tbuckley/cabot-search huggingface dataset:
Tipifarnib, a farnesyltransferase inhibitor, for metastatic urothelial carcinoma harboring HRAS mutations.
Authors: Jiyun Lee, Hana Kim, Antonio Gualberto, Catherine Rose Scholz, Se Hoon Park
Journal: Journal of Clinical Oncology (2020)

5086 Background: Tipifarnib is a farnesyltransferase inhibitor known to block RAS signaling and attenuate cancer cell proliferation. We tested the activity and safety of tipifarnib in patients with previously treated urothelial carcinoma (UC) carrying HRAS mutations. Methods: In a prospective phase II clinical trial, genetic screening was performed in 224 UC patients; those with missense HRAS mutations or STK11:rs2075606 received study treatment. Eligible patients received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-d treatment cycles. The primary endpoint was progression-free survival at 6 mo (PFS6). With two-stage design, at least 18 patients were required. Results: Among the 224 patients screened, we found 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11: rs2075606 carriers. In 21 patients enrolled, 14 and 7 patients had HRAS mutations and STK11:rs2075606, respectively. The most frequent adverse events included fatigue and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as a STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. Response rate was 24% (4 missense and one nonsense frameshift HRAS mutation); no response observed in UC patients with wild type HRAS tumors. Conclusions: Oral tipifarnib showed a manageable safety profile and encouraging anti-tumor efficacy against treatment-refractory UC containing HRAS mutations. Clinical trial information: NCT02535650 .
Diagnosis and treatment of testicular torsion: a clinical analysis of 95 cases
Authors: Xiangzhong Wang, Liming Li, Guodong Zhu, Xiaolong Liu, Dongliang Xi
Journal: BMJ (2018)

Objective
To analyze the clinical features, diagnosis and treatment of testicular torsion.


Methods
The clinical data of 95 patients with testicular torsion admitted from March 2001 to April 2017 were analyzed retrospectively.


Results
The age of patients ranged from 13 to 42 years (mean 19.6 years). Among 95 patients, 91 cases had essential clinical symptoms of scrotal pain; 1 case reported the right testicular enlargement without pain, and 3 cases presented with left inguinal mass. Color Doppler flow imaging (CDFI) was performed in 91 patients, reduction or loss of blood flow signals were detected in 88 cases, and normal blood flow signals were presented in 3 cases. The diagnosis of testicular torsion was confirmed by CDFI in 91 cases before surgery, and 4 cases were diagnosed by medical history and physical examination. The duration from onset to surgery was  10 h in 60 cases. All the patients received operation, 92 cases were diagnosed as testicular torsion in scrotum and 3 cases as cryptorchidism torsion after surgery. Among 92 cases of testicular torsion in scrotum, twisted testicles were removed in 41 cases and the testicles were retained in 51 cases; while testicles were removed in 1 case of cryptorchidism torsion, and the testicles were fixed in the scrotum in other 2 cases of cryptorchidism. Sixty eight patients were postoperatively followed-up for 1 month to 15 years, the retained necrotic testis atrophy occurred in 1 case, and the testicular size was normal in other 67 cases. In the 68 cases, there was no testicular discomfort and no testicular torsion after operation.


Conclusions
CDFI is valuable in preoperative diagnosis of testicular tortion. Once the diagnosis is made, it should be operated as soon as possible to retain the testicular function, and the affected testicle should be retained with caution for cryptorchidism torsion.


Key words: 
Spermatic cord torsion; Cryptorchidism; Ultrasonography, Doppler, color; Diagnosis; Treatment
Assessment for markers of poor prognosis in a real-world evidence study of treatment patterns in patients with HR+/HER2- locally advanced or metastatic breast cancer in Korea and Taiwan.
Authors: Diego Novick, Narayan Rajan, Rebecca Ming-Huei Cheng, Sae Young Lee, Dong Hyun Koo, Alice Wei, Agota Szende, Sam Colman
Journal: Journal of Clinical Oncology (2020)

