Morpho-functional analysis of patient-derived xenografts reveals differential impact of gastric cancer and chemotherapy on the tumor ecosystem, affecting immune check point, metabolism, and sarcopenia.

OBJECTIVES: Gastric cancer (GC) is an aggressive disease due to late diagnosis resulting from the lack of easy diagnostic tools, resistances toward immunotherapy (due to low PD-L1 expression), or chemotherapies (due to p53 mutations), and comorbidity factors, notably muscle atrophy. To improve our understanding of this complex pathology, we established patient-derived xenograft (PDX) models and characterized the tumor ecosystem using a morpho-functional approach combining high-resolution imaging with molecular analyses, regarding the expression of relevant therapeutic biomarkers and the presence of muscle atrophy. MATERIALS AND METHODS: GC tissues samples were implanted in nude mice. Established PDX, treated with cisplatin or not, were imaged by magnetic resonance imaging (MRI) and analyzed for the expression of relevant biomarkers (p53, PD-L1, PD-1, HER-2, CDX2, CAIX, CD31, a-SAM) and by transcriptomics. RESULTS: Three well-differentiated, one moderately and one poorly differentiated adenocarcinomas were established. All retained the architectural and histological features of their primary tumors. MRI allowed in-real-time evaluation of differences between PDX, in terms of substructure, post-therapeutic changes, and muscle atrophy. Immunohistochemistry showed differential expression of p53, HER-2, CDX2, a-SAM, PD-L1, PD-1, CAIX, and CD31 between models and upon cisplatin treatment. Transcriptomics revealed treatment-induced hypoxia and metabolic reprograming in the tumor microenvironment. CONCLUSION: Our PDX models are representative for the heterogeneity and complexity of human tumors, with differences in structure, histology, muscle atrophy, and the different biomarkers making them valuable for the analyses of the impact of platinum drugs or new therapies on the tumor and its microenvironment.

Letermovir breakthroughs during the French Named Patient Programme: interest of monitoring blood concentration in clinical practice.

OBJECTIVES: To analyse mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis. METHODS: Mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis were analysed in four patients from the French Named Patient Programme by the French National Reference Centre for Herpesviruses. RESULTS: Of three absolute resistance cases, two were associated with treatment interruption or low letermovir concentrations in blood. A fourth case of breakthrough was not associated with resistance. Next-generation sequencing (NGS) genotyping confirmed rapid emergence of resistant mutants, within 3 months of treatment initiation. CONCLUSIONS: Measurement of letermovir concentration and genotyping should be recommended for patient follow-up during letermovir therapy.

Radiative Rotational Lifetimes and State-Resolved Relative Detachment Cross Sections from Photodetachment Thermometry of Molecular Anions in a Cryogenic Storage Ring.

Photodetachment thermometry on a beam of OH^{-} in a cryogenic storage ring cooled to below 10 K is carried out using two-dimensional frequency- and time-dependent photodetachment spectroscopy over 20 min of ion storage. In equilibrium with the low-level blackbody field, we find an effective radiative temperature near 15 K with about 90% of all ions in the rotational ground state. We measure the J=1 natural lifetime (about 193 s) and determine the OH^{-} rotational transition dipole moment with 1.5% uncertainty. We also measure rotationally dependent relative near-threshold photodetachment cross sections for photodetachment thermometry.

Photodissociation of an Internally Cold Beam of CH

We have studied the photodissociation of CH^{+} in the Cryogenic Storage Ring at ambient temperatures below 10 K. Owing to the extremely high vacuum of the cryogenic environment, we were able to store CH^{+} beams with a kinetic energy of ∼60 keV for several minutes. Using a pulsed laser, we observed Feshbach-type near-threshold photodissociation resonances for the rotational levels J=0-2 of CH^{+}, exclusively. In comparison to updated, state-of-the-art calculations, we find excellent agreement in the relative intensities of the resonances for a given J, and we can extract time-dependent level populations. Thus, we can monitor the spontaneous relaxation of CH^{+} to its lowest rotational states and demonstrate the preparation of an internally cold beam of molecular ions.

A Rare Case of Ileocolic Obstruction Due to Lithophagia Associated with Cervical Oesophageal Perforation.

Lithophagia is a rare syndrome characterized by a repetitive ingestion of stones and pebbles. We herein report a case of a 61-year old mentally retarded man, with a past surgical history of multiple laparotomies for stone ingestion, presenting with cervical oesophagus perforation due to a large butterfly screw and massive impaction of 89 stones and other foreign bodies in the caecum, with consequent mechanical bowel obstruction.

