tbuckley/cabot-search huggingface dataset:
Case 52-1991
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, H.S. Winter, C.C. Compton
Journal: New England Journal of Medicine (1991)

Presentation of CaseAn eight-year-old girl with Hirschsprung's disease was admitted to the hospital because of recurrent abdominal pain, with abdominal distention and diarrhea.The patient was born of a full-term first pregnancy to a mother 24 years of age; the pregnancy was complicated by gestational diabetes mellitus. The child's birth weight was 3.37 kg. On the third day of life an operative procedure was performed because of intestinal volvulus. The patient's postoperative course was complicated by meningitis due to Escherichia coli, from which she gradually recovered and was discharged to her home. Thereafter she was irritable and "colicky." . . .
Current treatment strategies and patterns of recurrence in locally advanced colon cancer.
Authors: Caroline Huynh, Stephanie Minkova, Diane Kim, Heather Stuart, Trevor D Hamilton
Journal: Journal of Clinical Oncology (2019)

e15171 Background: Locally advanced colon cancer (LACC) is a frequent presentation and has a high rate of recurrence. The aim of this study was to evaluate current population-based strategies in LACC patients, and to analyze patterns of recurrence. Methods: We conducted a retrospective review of all patients treated at a regional cancer agency with a diagnosis of LACC between 2005 and 2015 treated with curative intent resection. Inclusion criteria were adults with T4 colon cancer, 16 cm above the anal verge, with no evidence of distant metastases. Descriptive statistics were used to define the study population. Kaplan-Meier and Cox-proportional hazards modeling were used for survival analysis. Results: 1394 patients with LACC were reviewed. Median age was 69 [IQR 60-77] and 49.3% were female. Primary tumor location was right-sided in 57.1% of cases. Most tumors were T4a (69.4%) and 39.4% were node positive. A total of 35.4% had urgent/emergent surgery, 46.4% were at least partially obstructed, 22.0% were perforated and 1.9% had a diverting ostomy as an initial operation. En-bloc multi-visceral resection occurred in 23.5% of cases. Positive margins were present in 14.3%. Only 1.6% had neoadjuvant chemotherapy and 0.8% had neoadjuvant chemoradiation. Adjuvant chemotherapy was delivered in 59.8% and adjuvant chemoradiation in 2.8%. Median follow up was 37 months. During follow up 681 (48.9%) patients died and 584 (41.9%) patients developed recurrence. In the entire cohort, rates of recurrences were local-regional (14.7%) and distant metastatic (35.1%). Overall survival for the entire cohort was 63 months [95% CI 55.7-70.3] and recurrence-free survival was 61 months [95% CI 38.8-83.2]. Multivariate analysis identified age (HR 1.03, 95% CI [1.02-1.05] p &lt; 0.001), node negative status (HR 0.62, 95% CI [0.45-0.84] p = 0.002) and positive margin (HR 1.79, 95% CI [1.24-2.57] p = 0.002) as predictive of overall survival after adjusting for confounding factors. Predictive factors for recurrence-free survival were node negative status (HR 0.55, 95% CI [0.39-0.77] p &lt; 0.001) and positive margin (HR 1.51, 95% CI [1.02-2.23] p = 0.038). Conclusions: Recurrence after curative intent treatment for LACC is common. Recurrence and survival patterns are significantly influenced by tumor nodal status and margin positivity.
Ferroptosis Promotes Photodynamic Therapy: Supramolecular Photosensitizer-Inducer Nanodrug for Enhanced Cancer Treatment
Authors: Ting Zhu, Leilei Shi, Chunyang Yu, Yabing Dong, Feng Qiu, Lingyue Shen, Qiuhui Qian, Guoyu Zhou, Xinyuan Zhu
Journal: Theranostics (2019)

