Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review.

PURPOSE Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. METHODS We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. RESULTS Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. CONCLUSION It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade

Rescue bedside laparotomy in the intensive care unit in patients too unstable for transport to the operating room

INTRODUCTION: The prognoses of critically ill patients with a requirement for emergency laparotomy and severe respiratory and/or hemodynamic instability precluding transport to the operating room (OR) are often fatal without surgery. Attempting emergency surgery at the bedside might equally result in an adverse outcome. However, risk factors and predictors that could support clinical decision making have not been identified so far. This study describes the clinical characteristics, indicative pathophysiology and outcomes in patients undergoing resuscitative laparotomy in the intensive care unit (ICU). METHODS: This was a retrospective observational study of all critically ill adult patients undergoing resuscitative laparotomy in the ICUs of a German university hospital from January 2005 to July 2013. Clinical characteristics, risk factors, and treatments were compared between survivors and non-survivors. The primary endpoint was 28-day survival. RESULTS: A total of 41 patients with a median age of 64 (21 to 83) were included. The most frequent reasons for ICU admission were sepsis, pneumonia, and pancreatic surgery. All patients were mechanically ventilated, receiving vasopressors, and were in multiple organ failure. Twenty-nine patients (70.7%) were on renal replacement therapy and two patients (4.9%) on extracorporeal membrane oxygenation. The main reasons for surgery were suspected intra-abdominal bleeding (39.0%), suspected intestinal ischemia (24.4%) or abdominal compartment syndrome (24.4%). Twenty-eight-day, ICU and hospital mortalities were 75.6%, 80.5%, and 82.9%, respectively. In six out of ten patients (60%) who survived surgery for more than 28 days, bedside laparotomy was rated as a life-saving procedure by an interdisciplinary group of the investigators. CONCLUSIONS: These findings suggest that in selected critically ill patients with a vital indication for emergency laparotomy and severe cardiopulmonary instability precluding transport to the OR, a bedside resuscitative laparotomy in the ICU can be considered as a rescue procedure, even though very high mortality is to be expected

Perivascular epitheloid cell tumour (PEComa) of the retroperitoneum – a rare tumor with uncertain malignant behaviour: a case report

<p>Abstract</p> <p>Introduction</p> <p>Perivascular epitheloid cell tumours are rare mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epitheloid phenotype and expression of myomelanocytic markers.</p> <p>Case presentation</p> <p>Here we present the case of a cystic perivascular epitheloid cell tumour of the retroperitoneum associated with multifocal lung lesions. A 27-year-old woman underwent laparotomy to remove a 10 × 6 × 4 cm sized retroperitoneal mass. The resected specimen was subjected to frozen and permanent histological sections with conventional and immunohistochemical stains, including antibodies against HMB45. The tumour displayed the typical morphological and immunohistochemical features of a perivascular epitheloid cell tumour. Focal necrosis and a proliferative index of 10% suggested a malignant potential. Moreover, postoperative computed tomography scans demonstrated multiple lung lesions, which were radiologically interpreted as being most likely compatible with lymphangioleiomyomatosis.</p> <p>Conclusion</p> <p>Since lymphangioleiomyomatosis, an otherwise benign condition, belongs to the family of perivascular epitheloid cell tumours, it cannot be excluded that the lung lesions in this case in fact represent metastases from the retroperitoneal perivascular epitheloid cell tumour rather than independent neoplasms. More experience with this new and unusual tumour entity is clearly needed in order to define reliable criteria for benign or malignant behaviour.</p

Abscess of adrenal gland caused by disseminated subacute Nocardia farcinica pneumonia. A case report and mini-review of the literature

<p>Abstract</p> <p>Background</p> <p>Infections caused by <it>Nocardia farcinica </it>are uncommon and show a great variety of clinical manifestations in immunocompetent and immunocompromised patients. Because of its unspecific symptoms and tendency to disseminate it may mimic the clinical symptoms and radiologic findings of a tumour disease and the diagnosis of nocardiosis can easily be missed, because there are no characteristic symptoms.</p> <p>Case presentation</p> <p>We present a case of an adrenal gland abscess caused by subacute disseminated <it>N. farcinica </it>pneumonia.</p> <p>Conclusion</p> <p>An infection with <it>N. farcinica </it>is potentially lethal because of its tendency to disseminate -particularly in the brain- and its high resistance to antibiotics. Awareness of this differential diagnosis allows early and appropriate treatment to be administered.</p