e13083 Background: To assess how patient characteristics impact treatment patterns and real-world effectiveness among patients with hormone receptor (HR+)/human epidermal growth receptor 2-negative (HER2-) locally advanced and metastatic breast cancer (ABC) in Korea and Taiwan. Methods: We conducted a retrospective chart review comprising 227 female patients aged ≥ 18 years and diagnosed HR+/HER2- ABC in Korea and Taiwan between 2015-2017. Those having at least one of the following characteristics, shown previously to negatively impact prognosis, formed the poor prognostic cohort (PPC): ECOG PS &gt; 0, not bone-only disease, liver metastases, or negative PgR status. Anonymized data on patient characteristics, treatment pathways, progression-free survival, and grade 3 or higher adverse events (AEs) of interest was abstracted. Descriptive statistics and Kaplan Meier methods were used to assess the outcomes. Results: The mean (range) age was 57.1 (29 - 83) years. A total of 193 (85.0%) patients were PPC. Endocrine regimens were the most frequent first-line therapies used by 50.3% and 67.6% of patients in the PPC and non-PPC cohorts, respectively. Chemotherapy regimens were used by 25.9% and 17.6% as initial systemic therapy and by 60.1% and 35.3% at any time following diagnosis of ABC, for PPC and non-PPC, respectively. The median progression-free survival time, based on first-line therapy, was 8.3 (95%CI: 6.9 – 10.4) months for PPC versus 11.5 (95%CI: 5.5 – 12.0) months in non-PPC. The proportion of patients with at least 1 grade 3 or higher AEs of interest during first-line therapy was higher in the PPC cohort compared to the non-PPC cohort, 54.4% vs. 44.1% respectively. The most common AEs reported were leukopenia, asthenia/fatigue and neutropenia occurring in 27.5%, 28.0% and 20.7% of the PPC cohort and 23.5%, 2.9%, and 14.7% of the non-PPC cohort, respectively. Conclusions: The existence of one or more poor prognostic factors is associated with a higher chemotherapy use any time following diagnosis of ABC, as well as lower median progression-free survival and a higher likelihood of having an adverse event during first line therapy, compared to non-PPC cohort. These results suggest that patient poor prognostic characteristics can be drivers for therapy selection.
良性前列腺增生与代谢综合征
Authors: 张祥华
Journal: BMJ (2010)

良性前列腺增生(benign prostatic hyperplasia,BPH)的病因学研究涉及很多方面,包括激素内分泌学说、生长因子学说、上皮-间质细胞相互作用学说、细胞凋亡学说等.但BPH的发病原因至今尚未阐明。
Exceptional sustained responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with advanced pancreaticobiliary cancers and germline DNA damage repair (DDR) mutations.
Authors: Gretel Terrero, Jashodeep Datta, Terri Pollack, Alissette Naveda, Laith I. Abushahin, Daniel A. Sussman, Agustin Pimentel, Albert Craig Lockhart, Peter Joel Hosein
Journal: Journal of Clinical Oncology (2020)

e16757 Background: Immune checkpoint inhibitors (ICIs) have not shown meaningful clinical activity in unselected pts with pancreaticobiliary cancer. DDR-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with DDR deficiency may be sensitive to ICIs. Methods: Utilizing the IRB-approved database at the University of Miami, we identified pts with advanced pancreaticobiliary cancer with germline DDR mutations who were treated with dual ICI. Results: Eleven pts were identified (3 BRCA1, 4 BRCA2, 1 RAD51C, 1 RAD51D, 1 ATM, and 1 PALB2). There were two complete responses (CR), one partial response (PR), three stable disease (SD), two progressive disease (PD), and three pending evaluation. Evaluable responses are sustained for 22 months (m), 19m, and 7m, respectively. All pts had microsatellite stable tumors and none had high TMB. Among pts with responses, TMB was 4, 8, and 8 mut/Mb, respectively. One pt with a CR had gBRCA1 with pancreatic adenocarcinoma (PDAC) s/p distal pancreatectomy/splenectomy, adjuvant gemcitabine (gem)/capecitabine, biopsy-proven recurrence in lung and retroperitoneum 12m later, initiated ipi/nivo, and achieved a CR ongoing for 22m on nivo maintenance. Second pt with a CR had gBRCA1 and unresectable cholangiocarcinoma (CC), with disease progression after gem/cisplatin (cis), therapy switched to ipi/nivo. After 4 doses, an incidental cerebellar lesion was found which was biopsy-proven CC, therefore taken off treatment. Pt has been in CR for 19m without further therapy. The pt with a PR had RAD51C and metastatic PDAC s/p FOLFIRINOX for 6m, followed by olaparib for 12m. At progression, disease rapidly progressed through 5-fluorouracil/nanoliposomal irinotecan, gem/nab-paclitaxel/cis, and FOLFIRINOX. Pt was initiated on ipi/nivo with immediate improvement in pain and tumor markers; PR ongoing for 7m with continued clinical and tumor marker improvement on nivo maintenance. Additional correlative studies (RNA sequencing, Hyperion Imaging, mutation allele fraction analysis) among responders vs. nonresponders will be reported at the meeting. Conclusions: In this series, 6 out of 8 evaluable pts with advanced pancreaticobiliary cancers had disease control with ipi/nivo. This series suggests that tumors with germline DDR mutations may be responsive to ICIs. Further evaluation is warranted.
Progress in vertebrobasilar dolichoectasia
Authors: 孔朝红, 刘煜敏
Journal: BMJ (2011)

