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The incidence of oesophageal adenocarcinoma (OAC) is rising in Western countries, with a 5-year overall survival (OS) rate of 14%. Curative treatment based on oesophagectomy is only suitable for ~50% of patients due to late-stage diagnosis. While the addition of preoperative chemotherapy or chemoradiotherapy has improved OS in OAC patients, little is known about the molecular basis of treatment response and patient outcomes. We investigated multi-omics data including whole-genome sequencing, RNA sequencing, methylation profiles and immunohistochemistry from 115 OAC patients mostly from DOCTOR phase II clinical trial that utilized neoadjuvant therapy (ANZCTR-ACTRN12609000665235). We identified genomic features associated with poor OS, such as the APOBEC mutational signature. We also showed that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. RNA sequencing and methylation profiles suggested four immune clusters associated with OS and progression-free survival. The immune-suppressed cluster was associated with worse survival and epithelial-mesenchymal transition signature and enriched with myeloid-derived cells. The immune hot cluster was associated with better survival and enriched with T-cells, myeloid-derived cells, interferon-gamma and alpha responses, and immune markers such as CCL5, CD8A, and NKG7. We investigated multi-omic features of OAC tumours from patients who were part of phase II clinical trial. We discovered prognostic features such as mutational signatures and complex genomic events. We identified distinct immune clusters associated with patient outcomes and the potential of immunotherapy for select clusters. We characterized molecular features of OAC patients which has the potential to predict responses to neoadjuvant therapy and develop better-selected therapy, monotherapy, or combination therapy in the future.

Introduction ROHHAD syndrome is a rare disorder of respiratory control and autonomic nervous system regulation with endocrine abnormalities. Although children may present with obstructive sleep apnea, their blunted respond to hypoxemia and hypercapnia is a life-threating feature, often leading to cardiorespiratory arrest. There is limited literature regarding non-invasive positive pressure ventilation (NIPPV) in these children. We report a trial of AVAPS in a child with ROHHAD syndrome. Report of case(s) Our patient is a 6-year-old male with history of rapid weight-gain (49.9 kg in 2.5 years), type-2 diabetes, and mild OSA who presented to an outside hospital (OSH) in March 2020 with acute hypercapnic hypoxemic respiratory failure. He required bilevel PAP therapy, steroids, and bromocriptine for thermoregulatory dysfunction. His clinical presentation, along with negative PHOX2B gene mutation and absence of parenchymal lung disease on chest computerized tomography suggested a diagnosis of ROHHAD syndrome. Outpatient, he was successfully transitioned to empiric AVAPS therapy. In November 2020, he presented again to an OSH in hypercapnic hypoxemic respiratory failure with new systolic heart failure with ejection fraction of 28%. After clinical stabilization, he was transferred to our hospital on CPAP 10 cmH20 with 100% FiO2 for further management. Awake blood gas was consistent with chronic hypercapnic respiratory failure; therefore, the patient was placed initially on bilevel PAP therapy empirically until an inpatient bilevel PAP titration polysomnogram was conducted. The patient remained hypercapnic and was converted to continuous AVAPS therapy starting at a tidal volume of 8.6mL/kg based on ideal body weight. AVAPS was titrated until achieving adequate ventilation, but the patient was unable to tolerate continuous NIPPV. Because of his heart failure in the setting of expected worsening respiratory failure, the decision was made to pursue tracheostomy placement for invasive positive pressure ventilation. Conclusion ROHHAD syndrome is a rare disorder that begins within the first decade of life, making adherence to daytime NIPPV difficult. This case illustrates a trial of AVAPS in a child with ROHHAD syndrome prior to tracheostomy placement. It highlights the need for future research in advanced ventilatory support strategies in children. Support (if any)

