tbuckley/cabot-search huggingface dataset:
Application of ultrasonography in diagnosis and treatment of intrauterine pregnancy complicated with cornual pregnancy after in-vitro fertilization embryo transfer
Authors: Qinghong Zhao, Hua Shi, Yuguo Zhang, Jiaqi Hu
Journal: BMJ (2017)

The clinical data of 39 cases of intrauterine pregnancy complicated with cornual pregnancy after in-vitro fertilization embryo transfer(IVF-ET) were analyzed retrospectively.All the patients were diagnosed by transvaginal ultrasound in early pregnancy, and the position of the gestational sac and its external process were determined by transvaginal ultrasound. According to the location and size of the gestational sac, the patients were divided into two groups: in group A (n=29) the gestational sac was located close to the interstitial tube and the gestational sac was larger, prominent out of the corners of the uterus; in group B (n=10) the gestational sac was located towards the uterine cavity, gestational sac was smaller and the embryo was not active. The laparoscopic angle wedge resection for group A and ultrasound-guided embryo reduction for group B were performed respectively. After treatment, 38 cases were stable to term delivery with intrauterine pregnancy; abortion occurred in 1 case of group A 2 weeks after operation. The early diagnosis and treatment is very important for intrauterine pregnancy complicated with cornual pregnancy. Ultrasonography provides an accurate preoperative assessment and intraoperative real-time monitoring during embryo reduction, which provides an alternative approach for the treatment of intrauterine pregnancy combined with cornual pregnancy.


Key words: 
Ultrasonography, prenatal, three-dimensional; Pregnancy, ectopic; Embryo transfer
WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition
Authors: Yu-Ru Lee, Lamis Yehia, Takahiro Kishikawa, Ying Ni, Brandie Leach, Jinfang Zhang, Nivedita Panch, Jing Liu, Wenyi Wei, Charis Eng, Pier Paolo Pandolfi
Journal: New England Journal of Medicine (2020)

Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants.The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).
Heparanase in myeloma related renal dysfunction: Role in promoting nephrotoxicity and potential as a novel biomarker for early detection.
Authors: Sunil Rangarajan, Kaushlendra Tripathi, Shyam Kumar Bandari, Elizabeth E Brown, Ralph D Sanderson
Journal: Journal of Clinical Oncology (2020)

e20554 Background: Our laboratory previously demonstrated that heparanase (HPSE), an enzyme that cleaves heparan sulfate, upregulates growth factors and their receptors, resulting in enhanced multiple myeloma (MM) growth, chemoresistance, and metastasis. Targeting HPSE therapeutically decreases chemoresistance and relapse. Renal dysfunction is a major problem in MM patients with nearly 50% having renal dysfunction at diagnosis of which 19% are advanced, and 8% require dialysis. There is no specific therapy for myeloma associated renal dysfunction highlighting the need to identify novel mechanisms that lead to the development of targeted therapies. This is the first study to investigate the association between HPSE activity and renal dysfunction in MM patients by utilizing high-sensitivity biomarkers. Methods: Human Kidney 2 (HK-2) cells were treated with HPSE. Necrosis and apoptosis were assessed by flow cytometry. Cell lysates were examined for expression of kidney injury biomarkers by western blotting. HK-2 clusters were co-cultured with MM-spheroids with low or high HPSE. SCID mice were injected with 3 million luciferase-positive myeloma cells with low or high level of HPSE. Kidneys were harvested after 3 weeks and processed for studies. HPSE activity and biomarkers using multiplex magnetic bead ELISA were assessed in peripheral blood from a MM patient with serum creatinine 1.2 mg/dL and a healthy control donor. Results: HPSE induced HK-2 cell necrosis and apoptosis. HPSE induced significant expression by HK-2 cells of KIM-1, NGAL and IGFBP-7. Co-culturing HK-2 organoids with MM-spheroids expressing high HPSE compromised HK-2 organoids survival over 7 days. Damage to HK-2 cells was prevented by HPSE inhibitors Roneparstat or OGT-2115. Kidney tissues from mice harboring HPSE-high myeloma tumors expressed more KIM-1 and NGAL than those harboring HPSE-low myeloma tumors. HPSE activity was 6-fold higher and kidney injury biomarkers were many fold (range 2 – 84) higher in the plasma of a MM patient than in plasma from healthy control. Conclusions: HPSE causes kidney cellular injury which can be detected early by the measurement of high sensitivity biomarkers and can be prevented by treatment with HPSE inhibitors, Roneparstat and OGT-2115. Further studies are ongoing to investigate the association between HPSE activity and renal dysfunction in a larger cohort of MM patients which have been accrued as a part of the UAB-Integrative Molecular And Genetic Epidemiology (IMAGE) Study of Myeloma.
A phase I/II, open-label, dose-escalation, and cohort-expansion study evaluating the safety, pharmacokinetics, and therapeutic activity of OBI-999 in patients with advanced solid tumors.
Authors: Apostolia Maria Tsimberidou, Jaffer A. Ajani, Pei Hsu, I-Ju Chen, Tillman E. Pearce
Journal: Journal of Clinical Oncology (2020)

