lee, Daniel A. Laheru, Elizabeth M. Jaffee
Journal: Clinical Cancer Research (2017)

Abstract Immunotherapy has changed the standard of care for multiple deadly cancers, including lung, head and neck, gastric, and some colorectal cancers. However, single-agent immunotherapy has had little effect in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single-agent immunotherapies. In this review, we discuss differences between immunotherapy-sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor-infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are druggable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes. Clin Cancer Res; 23(7); 1656–69. ©2017 AACR. See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice
Authors: Silvia Monticone, Jacopo Burrello, Davide Tizzani, Chiara Bertello, Andrea Viola, Fabrizio Buffolo, Luisa Gabetti, Giulio Mengozzi, Tracy A. Williams, Franco Rabbia, Franco Veglio, Paolo Mulatero
Journal: Journal of the American College of Cardiology (2017)
Selecting renal cell carcinoma therapy: Ranking of patient perspective on toxicities.
Authors: Michael K.K. Wong, Ateesha F Mohamed, A. Brett Hauber, Jui-Chen Yang, Zhimei Liu, Jaqueline Willemann Rogerio, Carlos A. Garay
Journal: Journal of Clinical Oncology (2012)

4608 Background: Oral therapies (angiogenesis inhibitors and mammalian target of rapamycin (mTOR) inhibitors) for renal cell carcinoma (RCC) have demonstrated significant improvements in progression-free survival but also possess toxicities. The objective of this study was to evaluate whether different toxicities of oral RCC therapies had equal importance to patients. Methods: US adults from the Kidney Cancer Association with a self-reported diagnosis of RCC completed a web-enabled survey. Respondents were asked to select the 3 most and 3 least troublesome toxicities from a list of 20 common RCC therapy toxicities. For each respondent, a value of 1 was assigned to each of the 3 most troublesome toxicities, a value of -1 was assigned to each of the 3 least troublesome toxicities, and a value of 0 was assigned to the remaining toxicities. A straight count method was applied to estimate the mean relative importance of each toxicity. Respondents also answered 10 treatment-choice questions, each of which included a pair of hypothetical RCC medication profiles described by survival, toxicities, and serious adverse events. Four toxicities including fatigue, mouth sores, hand-foot syndrome, and stomach problems were included in both exercises. Results: 264 of the 272 respondents completed the entire ranking exercise. Among the 20 toxicities, stomach problems was the most troublesome and was assigned an importance of 10. Changes in hair color was the least troublesome and was assigned an importance of 0. Patients ranked fatigue (8.2), mouth sores (7.7), hand-foot syndrome (6.6) by order of importance. When given choices among eliminating severe toxicities, fatigue was as important as stomach problems, both fatigue and stomach problems were more import than mouth sores, and mouth sores was more important than hand-foot syndrome; although not statistically significant. Conclusions: This statistical approach offers insight into those toxicities important to patients on chronic RCC therapies.