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma

Acknowledgments We thank Dr Stuart MacGregor for his input on the study proposal and review of prior versions of this manuscript. We also thank all patients and controls for participating in this study. The MD Anderson controls were drawn from dbGaP (study accession: phs000187.v1.p1). Genotyping of these controls were done through the University of Texas MD Anderson Cancer Center (UTMDACC) and the Johns Hopkins University Center for Inherited Disease Research (CIDR). We acknowledge the principal investigators of this study: Christopher Amos, Qingyi Wei, and Jeffrey E. Lee. Controls from the Genome-Wide Association Study of Parkinson Disease were obtained from dbGaP (study accession: phs000196.v2.p1). This work, in part, used data from the National Institute of Neurological Disorders and Stroke (NINDS) dbGaP database from the CIDR: NeuroGenetics Research Consortium Parkinson’s disease study. We acknowledge the principal investigators and coinvestigators of this study: Haydeh Payami, John Nutt, Cyrus Zabetian, Stewart Factor, Eric Molho, and Donald Higgins. Controls from the Chronic Renal Insufficiency Cohort (CRIC) were drawn from dbGaP (study accession: phs000524.v1.p1). The CRIC study was done by the CRIC investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Data and samples from CRIC reported here were supplied by NIDDK Central Repositories. This report was not prepared in collaboration with investigators of the CRIC study and does not necessarily reflect the opinions or views of the CRIC study, the NIDDK Central Repositories, or the NIDDK. We acknowledge the principal investigators and the project officer of this study: Harold I Feldman, Raymond R Townsend, Lawrence J. Appel, Mahboob Rahman, Akinlolu Ojo, James P. Lash, Jiang He, Alan S Go, and John W. Kusek. The following UK hospitals participated in sample collection through the Stomach and Oesophageal Cancer Study (SOCS) collaboration network: Addenbrooke’s Hospital, University College London, Bedford Hinchingbrooke Hospital, Peterborough City Hospital, West Suffolk Norfolk and Norwich University Hospital, Churchill Hospital, John Hospital, Velindre Hospital, St Bartholomew’s Hospital, Queen’s Burton, Queen Elisabeth Hospital, Diana Princess of Wales, Scunthorpe General Hospital, Royal Devon & Exeter Hospital, New Cross Hospital, Belfast City Hospital, Good Hope Hospital, Heartlands Hospital, South Tyneside District General Hospital, Cumberland Infirmary, West Cumberland Hospital, Withybush General Hospital, Stoke Mandeville Hospital, Wycombe General Hospital, Wexham Park Hospital, Southend Hospital, Guy’s Hospital, Southampton General Hospital, Bronglais General Hospital, Aberdeen Royal Infirmary, Manor Hospital, Clatterbridge Centre for Oncology, Lincoln County Hospital, Pilgrim Hospital, Grantham & District Hospital, St Mary’s Hospital London, Croydon University Hospital, Whipps Cross University Hospital, Wansbeck General Hospital, Hillingdon Hospital, Milton Keynes General Hospital, Royal Gwent Hospital, Tameside General Hospital, Castle Hill Hospital, St Richard’s Hospital, Ipswich Hospital, St Helens Hospital, Whiston Hospital, Countess of Chester Hospital, St Mary’s Hospital IOW, Queen Alexandra Hospital, Glan Clwyd Hospital, Wrexham Maelor Hospital, Darent Valley Hospital, Royal Derby Hospital, Derbyshire Royal Infirmary, Scarborough General Hospital, Kettering General Hospital, Kidderminster General Hospital, Royal Lancaster Infirmary, Furness General Hospital, Westmorland General Hospital, James Cook University Hospital, Friarage Hospital, Stepping Hill Hospital, St George’s Hospital London, Doncaster Royal Infirmary, Maidstone Hospital, Tunbridge Hospital, Prince Charles Hospital, Hartlepool Hospital, University Hospital of North Tees, Ysbyty Gwynedd, St. Jame’s University Hospital, Leeds General Infirmary, North Hampshire Hospital, Royal Preston Hospital, Chorley and District General, Airedale General Hospital, Huddersfield Royal Infirmary, Calderdale Royal Hospital, Torbay District General Hospital, Leighton Hospital, Royal Albert Edward Infirmary, Royal Surrey County Hospital, Bradford Royal Infirmary, Burnley General Hospital, Royal Blackburn Hospital, Royal Sussex County Hospital, Freeman Hospital, Royal Victoria Infirmary, Victoria Hospital Blackpool, Weston Park Hospital, Royal Hampshire County Hospital, Conquest Hospital, Royal Bournemouth General Hospital, Mount Vernon Hospital, Lister Hospital, William Harvey Hospital, Kent and Canterbury Hospital, Great Western Hospital, Dumfries and Galloway Royal Infirmary, Poole General Hospital, St Hellier Hospital, North Devon District Hospital, Salisbury District Hospital, Weston General Hospital, University Hospital Coventry, Warwick Hospital, George Eliot Hospital, Alexandra Hospital, Nottingham University Hospital, Royal Chesterfield Hospital, Yeovil District Hospital, Darlington Memorial Hospital, University Hospital of North Durham, Bishop Auckland General Hospital, Musgrove Park Hospital, Rochdale Infirmary, North Manchester General, Altnagelvin Area Hospital, Dorset County Hospital, James Paget Hospital, Derriford Hospital, Newham General Hospital, Ealing Hospital, Pinderfields General Hospital, Clayton Hospital, Dewsbury & District Hospital, Pontefract General Infirmary, Worthing Hospital, Macclesfield Hospital, University Hospital of North Staffordshire, Salford Royal Hospital, Royal Shrewsbury Hospital, and Manchester Royal Infirmary. Conflict of interest The authors disclose no conflicts. Funding This work was primarily funded by the National Institutes of Health (NIH) (R01CA136725). The funders of the study had no role in the design, analysis, or interpretation of the data, nor in writing or publication decisions related to this article. Jing Dong was supported by a Research Training Grant from the Cancer Prevention and Research Institute of Texas (CPRIT; RP160097) and the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin (AHW). Quinn T. Ostrom was supported by RP160097. Puya Gharahkhani was supported by a grant from National Health and Medical Research Council of Australia (1123248). Geoffrey Liu was supported by the Alan B. Brown Chair in Molecular Genomics and by the CCO Chair in Experimental Therapeutics and Population Studies. The University of Cambridge received salary support for Paul D. Pharoah from the NHS in the East of England through the Clinical Academic Reserve. Brian J. Reid was supported by a grant (P01CA91955) from the NIH/National Cancer Institute (NCI). Nicholas J. Shaheen was supported by a grant (P30 DK034987) from NIH. Thomas L. Vaughan was supported by NIH Established Investigator Award K05CA124911. Michael B. Cook was supported by the Intramural Research Program of the NCI, NIH, Department of Health and Human Services. Douglas A. Corley was supported by the NIH grants R03 KD 58294, R21DK077742, and RO1 DK63616 and NCI grant R01CA136725. Carlo Maj was supported by the BONFOR-program of the Medical Faculty, University of Bonn (O-147.0002). Jesper Lagergren was supported by the United European Gastroenterology (UEG) Research Prize. David C. Whiteman was supported by fellowships from the National Health and Medical Research Council of Australia (1058522, 1155413).Peer reviewedPostprin