The noninvasive nature of photodynamic therapy (PDT) enables the preservation of organ function in cancer patients.However, PDT is impeded by hypoxia in the tumor microenvironment (TME) caused by high intracellular oxygen (O 2 ) consumption and distorted tumor blood vessels.Therefore, increasing oxygen generation in the TME would be a promising methodology for enhancing PDT.Herein, we proposed a concept of ferroptosis-promoted PDT based on the biochemical characteristics of cellular ferroptosis, which improved the PDT efficacy significantly by producing reactive oxygen species (ROS) and supplying O 2 sustainably through the Fenton reaction.In contrast to traditional strategies that increase O 2 based on decomposition of limited concentration of hydrogen peroxide (H 2 O 2 ), our methodology could maintain the concentration of H 2 O 2 and O 2 through the Fenton reaction.Methods: For its association with sensitivity to ferroptosis, solute carrier family 7 member 11 (SLC7A11) expression was characterized by bioinformatics analysis and immunohistochemistry of oral tongue squamous cell carcinoma (OTSCC) specimens.Afterwards, the photosensitizer chlorin e6 (Ce6) and the ferroptosis inducer erastin were self-assembled into a novel supramolecular Ce6-erastin nanodrug through hydrogen bonding and π-π stacking.Then, the obtained Ce6-erastin was extensively characterized and its anti-tumor efficacy towards OTSCC was evaluated both in vitro and in vivo.Results: SLC7A11 expression is found to be upregulated in OTSCC, which is a potential target for ferroptosis-mediated OTSCC treatment.Ce6-erastin nanoparticles exhibited low cytotoxicity to normal tissues.More significantly, The over-accumulated intracellular ROS, increased O 2 concentration and inhibited SLC7A11 expression lead to enhanced toxicity to CAL-27 cells and satisfactory antitumor effects to xenograft tumour mouse model upon irradiation.Conclusion: Our ferroptosis promoted PDT approach markedly enhances anticancer actions by relieving hypoxia and promoting ROS production, thereby our work provides a new approach for overcoming hypoxia-associated resistance of PDT in cancer treatment.
Presenting symptoms and patient prognosticators in neoplastic meningitis: A single institution experience.
Authors: Shilpa Ghatnekar, Hilal Hachem, Rima Patel, Richard Dowd, Amandeep Godara, Hong Chang, Suriya A. Jeyapalan
Journal: Journal of Clinical Oncology (2019)

e13593 Background: Neoplastic meningitis (NM) occurs in 5-15% of cancer patients, with less than 15% surviving one year. Untreated, median survival is estimated at 1.5-2 months. The purpose of this study is to identify the presenting symptoms of NM disease and the patient characteristics which are prognostic of overall survival (OS). Methods: We performed a single-institution retrospective analysis of 123 patients diagnosed with NM disease at TMC between January 2006 and January 2016. Patients were identified via cytopathology and radiology. Patient data was obtained from the hospital electronic medical record. Survival analysis was generated using Kaplan-Meier methods and chi square tests for categorical data. Results: Breast cancer was the most common primary malignancy (22%, n = 27), followed by lymphoma (19%, n = 23), and lung cancer (15%, n = 18). The most common presenting symptoms were headache (33%, n = 41), extremity weakness (33%, n = 41), and gait abnormalities (25%, n = 31). Median age and Karnofsky performance status (KPS) at diagnosis were 56 years [18-93] and 58 [10-100], respectively. Median OS was 4.08 months [0-130], with a 23% one-year survival rate. Higher KPS was associated with a significantly improved OS (p &lt; 0.05). Although survival was worse in the age group &gt; 67 yrs compared to &lt; 45 yrs the difference was not significant (p = 0.053, 95% CI (0.994- 2.944)). Conclusions: To our knowledge, this is one of the largest analyses of patient characteristics and outcomes in NM. Results show that KPS, when adjusted for confounders, is an important prognostic biomarker. In contrast to other studies, age was not a significant prognosticator of survival. Headaches combined with extremity weakness were the most common presenting symptoms of NM disease. When present together in the cancer patient, the treating physician should strongly consider further workup for the presence of NM disease.
Three-Dimensional Ultrasound Imaging
Authors: Aaron Fenster, Donal B. Downey
Journal: Annual Review of Biomedical Engineering (2000)