TPS3657 Background: Aberrant glycosylation is a hallmark of cancer. Glycosphingolipids (GSLs), glycans conjugated to a lipid (ceramide) core, are essential for the recruitment of immune-related proteins to specific membrane microdomains. Globo H (GH) is a GSL found on normal cells but highly overexpressed on various epithelial tumors playing a role in tumor development and progression. GH is a promising target for immunotherapy. OBI-999 is an ADC composed of a human recombinant immunoglobulin G (IgG) monoclonal antibody that selectively and specifically binds to GH, attached by a linker to the antimitotic agent monomethyl auristatin E (MMAE). Its mechanism of action is based on tumor-selective delivery of MMAE to GH-expressing tumors with subsequent tumor cell death. Preclinical studies demonstrated that OBI-999 antibody binds specifically to the GH antigen, and antitumor efficacy was noted in breast, gastric, pancreatic, and lung cancer xenograft models. The pharmacokinetics (PK) of OBI-999 were determined in normal and tumor-bearing mice, rats, and monkeys. Exposure of OBI-999 increased proportionally with dose. No sex difference or accumulation was seen. The primary objectives are to determine dose limiting toxicities (DLTs), the maximum tolerated dose (MTD), and the phase 2 recommended dose (P2RD). The secondary objectives are to assess the rates of objective response and clinical benefit, the duration of progression-free survival, the immunogenicity of OBI-999, and the PK and pharmacodynamics (PD) of OBI-999 and MMAE. Methods: In Part 1, a "3+3" dose-escalation part of the study, up to 30 patients with advanced solid tumors refractory to ≥1 line of systemic therapy, who cannot tolerate standard therapy, or for whom no standard treatment is available, regardless of GH status will be treated. OBI-999 will be administered as a 60-minute IV infusion using a dose range of 0.4, 0.8, 1.2, 1.6, and 2.0 mg/kg on day 1 of every 21-day cycle. In Part 2, the cohort-expansion portion of the study, patients will be treated at the MTD or at a lower RP2D as determined by cumulative toxicities and tolerability profile. The study will determine the preliminary clinical activity and safety of OBI-999 in up to 155 patients with advanced solid tumors, pancreatic, gastric, esophageal, and colorectal cancer according to a Simon two-stage phase 2 design. Patients must have GH overexpression defined as an H-score of ≥100 according to an FDA Investigational Device Exempt (IDE) validated IHC assay. Clinical trial information: NCT04084366 .
Financial toxicity and patient-reported outcomes over time: A longitudinal study of women with recurrent ovarian cancer.
Authors: Larissa Meyer, Amy Schneider, Tsun Hsuan Chen, Xin Shelley Wang, Charlotte C. Sun
Journal: Journal of Clinical Oncology (2020)