Background: Chylothorax is a potentially fatal complication of oesophagectomy. This study aims to report the incidence, risk factors and management of chylothorax in patients undergoing oesophagectomy for oesophageal carcinoma. Methods: This study reviewed all patients who underwent oesophagectomy from 2009 to 2018 in an Australian institution. Preoperative, perioperative and postoperative data were collected retrospectively and analysed. Results: Chylothorax occurred in 13 out of 144 patients (9%). Pre-operative albumin [odds ratio (OR) 0.836, P=0.027) and the number of lymph nodes resected (OR 1.141, P=0.001) were significant predictors of chylothorax. Chylothorax was associated with increased reoperation rate (77% vs. 11%, P

Background Segmental arterial mediolysis (SAM) is an under-recognized degenerative vascular disorder with variable clinical presentations. It affects medium to large calibre arteries, typically those arising from the coeliac axis, and its diagnosis is complicated by overlap with other clinical entities like fibromuscular dysplasia. Diagnosis requires histopathological examination of the affected tissue, although radiographic appearances can be suggestive of SAM. Methods We report on two patients presenting with acute rupture of an intrahepatic artery affected by SAM. Results Both patients ultimately required right hemi-hepatectomy in order to either control ongoing bleeding or for removal of liver rendered ischaemic by intra-arterial embolization. This was achieved safely despite additional SAM lesions present throughout the vasculature. Conclusion In both cases described, presentation followed recent, unrelated abdominal surgery and we propose a link between these two events. Recent research has identified the potential role of noradrenaline in the development of SAM lesions in greyhounds, with levels of endogenous noradrenaline known to rise in the setting of surgery.

Many colorectal liver metastasis patients are denied surgical resection on the basis of tumour size. The aim of this study was to explore the impact of metastasis size on modern liver resection.Using a prospectively collected database, this was a retrospective analysis of 484 consecutive patients who underwent liver resection for colorectal liver metastases between 1993 and 2003. The cohort was divided into two groups: smaller metastases (8 cm) and larger metastases (or = 8 cm). Those with larger metastases were then further stratified into big metastases (8-12 cm) and giant metastases (12 cm). Demographic, pathological, surgical technique and outcome data were compared between the groups.There were 88 (18%) patients with metastases measuring 8 cm or larger. There was an association between higher carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 levels and larger metastases. The actuarial 5-year survival for patients with larger metastases was 38% compared with 42% for smaller metastases (not statistically significant). Patients with giant metastases had poorer overall and disease-free survival (both nonsignificant) compared with those with big metastases: 29% and 28% at 5 years, respectively.Patients with colorectal liver metastasis greater than 8 cm and up to 12 cm in size should not be treated differently from those with smaller lesions.

Familial adenomatous polyposis, caused by mutations in the adenomatous polyposis coli gene located at chromosome 5q21, is an autosomal dominant syndrome characterized by polyposis of the colon and rectum and nearly 100 percent progression to colorectal cancer. We report a case of familial adenomatous polyposis and mental retardation caused by a chromosomal deletion at 5q15-q22. Chromosomal analysis is considered part of the evaluation of children with mental retardation and developmental delay. The resulting karyotypes from high-resolution chromosomal analysis can help characterize large deletions, some of which involve known tumor suppressor genes. Because familial adenomatous polyposis may arise from de novo chromosomal deletions involving the adenomatous polyposis coli gene locus, individuals with chromosomal deletions involving 5q21 should be considered at-risk for familial adenomatous polyposis and offered standard screening with flexible sigmoidoscopy by 10 to 12 years of age.