椎基底动脉延长扩张症(vertebrobasilar dolichoectasia,VBD)是一种特殊的脑血管变异性病变,是临床上后循环病变的病因之一.动脉的延长扩张主要是指动脉血管的显著伸长、扩张、迂曲,随之出现血流动力学和凝血功能障碍形成血栓和微小栓塞,可以伴或不伴动脉瘤形成,主要发生于椎动脉和(或)基底动脉[1].VBD以往又称巨大延长的基底动脉瘤畸形、血管曲张样动脉瘤和动脉瘤样扩张等.Smoker等[2]对126例患者进行头颅CT分析后,根据其血管病变的特点并命名,并逐渐被广泛接受.以往报道国外发病率约为人口的0.05%[3],国内约为0.60%[4]。
Relationship between hemoglobin level and nonalcoholic fatty liver disease in male patients with primary gout
Authors: Xiuling Nie, Linling Song, Yue Su, Mingzhen Li, Junwei Wang, Lijin Shen, Wei Zhao, Lirong Sun
Journal: BMJ (2020)

Four hundred and four male patients with primary gout were enrolled. According to the degree of nonalcoholic fatty liver diseases (NAFLD), the patients were divided into simple gout (n=121), gout combined with mild NAFLD (n=149) and gout combined with moderate-severe NAFLD (n=134). The height, weight, waist, hip, blood pressure and blood biochemistry parameters of patients were measured. The degree of NAFLD was negatively correlated with the age of patients in three groups. The BMI, ratio of waist/hip, count of red cells, hemoglobin, hematocrit, red blood cell distribution width (SD and CV), triglyceride, alanine aminotransferase and HOMA-IR were increased with the increasing of NAFLD severity (all P<0.05). Red blood cell count, hemoglobin, alanine aminotransferase, serum uric acid increased with the increasing of NAFLD severity (all P<0.05). Platelet, serum urea nitrogen and serum creatinine were decreased with the increase of NAFLD severity. Logistic regression showed that BMI, hemoglobin and HOMA-IR were independent risk factors for NAFLD. The prevalence and the severity of NAFLD was increased with increasing quadrates of hemoglobin. Taking group Q1 as a control, OR of NAFLD in group Q2 was 1.166(95%CI:0.638-2.133),OR in group Q3 was 2.011(95%CI:1.122-3.605)and OR in group Q4 was 3.120(95%CI:1.613-6.034). The result indicates that hemoglobin levels are associated with the development and the severity of NAFLD in male patients with primary gout.

Key words: 
Gout, male; Hemoglobin; Non-alcoholic fatty liver disease; Insulin resistant
アドレノメデュリンによる麻酔モルモットにおけるヒスタミン・チャレンジに対する血管作用性と小腸ペプチド、イソプレナリンとテオフィリンの気管支保護効果の相乗作用
Authors: Kanazawa H, Kawaguchi T, Fujii T, Shoji S, Hirata K, Kudoh S, Kurihara N, Yoshikawa J
Journal: Thorax (1996)
Treatment outcomes of well-differentiated high-grade (G3) neuroendocrine tumors.
Authors: Alex John Liu, Benjamin Edward Ueberroth, Skye Buckner Petty, Patrick Walsh McGarrah, Ayse T. Kendi, Timothy J. Hobday, Thorvardur Ragnar Halfdanarson, Mohamad Bassam Sonbol
Journal: Journal of Clinical Oncology (2020)