6079 Background: The chronic nature of treatment for ovarian cancer (OC) can place women at increased risk of financial toxicity (FT) from ongoing direct and indirect costs coupled with potential loss of income. We explored FT and its association with anxiety, depression, and quality of life over time in women with recurrent OC. Methods: Women with recurrent OC enrolled in a longitudinal study were given the following validated instruments at baseline and every 3 months: FACIT Comprehensive Score for Financial Toxicity (COST), GAD-7 (anxiety), CES-D (depression) and FACT-Ovary. Mixed models were performed on longitudinal data over 12 months of follow-up. Multivariable analysis of demographic data was performed. Results: 225 patients were divided into low FT (top 2 terciles, n = 152) and high FT (bottom tercile, n = 73,) by baseline COST scores. The median age was 59 (range 22.9-78.9). There were no significant differences between the groups in regards to marital status, number of people in household or education level. There were significant differences between the low and high financial toxicity groups in terms of median age (low FT = 61 yrs vs. high FT = 54 yrs, p &lt; 0.0001); race (5.4% black in low FT vs. 15.1% in high FT, p = 0.04), number of children &lt; 18 years in the home ((p = 0.02), employment status p( &lt; 0.0001) and annual income p( &lt; 0.0001). On multivariable analysis, only income and age remained significantly associated with FT. The mean baseline COST score in the low FT group was 34 vs. 16 in the high FT group. Interestingly, pts with low baseline FT had significant worsening of FT over the 12 month time period while those with high FT had slight improvement over time. Consistently, the high FT group had higher scores on screening measures for anxiety and depression, as well as lower overall quality of life which persisted over time. Conclusions: Financial toxicity is a measurable and clinically relevant patient reported outcome. The cohort of women with high FT demonstrated higher mean scores on screening measures for depression and anxiety as well as persistently lower quality of life. Targeted interventions to decrease financial toxicity may provide more global improvements in mental health and quality of life.
A phase II trial of atezolizumab and bevacizumab in patients with relapsed/refractory and unresectable malignant peritoneal mesothelioma.
Authors: Kanwal Pratap Singh Raghav, Michael J. Overman, Suyu Liu, Anneleis Willett, Richard Eldon Royal, Anais Malpica, Christopher Scally, Ignacio Ivan Wistuba, Andrew Futreal, Armeen Mahvash, Cindy Yun, Shannon Dervin, Edward Francis Mckenna, Katja Schulze, Patrick Hwu, James C. Yao, Scott Kopetz, Gauri Rajani Varadhachary, Daniel M. Halperin
Journal: Journal of Clinical Oncology (2020)

9013 Background: Malignant peritoneal mesothelioma (MPeM) is an orphan malignancy. No recommended/FDA approved therapies exist for salvage treatment beyond first-line platinum and pemetrexed based chemotherapy. While immune checkpoint inhibition has shown preliminary efficacy in mesotheliomas, data and efficacy is limited in MPeM patients (pts) [objective response rate (ORR) ~ 11%; median progression-free survival (mPFS) ~ 4 months (m); median overall survival (mOS) ~ 11 m]. We aimed to prospectively assess the safety and efficacy of combined anti-PD1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) in pts with MPeM. Methods: In this phase 2 study, eligible pts with histologically confirmed MPeM, ECOG PS 0-1, and prior platinum and pemetrexed treatment were treated with 1200 mg of atezolizumab and 15 mg/kg of bevacizumab IV every 21 days until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint was confirmed ORR by RECIST 1.1 by independent radiology review. Duration of response (DOR), PFS and OS were pre-specified secondary endpoints. Results: Among 20 enrolled pts (3/2017 - 2/2019), median age was 63 (range, 33-87) years, 12 (60%) were female, 12 (60%) had PS 0, and 2 (10%) had biphasic MPeM. Among 20 evaluable pts (median cycles 14), confirmed ORR was 35% (7 pts; 95% CI: 15.4-59.2) (median DOR 8.8 m). Responses were ongoing in 5/7 (71.4%) pts at data cutoff. The median follow-up was 20.5 months. Six deaths were observed during follow-up, and the 1-year OS was 79% (95% CI: 52 – 91) (median OS ~ NR). Median PFS was estimated as 17.6 m (95% CI: 9.1 – NR). The 1-year PFS was 54% (95% CI: 28 – 74). Grade 3 (no grade 4/5) treatment-emergent adverse events occurred in 10 (50%) pts; most common being hypertension (40%) and anemia (10%). Two (10%) pts had grade 3 immune-related adverse events. Translational studies are ongoing. Conclusions: AtezoBev showed promising and durable efficacy in relapsed/refractory MPeM with acceptable safety profile. Ongoing multiomic analyses of pre and on-treatment tissue/liquid biopsies obtained on all these pts will provide additional insight into mechanisms and biomarkers of response and resistance. Clinical trial information: NCT03074513.
Clinical efficacy of Jiawei Dihuang decoction combined with valsartan in treatment of early diabetic nephropathy
Authors: Junhua Hu, Shuo Yang, Yajuan Wang
Journal: BMJ (2017)

One hundred patients with early diabetic nephropathy were randomly divided into control group and study group with 50 cases in each group. All patients received conventional antidiabetic therapy with valsartan tablets 80mg, q. d; patients in study group were given additional TCM Jiawen Dihuang decoction. TCM syndrome scores, relevant biochemical testing and renal function changes were evaluated before and after treatment in two groups. After 8 weeks of treatment, the results showed than the TCM scores in both groups were significantly reduced (study group: 18.9±1.6 vs. 7.2±5.1, control group 18.8±1.5 vs. 10.3±6.2. both P<0.05); the improvement rate of TCM syndrome in study group was significantly higher than that of control group (90% vs. 68%, χ2=5.3, P<0.05) ; and the improvement of relevant biochemical index and renal function in study group was more marked than that in control group. The study indicates that the integrated TCM and Western medicine can enhance the efficacy in treatment of early diabetic hephropathy.