Background: A hiatal hernia is present in up to 50% of patients undergoing bariatric surgery. It has been claimed that laparoscopic adjustable gastric banding (LAGB) can both improve and induce reflux symptoms. The effect of a simultaneous crural repair and gastric banding has not yet been reported. Methods: Since 1999, all patients undergoing LAGB have a simultaneous crural repair if a hiatal hernia is present. Gastroesophageal reflux disease and dysphagia were assessed preoperatively and postoperatively using the modified DeMeester symptom-scoring system and the use of anti-reflux medication. Results: 62 patients with a hiatal hernia have undergone simultaneous LAGB and crural repair, with a median follow up of 14 (3-38) months. There was no mortality, and complications occurred in 3 patients, namely pulmonary embolus, slippage requiring repositioning of the band and persistent dysphagia requiring band removal. 24 months following LAGB and crural repair, median BMI had fallen from 43 to 31 kg/m2 and median excess weight loss was 53%. Modified DeMeester symptom-score fell from a preoperative median of 3 (0-5) to a postoperative median of 0 (0-2) (P < 0.01, Mann Whitney U), and the number of patients on anti-reflux medication decreased from 44 to 6 (P < 0.01, Chi-squared). Conclusion: Crural repair in addition to LAGB does not increase the risk of slippage or dysphagia, significantly improves reflux symptoms and decreases the need for anti-reflux medication.

Segmental arterial mediolysis (SAM) is an under-recognized degenerative vascular disorder with variable clinical presentations. It affects medium to large calibre arteries, typically those arising from the coeliac axis, and its diagnosis is complicated by overlap with other clinical entities like fibromuscular dysplasia. Diagnosis requires histopathological examination of the affected tissue, although radiographic appearances can be suggestive of SAM.We report on two patients presenting with acute rupture of an intrahepatic artery affected by SAM.Both patients ultimately required right hemi-hepatectomy in order to either control ongoing bleeding or for removal of liver rendered ischaemic by intra-arterial embolization. This was achieved safely despite additional SAM lesions present throughout the vasculature.In both cases described, presentation followed recent, unrelated abdominal surgery and we propose a link between these two events. Recent research has identified the potential role of noradrenaline in the development of SAM lesions in greyhounds, with levels of endogenous noradrenaline known to rise in the setting of surgery.

Ventilator-induced lung injury is a recognized risk factor for bronchopulmonary dysplasia.To determine whether primary continuous positive airway pressure (CPAP), defined as CPAP without previous endotracheal intubation for any indication, can reduce the need for intubation and mechanical ventilation in infants born at ≤32 weeks' gestational age.The literature was reviewed using the methodology for systematic reviews for the Consensus on Resuscitation Science adapted from the American Heart Association's International Liaison Committee on Resuscitation.Fourteen studies were reviewed. Eleven studies provided varying degrees of supportive evidence (level of evidence 3 to 4) that the use of primary CPAP can reduce the need for intubation and mechanical ventilation.The use of CPAP as a primary intervention and mode of respiratory support is an option for infants ≤32 weeks' gestation, but avoidance of intubation and mechanical ventilation is more likely in mature infants27 weeks' gestation.

OBJECTIVES: A genetic locus for pediatric reflux was proposed on chromosome 13q14, but is unconfirmed in independent kindreds. We sought to test this locus in families with multiple affected infants from our database of well characterized infants with reflux. METHODS: We screened the database for families with multiple affected infants. Affected proband phenotype required histological esophagitis; affected sibling/cousin phenotype required a threshold score on a diagnostic questionnaire. Screened families were reduced to five based on pedigree, consent, and phenotypic clarity. Linkage of the phenotype with the four previously reported markers (D13S218, D13S1288, D13S1253, and D13S263) was tested, using an autosomal dominant, 70% penetrance model. Linkage required logarithm-of-odds score ≥3. RESULTS: Of 54 individuals in the five probands’ generation, 21 (39%) were affected based on questionnaire, of whom nearly one half also had histological confirmation of esophagitis. Linkage to the defined region was excluded for the five families by two-point LOD scores (−1.47 at D13S218, −1.32 at D13S1288, −3.43 at D13S1253, and −3.92 at D13S263) and by multipoint (multipoint LOD scores less than −2 between D13S218 and D13S263) linkage analysis. No family demonstrated even suggestive positive linkage ( i.e ., LOD score >1). CONCLUSIONS: In five rigorously phenotyped families with autosomal dominant pattern infantile reflux, we excluded genetic linkage to the region of 13q14 previously identified responsible for an autosomal dominant form of pediatric reflux. These results suggest genetic heterogeneity, possibly related to phenotypic heterogeneity, in familial pediatric gastroesophageal reflux disease.