▪ Abstract Two-dimensional viewing of three-dimensional anatomy by conventional ultrasound limits our ability to quantify and visualize a number of diseases and is partly responsible for the reported variability in diagnosis. Over the past two decades, many investigators have addressed this limitation by developing three-dimensional imaging techniques, including three-dimensional ultrasound imaging. In this paper we describe the development of a number of three-dimensional ultrasound imaging systems that make use of B mode, color Doppler, and power Doppler. In these systems, the conventional ultrasound transducer is scanned mechanically or by a freehand technique. The ultrasound images are digitized and then reconstructed into a three-dimensional volume, which can be viewed and manipulated interactively by the diagnostician with a variety of image-rendering techniques. These developments as well as future trends are discussed with regard to their applications and limitations.
Microbiome signature of bile from pancreatic and biliary tract cancer patients: A pilot study.
Authors: Shyam K. Poudel, Roshan Padmanabhan, Prabhleen Chahal, Madhusudhan Sanaka, Tyler Stevens, Kathryn Guinta, Alok A. Khorana, Davendra Sohal, Charis Eng
Journal: Journal of Clinical Oncology (2019)

e15744 Background: Recent studies especially in murine models have linked meta-organismal pathways in the gut microbial community to cancers of the pancreas and the biliary tract. However, data on microbiome in the biliary pool in patients to establish models for oncogenesis in the pancreatobiliary (PB) habitat have been limited. We analyzed bile collected from a pilot series of patients to identify microbiome signatures associated with malignancy. Methods: We collected bile samples from patients during routine endoscopic retrograde cholangiopancreatography in this study approved by the Cleveland Clinic Institutional Review Board for Human Subjects’ Protection. Of 10 patients, there were 5 with pancreatic ductal adenocarcinoma (PDA), 3 with cholangiocarcinoma (CC), 1 with ampullary adenocarcinoma, and 1 with gallstone pancreatitis. DNA was extracted from bile specimens using PowerViral RNA/DNA Isolation kit. Bacterial 16S rRNA gene amplification and library construction were performed according to the 16S Metagenomic Sequencing Library Preparation guide from Illumina. Post-sequencing analysis was done using QIIME (Quantitative Insights Into Microbial Ecology) and MICCA (MICrobial Community Analysis). Results: Most reads were from phyla Firmicutes (57.9%) and Proteobacteria (14.9%). One benign specimen (pancreatitis) separated clearly from the rest showing 98.9% of reads from Clostridium sensu stricto (phylum Firmicutes). Analysis of beta diversity showed six samples clustering tightly. Of these, 5 were PDA and 1 was CC. A second cluster included remaining 3 samples, 2 with CC and 1 with PDA; this latter had higher abundance of phyla Fusobacteria (90.6%) and Verrucomicrobia (92.9%). Conclusions: Select bacteria are differentially increased in malignant and benign PB diseases. Furthermore, distinct microbiome signatures may be associated with cancer in the pancreatic and biliary habitats. We intend to evaluate these findings in larger sample sizes and determine associations with clinical outcomes and response to treatment.
Safety, Efficacy, and Biomarker Analysis of Pyrotinib in Combination with Capecitabine in HER2-Positive Metastatic Breast Cancer Patients: A Phase I Clinical Trial
Authors: Qiao Li, Xiuwen Guan, Shanshan Chen, Zongbi Yi, Bo Lan, Puyuan Xing, Ying Fan, Jiayu Wang, Yang Luo, Peng Yuan, Ruigang Cai, Pin Zhang, Qing Li, Dafang Zhong, Yifan Zhang, Jianjun Zou, Xiaoyu Zhu, Fei Ma, Binghe Xu
Journal: Clinical Cancer Research (2019)

Abstract Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers. Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%–91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%–96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0–26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naïve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P = 0.006). Conclusions: In a population largely naïve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC.
Using real-world cohorts to assess the generalizability and relevance of randomized clinical trials (RCTs).
Authors: Caroline Savage Bennette, Nathan Coleman Nussbaum, Melissa D. Curtis, Neal J. Meropol
Journal: Journal of Clinical Oncology (2019)