Key words: 
Early diabetic nephropathy; Valsartan Tablets; insulin; TCM therapy; clinical effect
胃食管反流性咳嗽32例临床分析
Authors: 王鲁峰
Journal: BMJ (2007)

对32例有长期咳嗽病史,且有明显反流性食管炎症状的60岁以上患者,给予奥美拉唑20 mg/d,多潘力酮10 mg,每日3次,疗程8周.治疗2周、8周《Leicester咳嗽问卷》评分的总分分别为16.5±3.2、19.8±1.4,与治疗前比较差异均有统计学意义(P＜0.05).治疗前内镜分级总分为2.6±0.9,治疗2周后为1.1±1.1,与治疗前比较下降了57.4%,差异有统计学意义(P＜0.05);治疗8周为0.2±0.4,与治疗前和治疗2周比较下降了92.6%和82.6%,差异均有统计学意义(P＜0.05).表明质子泵抑制剂及胃肠动力药物能显著改善反流性食管炎咳嗽者的症状。
ROS1 immunohistochemistry as a screening tool for detection of ROS1 rearrangement in non-small cell lung cancer: Comparison between SP384 and D4D6 clones.
Authors: Yi-wen Chang, Yun-hsin Liang, Li-rung Liao, Yi-chen Yeh, Teh-Ying Chou
Journal: Journal of Clinical Oncology (2020)

e21733 Background: ROS1 rearrangement occurs in approximately 1%-2% of non-small cell lung cancer, and it is predictive of treatment response to tyrosine kinase inhibitor. The gold standard method to detect ROS1 rearrangement is break-apart fluorescence in situ hybridization (FISH). ROS1 immunohistochemistry has been proposed as a cost-effective screening test for detection of ROS1 rearrangement. Most studies about the correlation between ROS1 FISH and immunohistochemistry derived from the D4D6 clone anti-ROS1 antibody. Recently, a novel anti-ROS1 antibody (SP384 clone) is available. However, data regarding the performance of this new anti-ROS1 antibody is still limited. In this study, we evaluated the performance of these two anti-ROS1 antibody as a screening tool to detect ROS1 rearrangement. Methods: Two hundred non-small cell lung cancers, including 18 ROS1 FISH-positive and 182 ROS1 FISH-negative samples, were studied. All specimens were stained with D4D6 clone and SP384 clone anti-ROS1 antibodies. The stained slides were scored by a pathologist using the H-score method, which was defined as the sum of products of multiplying intensity (0, 1, 2, and 3) by extent of each staining intensity (%). Receiver Operating Characteristics (ROC) curves were used to determine the optimal cut-off value that discriminates between ROS1-rearranged and non-rearranged tumors. Results: There was high correlation between the H-score of D4D6 clone and SP384 clone (Spearman's rho correlation coefficient = 0.862, P-value &lt; 0.001). The SP384 clone showed a higher H-score than D4D6 clone (Wilcoxon signed rank test, P-value &lt; 0.001). ROC analysis showed H-score of ≥ 150 was the optimal cut-off value for both D4D6 clone and SP384 clone to discriminate between ROS1-rearranged and non-rearranged tumors. Using this cut-off value, the D4D6 clone showed 100% sensitivity and 96.7% specificity; the SP384 clone showed 100% sensitivity and 95.1% specificity. The areas under ROC curve for D4D6 clone and SP384 clone were 0.992 and 0.990, respectively. Conclusions: The performance of D4D6 clone or SP384 clone is comparable. ROS1 IHC with either D4D6 clone or SP384 clone is a cost-effective screening tool for the presence of ROS1 rearrangements. [Table: see text]
Diagnosis and treatment of adrenal teratoma: a report of 5 cases and review of literature
Authors: Liang Wang, Feng Zhang, Kunlong Tang
Journal: BMJ (2014)

Objective
To discuss the feature, diagnosis and treatment, and proguosis of adrenal teratoma.