e16691 Background: Recent WHO classification of NET has defined high-grade well-differentiated NET (NET G3) as a distinct entity that is clinically different from neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aims to evaluate NET G3 response to different treatment regimens. Methods: This is a retrospective study of NET G3 patients within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics along with treatment responses and survival were assessed. Primary end points were progression-free survival (PFS) and objective response rate (ORR) by RECIST 1.1 criteria. Results: 71 patients with NET G3 were identified. Systemic treatment data was available in 30 patients who had a median age of 59.5 years at time of diagnosis. The primary tumor was most commonly pancreatic (73.3%). Ki 67 index was ≥55% in 26.7% of cases. 56.7% of cases had &gt; 1 metastatic site. Treatment regimens included: capecitabine+temozolomide (CAPTEM) (n = 20), somatostatin analog (SSA) (n = 14), carboplatin/cisplatin+etoposide (EP) (n = 7), everolimus (n = 2), FOLFOX (n = 7), and lutetium Lu 177 DOTATATE (PRRT) (n = 10). CAPTEM was the most commonly used regimen (10 first-line, and 10 second-line) with ORR of 35%, disease control rate (DCR) of 65%, and median PFS of 9.4 months. The table summarizes the treatment data and responses rates for the various therapies used. Conclusions: Among NET G3 patients treated at Mayo Clinic, CAPTEM was found to be the most commonly used treatment with reasonable efficacy and disease control. Other treatment options include SSA, PRRT, FOLFOX, and EP. Prospective studies evaluating different treatments effects in NET G3 patients are needed to determine an optimal treatment strategy. [Table: see text]
保肝药物的合理使用
Authors: 周宝桐
Journal: BMJ (2005)

保肝药物是临床使用非常普遍的一类药物,一方面,因为我国是肝炎大国,肝病患者众多;另一方面,肝功异常可发生于各类疾病或因多种药物引起(如广泛使用的解热镇痛药物、降血脂药、抗生素等),因此,不仅肝病专科医生,其他各科医生都会应用到此类药物.目前,保肝药物种类繁多,作用各异,价格相差也很大.虽然本类药物一般而言毒副作用轻微,安全性较好,但如果选择和用药方法不当,也会影响治疗效果,增加患者经济负担,甚至产生某些不良反应.本文旨在简要介绍各类常用保肝药物的功效、特点以及应用过程中的一些注意事项,以帮助临床医生,特别是非肝病专业医生更合理的应用保肝药物。
Survey on standardized general practice residency training program in Shanxi province
Authors: Zhaoxia Duan, Wei Zhao, Lu Tan, Tianhui Hou
Journal: BMJ (2019)

A Survey on the current general practice residency training was carried out in January 2018 among 1 114 general practitioners (GPs) who attended the standardized residency training program during 2014-2017. Basic information was obtained from the management department, other information was obtained from questionnaire. Total 1089 valid questionnaires were received with a retrieval rate of 97.8%. The survey showed that the ratios of male trainees, trainees aged 20-30 years and with bachelor degree were increasing during 2014-2017. The participants were more satisfied with the teaching quality in general hospital bases than that in community practice bases. Participants suggested to improve teaching quality, add teaching contents of humanity courses and TCM knowledge. Only14.4%(157/1 089) participants choose GPs as their career because liked this specialty. And 77.7%(846/1 089) GPs understood the main work of GP. There were 81.4%(887/1 089) participants wanted to work in; 77.7%(846/1 089) participants thought that the prospect of general practice would be excellent or good. Increasing income, professional promotion and a sense of social recognition were their wishes. Standardized residency training is crucial for general practitioners to upgrade their quality and competence, to improve training quality and to develop incentive policies are necessary.


Key words: 
General practitioner; Standardized training program; Shanxi Province; Status
Breast cancer frequency and survival by molecular subtype in central Illinois.
Authors: Hamsa Sahib, Sabree Abedrabo, Zurain Niaz, Cameron Koester, Ruby Maini, Odalys Estefania Lara Garcia, Nitin Tandan, Priyanka Parajuli, Manjari Rani Regmi, Asad Cheema, Noupama Mirihagalle, Abdisamad M. Ibrahim, Bishal Bhandari, Alexander Johnson, Kristin Delfino, Kathy Robinson, Meghna R. Desai, Abhishek Kulkarni
Journal: Journal of Clinical Oncology (2020)