6540 Background: RCTs are the gold standard for understanding the efficacy of new treatments, however, patients (pts) in RCTs often differ from those treated in the real-world. Further, selecting a standard of care (SOC) arm is challenging as treatment options may evolve during the course of a RCT. Our objective was to assess the generalizability and relevance of RCTs supporting recent FDA approvals of anticancer therapies. Methods: RCTs were identified that supported FDA approvals of anticancer therapies (1/1/2016 - 4/30/2018). Relevant pts were selected from the Flatiron Health longitudinal, EHR-derived database, where available. Two metrics were calculated: 1) a trial’s pt generalizability score (% of real-world pts receiving treatment consistent with the control arm therapy for the relevant indication who actually met the trial's eligibility criteria) and 2) a trial’s SOC relevance score (% of real-world pts with the relevant indication and meeting the trial's eligibility criteria who actually received treatment consistent with the control arm therapy). All analyses excluded real-world pts treated after the relevant trial’s enrollment ended. Results: 14 RCTs across 5 cancer types (metastatic breast, advanced non-small cell lung cancer, metastatic renal cell carcinoma, multiple myeloma, and advanced urothelial) were included. There was wide variation in the SOC relevance and pt generalizability scores. The median pt generalizability score was 63% (range 35% - 88%), indicating that most real-world pts would have met the RCT eligibility criteria. The median SOC relevance score was 37% (range 15% - 74%), indicating that most RCT control arms did not reflect the way trial-eligible real-world pts in the US were actually treated. Conclusions: There is great variability across recent RCTs in terms of pt generalizability and relevance of SOC arms. Real-world data can be used to inform selection of control arms, predict impact of inclusion/exclusion criteria, and also assess the generalizability of the results of completed trials. Incorporating real-world data in planning and interpretation of prospective clinical trials could improve accrual and enhance relevance of RCT outcomes.
The Birth and Death of Toxins with Distinct Functions: A Case Study in the Sea Anemone Nematostella
Authors: Maria Y Sachkova, Shir A Singer, Jason Macrander, Adam M Reitzel, Steve Peigneur, Jan Tytgat, Yehu Moran
Journal: Molecular Biology and Evolution (2019)

Abstract The cnidarian Nematostella vectensis has become an established lab model, providing unique opportunities for venom evolution research. The Nematostella venom system is multimodal: involving both nematocytes and ectodermal gland cells, which produce a toxin mixture whose composition changes throughout the life cycle. Additionally, their modes of interaction with predators and prey vary between eggs, larvae, and adults, which is likely shaped by the dynamics of the venom system. Nv1 is a major component of adult venom, with activity against arthropods (through specific inhibition of sodium channel inactivation) and fish. Nv1 is encoded by a cluster of at least 12 nearly identical genes that were proposed to be undergoing concerted evolution. Surprisingly, we found that Nematostella venom includes several Nv1 paralogs escaping a pattern of general concerted evolution, despite belonging to the Nv1-like family. Here, we show two of these new toxins, Nv4 and Nv5, are lethal for zebrafish larvae but harmless to arthropods, unlike Nv1. Furthermore, unlike Nv1, the newly identified toxins are expressed in early life stages. Using transgenesis and immunostaining, we demonstrate that Nv4 and Nv5 are localized to ectodermal gland cells in larvae. The evolution of Nv4 and Nv5 can be described either as neofunctionalization or as subfunctionalization. Additionally, the Nv1-like family includes several pseudogenes being an example of nonfunctionalization and venom evolution through birth-and-death mechanism. Our findings reveal the evolutionary history for a toxin radiation and point toward the ecological function of the novel toxins constituting a complex cnidarian venom.
Comparative benefit of interstitial needles in addition to intracavitary applicators in the treatment of locally advanced cervical cancer.
Authors: Dorothy Chilambe Lombe, Juanita M. Crook, Francois Bachand, Deidre Batchelar, Jocelyn Moore, Tracey Rose, Danielle Sherin
Journal: Journal of Clinical Oncology (2019)