Hereditary pancreatitis (HP) was defined on a clinical basis alone until the first cationic trypsinogen gene (PRSS1) mutation was discovered through the initial phase of the current Pittsburgh Midwest Multi-Center Pancreatic Study Group (MMPSG) HP study in 1996, making genetic testing available.To evaluate the regional distribution of HP in the United States, and to compare the study's gene mutation database with the pedigree databases to determine whether family history alone predicts the likelihood of detecting mutations in the cationic trypsinogen gene.Probands of families with HP, familial pancreatitis and idiopathic chronic pancreatitis were recruited through referrals from MMPSG collaborating centers, other physicians and self-referral of patients who had learned of the study through the World Wide Web (www.pancreas.org). Pedigrees were constructed, detailed questionnaires were completed and a blood sample was drawn for each proband and participating family members. The birthplace and current location of each patient was recorded, DNA was analyzed for known mutations and the pattern of phenotype inheritance was determined from analysis of each pedigree.A total of 717 individuals were ascertained; 368 (51%) had clinical pancreatitis confirmed and the rest were primarily unaffected family members used for linkage studies. Forty-six clinically unaffected individuals were silent mutation carriers (11% of mutation-positive individuals). HP was most common in Minnesota, New York and the central mid-Atlantic states plus Kentucky and Ohio. One hundred and fifteen of 150 kindreds fulfilled the strict definition of an HP family, and 60 (52%) had PRSS1 mutations. Of the families with a detected mutation, 11% did not fulfill the clinical definition of an HP kindred.The distribution of HP within the United States shows major regional differences. The etiology of HP can be identified in a small majority of HP families through genetic testing. However, family history alone is not a good predictor of finding a mutation in the cationic trypsinogen (PRSS1) gene.

Hereditary pancreatitis (HP) is usually caused by mutations in the cationic trypsinogen (PRSS1) gene, especially R122H or N29I. We sequenced the PRSS1 gene in the proband of families without these common mutations. Novel R122C and N29T mutations were detected in independent families that segregated with the disease in an autosomal dominant fashion. The R122C mutation eliminates the arginine autolysis site as with R122H mutations. The N29T mutation may also enhance intrapancreatic trypsin activity as has been demonstrated in vitro. Identification of these new mutations requires special attention as commonly used detection methods may fail.

Background & Aims: Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. Methods: Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography–based model building and statistical studies were performed. Results: Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. Conclusions: SPINK1 mutations are common in the population (~2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease. GASTROENTEROLOGY 2000;119:615-623

Background: This study was undertaken to determine the quality of information on the Internet regarding laparoscopy. Methods: Four popular World Wide Web search engines were used with the key word "laparoscopy." Advertisements, patient- or physician-directed information, and controversial material were noted. Results: A total of 14,030 Web pages were found, but only 104 were unique Web sites. The majority of the sites were duplicate pages, subpages within a main Web page, or dead links. Twenty-eight of the 104 pages had a medical product for sale, 26 were patient-directed, 23 were written by a physician or group of physicians, and six represented corporations. The remaining 21 were "miscellaneous." The 46 pages containing educational material were critically reviewed. At least one of the senior authors found that 32 of the pages contained controversial or misleading statements. All of the three senior authors (LKN, NAO, GAF) independently agreed that 17 of the 46 pages contained controversial information. Conclusion: The World Wide Web is not a reliable source for patient or physician information about laparoscopy. Authenticating medical information on the World Wide Web is a difficult task, and no government or surgical society has taken the lead in regulating what is presented as fact on the World Wide Web.

A force‐based scanning Kelvin probe microscope has been used to image dopant profiles in silicon for integrated circuit devices on a submicron scale. By measuring the potential difference which minimizes the electrostatic force between a probe and surface of a sample, an estimate of the work function difference between the probe and surface may be made. To the extent that this work function difference is a consequence of the dopant concentration near the sample surface, doping profiles are inferred from the measurements. An overview of the measurement technique is presented, along with several examples of resulting dopant imaging of integrated circuits.