Methods
Clinical data of 5 patients with confirmed adrenal teratoma were retrospectively reviewed.There were 2 males and 3 females, with a median age of 57 years (35-64). The mean tumor size was 5-8.5 cm.The tumors were located on the right side in 3 cases and the left side in 2.Two cases were detected by routine health check up, and 2 were detected with the complains of fatigue and 1 with complains of back pain.All cases had normal value of endocrinology and biochemistry tests.Ultrasound examination showed cystic tumor on adrenal gland with uneven echo.CT showed irregular, inhomogeneous adrenal neoplasms in adrenal gland.The tumor presented as inhomogenous high signal intensity on MRI T1 and T2.


Results
Five patients underwent laparoscopic adrenalectomy, and histopathology showed adrenal mature teratoma.No recurrence occurred after operation in all patients.


Conclusions
These cases combined with literature review indicate that adrenal teratoma is extremely rare which has no characteristic clinical manifestations; and laparoscopic adrenalectomy is a feasible, effective technique with excellent results.


Key words: 
Adrenal gland neoplasms; Teratoma; Laparoscopes
Leukocytes with bound platelets as a predictive biomarker for immune-related adverse events (irAEs) in advanced non-small cell lung cancer (NSCLC) patients (pts) receiving anti-PD-(L)1 agents.
Authors: Mariona Riudavets, Carlos Zamora, Ivana Sullivan, Leticia Alserawan, Andrés Barba, Pablo Gallardo, Javier Gavira, Jorgina Serra, Georgia Anguera, Agusti Barnadas, Sílvia Vidal, Margarita Majem
Journal: Journal of Clinical Oncology (2020)

e15047 Background: Anti-PD-(L)1 blocking agents can induce irAEs, compromising treatment continuation and patient safety. Since complexes of leukocyte-platelet have been shown to play a role in inflammation by reducing cytokine production, we hypothesize that the percentage of these complexes could be used as a predictor of irAEs in pts receiving anti-PD-(L)1 agents. Methods: From May 2015 to January 2019, 87 advanced NSCLC pts treated with anti-PD-(L)1 agents at our institution were prospectively included. Percentages of circulating CD4+T lymphocytes and monocytes with bound platelets (CD4+PLT+ and CD14+PLT+, respectively) were obtained by flow cytometry and compared between NSCLC pts and healthy donors (HD, n = 26). The association of leukocyte-platelet complexes with the presence of irAEs was analyzed. According to CD4+PLT+ and CD14+PLT+ levels, NSCLC pts were grouped as CD4+PLT+ high (n = 29), CD4+PLT+ low (n = 58) and as CD14+PLT+ high (n = 36) and CD14+PLT+ low (n = 51). Frequencies and grade of irAEs were compared between groups using Chi-square test. Results: NSCLC pts showed significant higher percentages of circulating CD4+PLT+ and CD14+PLT+ than HD (9.41±0.54% vs. 6.01±0.45% and 57.44±2.42 vs. 35.43±2.22, respectively; p&lt; 0.001). No significant differences in CD4+PLT+ and CD14+PLT+ were found according to the presence of irAEs. CD4+PLT+ high group presented a higher rate of dermatological irAEs while CD4+PLT+ low group showed higher rate of non-dermatological irAEs (dermatological: 44.85% vs. 8.6%; non-dermatological: 10.3% vs. 39.7%, respectively; p&lt; 0.001). Lower percentage of grade ≥2 irAEs was observed in the CD4+PLT+ high group than in the CD4+PLT+ low group (17.3% vs. 41.4%; p&lt; 0.05). No significant differences in the type of irAEs were observed between CD14+ PLT+ high and low groups. Pts with CD4+PLT+ high and CD14+PLT+ low levels showed the lowest rate of irAEs, presenting only grade ≤1 irAEs (53.8% dermatological, 7.7% dermatological + non-dermatological, 38.5% no-irAEs). In contrast, pts with CD4+PLT+ low and CD14+PLT+ high levels presented higher rate of grade ≥3 irAEs (50% grade 0-1, 20% grade 2, 30% grade ≥3; p&lt; 0.05) and predominantly developed non-dermatological irAEs (45% non-dermatological, 30% dermatological + non-dermatological, 25% no-irAEs; p&lt; 0.01). Conclusions: Combining CD4+ PLT+ and CD14+ PLT+ levels may be used as predictive of development and severity of irAEs in advanced NSCLC pts receiving anti-PD-(L)1 agents.