5528 Background: Cervical cancer is the leading cause of cancer mortality of women in Low and Middle Income Countries (LMIC). Interstitial needles (IN) have improved outcomes but the resources required in comparison to intracavitary brachytherapy (IC) alone has impeded uptake in endemic regions. We conducted a retrospective review of the utilisation of IN in the management of locally advanced cervical cancer and simulated 2D planning by loading the applicators using standard Manchester loading (ML) to explore the magnitude of benefit that interstitial needles provide. Methods: 72 brachytherapy plans of 18 patients who had undergone treatment using tandem and ring and had interstitial brachytherapy between 04/2016 and 10/2018 were reviewed. ML plans prescribed to point A were generated to represent a 2D scenario but the known HR-CTV was taken into consideration and its dosimetric outcomes were compared to those of the 3D based plans. Results: The median tumour volume was 23 cm 3 . IN was used in 82 % of the insertions. The median number of IN was 2 (range 0 – 6) with median percentage of IN dwell time 6.6 % (range 0.68 – 38.5). V100 was excellent 98.2% for ML 97.3% for 3D IN and 98.7% for 3D non-IN plans. The median HRCTV D90 was 8.5 Gy/fraction (cumulative EQD2 10 101.4 Gy) for ML plans and 8.0 Gy/fraction (cumulative EQD2 10 91.4 Gy) for 3D plans. The ML plans failed to meet the OAR goals except for the rectum, which was optimally distanced by the rectal paddle. The median bladder, sigmoid and small bowel doses were 24% above the recommended constraint in the individual plans and 15% cumulative EQD2. A statistically significant relationship was found between the number of needles utilised, tumour volume (p &lt; 0.001) and coverage (p = 0.006) but not delivered dose (p &lt; 0.068). Conclusions: 2D brachytherapy can provide adequate dose coverage for most tumours but IN provide a benefit in reducing the doses to OARs in a significant number of patients. This justifies investment in resources for uptake of interstitial needles to increase access to optimal treatment of cervical cancer for women in LMIC. This research was made possible an ASCO Conquer Cancer Foundation grant.
B-PRECISE-01 Study: A phase Ib trial of MEN1611, a PI3K Inhibitor, combined with trastuzumab ± fulvestrant for the treatment of HER2-positive advanced or metastatic breast cancer.
Authors: Martine J. Piccart-Gebhart, Philippe Georges Aftimos, Francois P. Duhoux, Hans Wildiers, Nicolas Isambert, Mario Campone, Diego Tosi, Andrea I. Varga, Valentina Boni, Bernard Doger, Javier Garcia Corbacho, Begona Jimenez-Rodriguez, Manuel Ruiz Borrego, Cristina Saura, Hendrik-Tobias Arkenau, Andrew M. Wardley, Inaki F Troconiz, Monica Binaschi, Cecilia Simonelli, Andrea Ugo Pellacani
Journal: Journal of Clinical Oncology (2019)

TPS1101 Background: MEN1611 is a potent, selective class I inhibitor of PI3K, a key enzyme in the transduction of various extracellular growth factor signals essential for cell survival and apoptosis. The discovery in human cancers of frequent PIK3CA mutations, that have been linked to a worse outcome in advanced HER2-positive breast cancer, makes PI3K an attractive therapeutic target. Preclinical and clinical evidences support the development of MEN1611 in combination with other agents in the context of solid tumors. Methods: B-PRECISE-01 is an open-label, multicenter, phase Ib dose escalation study in patients with PIK3CA mutant tumors, HER2-positive advanced or metastatic breast cancer which has progressed after at least 2 lines of anti-HER2 based therapy. PIK3CA mutations are assessed centrally by real-time PCR assay in DNA derived from archived tumor samples. MEN1611 will be administered orally BID for continuous 28-day cycles until disease progression, in combination with weekly IV infusions of trastuzumab. In addition, HR-positive postmenopausal patients will also be treated with fulvestrant. After the completion of the dose escalation phase (Step 1), the study will continue in an expansion cohort (Step 2) testing the Recommended Phase 2 dose (RP2D) in a total of 15 patients in each of the treatment groups. The primary study objective is to assess combination safety and select RP2D. Secondary objectives include assessment of pharmacokinetics and pharmacodynamics, preliminary clinical activity of MEN1611 in combination with trastuzumab +/- fulvestrant, and correlation with PIK3CA mutations and other relevant cancer genes mutational status. Adverse events will be graded according to NCI CTCAE v4.03. Responses will be evaluated according to RECIST v1.1. Study variables will be presented by dose-cohort and overall using appropriate descriptive statistics. The enrollment began in July 2018 at European sites and US sites will shortly participate; up to date the first dose cohort level has been achieved. Clinical trial information: NCT03767335.