When we think of seventeenth-and eighteenth-century French literature, we think of authors. We forget that two literatures existed, one with authors, one without, the latter ranging from almanacs to arithmetics, from works on the care of the horse to penny dreadfuls. Printed on poor stock roughly stitched into blank blue folders, these were sold in immense numbers all over France. No privilege was required, the contents having been always in the public domain. The corporation of printers and publishers valued this authorless literature as chief source of revenue. It had guaranteed their survival through the wars of the sixteenth century; with the coming of peace, its profits restored the printing on good paper of wellbound books, whose covers showed title and author. Damaged colleges and monasteries called for editions of the Church Fathers, erudite commentaries, reprints of the classics. A few of these were in Greek, the rest in Latin which, incidentally, in France was the language of science until 1665 and of diplomacy until 1714. Private homes called for books in French. Of these, the first half of the seventeenth century saw an increasing flow, until, by 1675, Paris, with a population of 300,000, had ninety-two private libraries of more than 4,000 volumes each, a number of which were by living French writers.

Laura Hofrichter, Heinrich Heine, reviewed by Hans Eichner Alfred Edward Carter, Baudelaire et la Critique Francaise, 1868–1917, reviewed by Robert Finch Walter Pater, Imaginary Portraits, reviewed by Catherine A. Cox

Few figures in the language of literary criticism have been more widely used and abused than that of the ivory tower. Invented, in its modern sense, over a hundred years ago, it became fashionable in the 1930's, popular in the '40s, and remains both fashionable and popular today. It has, presumably, not once but often passed the lips of any reader of these lines. It has engendered phrases that bid fair to become equally favoured, such as the ivory laboratory in which science segregates itself and the ivory sewer of dirt for art's sake. What is its background?

Biography: Art or Craft, reviewed by James L. Clifford Helmut Hatzfield, Trends and Styles in Twentieth Century French Literature, reviewed by Robert Finch

This series of thirty-eight intraoral minor salivary gland tumors consists of twenty-six benign and twelve malignant tumors. Twenty-three of the twenty-six benign tumors are mixed tumors, and eight of the twelve malignant tumors are low-grade mucoepidermoid tumors. The palate was the favored site for benign tumors (fourteen cases), whereas malignant tumors occurred most frequently in the retromolar pad (five cases). The most common clinical feature of all tumors was a painless swelling. The wide variation in the incidence of malignancy shown in published series of minor salivary gland tumors may be a result of two factors: (1) variation in histopathologic criteria for malignancy and (2) type of institution from which a series is reported.

Background The role of fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) scanning in operable pancreas cancer is unclear. We, therefore, wanted to investigate the impact of PET/CT on management, by incorporating it into routine work‐up. Methods This was a single‐institution prospective study. Patients with suspected and potentially operable pancreas, distal bile duct or ampullary carcinomas underwent PET/CT in addition to routine work‐up. The frequency that PET/CT changed the treatment plan or prompted other investigations was determined. The distribution of standard uptake values (SUV) among primary tumours, and adjacent to biliary stents was characterised. Results Fifty‐six patients were recruited. The surgical plan was abandoned in 9 (16%; 95% CI: 6–26) patients as a result of PET/CT identified metastases. In four patients, metastases were missed and seven were inoperable at surgery, not predicted by PET/CT. Unexpected FDG uptake resulted in seven additional investigations, of which two were useful. Among primary pancreatic cancers, a median SUV was 4.9 (range 2–12.1). SUV was highest around the biliary stent in 17 out of 28 cases. PET/CT detected metastases in five patients whose primary pancreatic tumours demonstrated mild to moderate avidity (SUV Conclusions PET/CT in potentially operable pancreas cancer has limitations. However, as a result of its ability to detect metastases, PET/CT scanning is a useful tool in the selection of such patients for surgery.