Persistent Megalocystic Ovary Following in Vitro Fertilization in a Postpartum Patient with Polycystic Ovarian Syndrome

SummaryObjectiveOvarian hyperstimulation syndrome (OHSS) is more severe when pregnancy occurs, as the developing pregnancy produces human chorionic gonadotropin, which stimulates the ovary's persistent growth. If no pregnancy occurs, the syndrome will typically resolve within 1 week. In a maintained pregnancy, slow resolution of symptoms usually occurs over 1-2 months.Case ReportA 31-year-old woman, gravida 2, para 1, aborta 1, with polycystic ovary syndrome underwent in vitro fertilization (IVF) with clomiphene citrate and follicle-stimulating hormone/gonadotropin releasing hormone-antagonist stimulation. During transvaginal oocyte retrieval, enlarged bilateral ovaries were noted. She had an episode of OHSS after IVF/embryo transfer, for which paracentesis was performed three times. Pregnancy was achieved. Throughout antenatal examinations, bilateral ovaries were enlarged. She delivered a healthy baby by cesarean section at term. However, 1 month after delivery, the bilateral ovary had not shrunk, and levels of tumor markers CA125 and CA199 were 50.84 and 41.34 U/mL, respectively. At laparotomy for suspected malignancy, both adnexae formed “kissing ovaries”, which were multinodulated with yellow serous fluid. Specimens from wedge resection submitted for frozen section showed a benign ovarian cyst. The final pathology report showed bilateral follicle cysts.ConclusionWith the increasing use of gonadotropins in the management of infertility, ovarian enlargement secondary to hyperstimulation is common. Generally, symptoms appear between the 6th and 13th weeks of pregnancy and disappear thereafter. The hyperstimulated ovary often subsides after the first trimester. This case is unusual as the megalocystic ovary persisted after delivery. To the best of our knowledge, we report the first case of enlarged bilateral ovaries persisting 2 months after delivery

No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council