e13631 Background: Breast cancer is the most common female malignancy. In 2019, it is estimated that there were 268,000 new cases of female breast cancer. The most common subtype was HR+/HER2 based on 2012-2016 cases, a much higher rate than triple negative breast cancer. Best survival rates are found among women with HR+/HER2- subtype followed by HR+/HER2+ and HR-/HER+ subtypes. Triple negative subtype comparatively had a poorer survival.Our objective was to determine breast cancer rate and survival by molecular subtype in the central Illinois population. Methods: A cohort of 478 patients diagnosed with breast cancer between January 2014 and December 2017 was identified by using ICD codes. Eligibility criteria included pathology confirmed breast cancer.Categorical variables were summarized as frequencies and percentages. Predictors of survival were assessed with Cox proportional hazards regression analyses.All significance was assumed at the p &lt; 0.05 level. Results: Luminal A breast cancer was the most common type in our population. In the cohort of 478 patients, 208 patients (74%) were found to have Luminal A. whereas, 37 patients (13.21%) had Basal subtype, 20 patients (7.14%) had Luminal B and 13 patients (5.36%) had Her2 enriched subtype. However, there was no statistical difference in survival between the subtypes. Conclusions: Although the frequency of cancer subtypes in our population is comparable to the national epidemiology data,we observed that there is no statistical difference in survival as compared to NCI SEERS data. This could be due to optimum care and patient’s adherence to chemo-radiation or due to small sample size. This could be an important area of future research to investigate if we can increase survival of poor prognosis subtypes (as triple negative) by following the same measures. Long term follow up for the patients in the study might also be necessary.
A phase II trial of nivolumab in combination with talazoparib in unresectable or metastatic melanoma patients with mutations in BRCA or BRCAness.
Authors: Tamara A. Sussman, Wei Wei, Brian Hobbs, C. Marcela Diaz-Montero, Ying Ni, Joshua Arbesman, Jennifer S. Ko, Brian Gastman, Pauline Funchain
Journal: Journal of Clinical Oncology (2020)

TPS10082 Background: Melanoma has a response rate of 10-15% with anti-PD-1 re-challenge in the refractory setting. Newer targeted therapies in melanoma are needed, especially once patients progress on immune checkpoint inhibitor (ICI) therapy. Analysis of TCGA and the Cleveland Clinic’s Gross Family Melanoma Registry reveals that a significant proportion (~40%) of melanoma patients possess somatic (31.6%) or germline (TCGA: 4.2%; Registry: 8.3%) mutations in homologous recombination repair genes, which may serve as a therapeutic target. PARP inhibitors, specifically talazoparib, have demonstrated synthetic lethality, potent PARP trapping activity, and increased immunogenicity of tumor cells by promoting T cell and NK cell infiltration in vitro and in vivo. Moreover, augmentation of the STING pathway via PARP inhibition modulates the tumor microenvironment, impacting PD-L1 expression and type I interferon production. Therefore, the use of talazoparib in combination with the ICI, nivolumab, may have a synergistic immunomodulatory and antitumor effect. Methods: This phase II, single arm, open label trial aims to enroll 37 primary or recurrent unresectable or metastatic melanoma patients harboring a somatic or germline mutation or deletion in BRCA or BRCAness (genes including ARID1A/B/2, ATM, ATR, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK4/12, CHEK1/2, DSS1, EMSY, ERCC3, FANCA/D2, HDAC2, IDH1, LIG3/4, MDC1, MLH1/3, MRE11, NBN, PALB2, PRKDC, RAD50/51/54, XRCC6) who have progressed on prior ICI therapy. Patients will be treated with nivolumab 480mg IV every 4 weeks and talazoparib 1mg PO daily. The primary objective is to determine clinical efficacy of the combination therapy, as measured by the objective response rate. The trial is designed to test the null hypothesis that ORR ≤ 10% and is powered to detect an effect size of ORR ≥ 30%. Secondary objectives include PFS, OS, immune-related objective response rate (irORR), irPFS, and treatment-related adverse events. Associations with clinical response will be assessed with correlative studies of PD-L1 expression, ctDNA, tumor mutational burden, copy number variation, and the phenotypic and functional characterization of circulating and tumor infiltrating immune cells. The study is currently open and enrolling patients. Clinical trial information: NCT04187833.
New perspectives on the role of Drp1 isoforms in regulating mitochondrial pathophysiology
Authors: Ayeshah A. Rosdah, William J. Smiles, Jonathan S. Oakhill, John W. Scott, Christopher G. Langendorf, Lea M.D. Delbridge, Jessica K. Holien, Shiang Y. Lim
Journal: Pharmacology & Therapeutics (2020)
Combination immunotherapy with ipilimumab and nivolumab in patients with rare gynaecological malignancies.
Authors: Oliver Klein, Damien Kee, Bo Gao, Ben Markman, Linda R. Mileshkin, Clare L. Scott, Yeojeong So, Richelle Linklater, Andreas Behren, Jodie Palmer, Matteo S. Carlino, Jonathan S. Cebon
Journal: Journal of Clinical Oncology (2020)

6091 Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti- PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Methods: 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Results: Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 – 25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusions: Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable responses being observed. Tumor agnostic biomarkers are required to assist with better patient selection. Clinical trial information: NCT02923934. [Table: see text]