Speciation in kleptoparasites of oak gall wasps often correlates with shifts into new tree habitats, tree organs, or gall morphospace.

Host shifts to new plant species can drive speciation for plant-feeding insects, but how commonly do host shifts also drive diversification for the parasites of those same insects? Oak gall wasps induce galls on oak trees and shifts to novel tree hosts and new tree organs have been implicated as drivers of oak gall wasp speciation. Gall wasps are themselves attacked by many insect parasites, which must find their hosts on the correct tree species and organ, but also must navigate the morphologically variable galls with which they interact. Thus, we ask whether host shifts to new trees, organs, or gall morphologies correlate with gall parasite diversification. We delimit species and infer phylogenies for two genera of gall kleptoparasites, Synergus and Ceroptres, reared from a variety of North American oak galls. We find that most species were reared from galls induced by just one gall wasp species, and no parasite species was reared from galls of more than four species. Most kleptoparasite divergence events correlate with shifts to non-ancestral galls. These shifts often involved changes in tree habitat, gall location, and gall morphology. Host shifts are thus implicated in driving diversification for both oak gall wasps and their kleptoparasitic associates.

Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

Signaling pathway deregulation and molecular alterations across pediatric medulloblastomas.

Medulloblastomas (MBs) account for 15% of brain tumors in children under the age of 15. To date, the overall 5-year survival rate for all children is only around 60%. Recent advances in cancer genomics have led to a fundamental change in medulloblastoma classification and is evolving along with the genomic discoveries, allowing to regularly reclassify this disease. The previous molecular classification defined 4 groups (WNT-activated MB, SHH-activated MB and the groups 3 and 4 characterized partially by NMYC and MYC driven MBs). This stratification moved forward recently to better define these groups and their correlation to outcome. This new stratification into 7 novel subgroups was helpful to lay foundations and complementary data on the understanding regarding molecular pathways and gene mutations underlying medulloblastoma biology. This review was aimed at answering the recent key questions on MB genomics and go further in the relevance of those genes in MB development as well as in their targeted therapies.

[Meckel's diverticulum and obstruction of the small intestine in adult patients: report of two cases]. / Diverticule de Meckel et occlusion de l'intestin grêle chez l'adulte: propos de deux cas.

Meckel's Diverticulum (MD) is the most frequent congenital anomaly of the ileum. However, its clinical manifestations in adult patients are rare. In this paper, we report cases with two different mechanisms of small intestine obstruction due to MD and we discuss diagnosis and management of these symptomatic lesions in adult patients.

Effect of the alloy/mould contact on surface crystallisation of a biocompatible ZrCoAl bulk metallic glass.

Casting of metallic glasses (MG) sometimes induces surface crystallisation despite the fact that the surface is expected to be the region where the cooling rate is the highest. This phenomenon has been observed on various MG, even for those with large critical diameters. Such surface crystallisation can be detrimental when the target applications are focused on surface properties, such as corrosion resistance for biomedical applications. In this paper, a Zr56Co28Al16 bulk metallic glass (BMG) with a large critical diameter was used. We reveal that samples processed using common copper-mould suction casting present surface crystallisation up to 20 µm in thickness, greatly deteriorating corrosion resistance. Using in-house highly reproducible suction casting and injection micro-casting processes, the influence of the processing parameters (mould material and temperature, working atmosphere, applied pressure) were investigated. The origin of surface crystallisation was found to arise from the complex thermal history of the alloy depending on the alloy/mould contact quality. By ensuring a tight contact between the solidifying alloy and the mould, BMG samples without crystalline surface defects were obtained.

Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping.

Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P<0.005), among which five in samples with low tumour cellularity. In adenocarcinoma, K-Ras mutation frequency increased from 7 out of 55 (13%) by direct sequencing to 15 out of 55 (27%) by clamped-PCR (P<0.005). K-Ras mutations detected by these sensitive techniques lost its prognostic value. In conclusion, a rapid and sensitive PCR-clamping test avoiding macro or micro dissection could be proposed in routine analysis especially for NSCLC samples with low percentage of tumour cells such as bronchial biopsies or after neoadjuvant chemotherapy.

EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib improves survival of lung cancer as second- or third-line therapy. However, after an initial response, most patients will recur, particularly within the central nervous system. The present study reports the case of a 27-yr-old nonsmoking male presenting with a metastatic lung adenocarcinoma with EGFR exon 19 deletion, associated with sensitivity to EGFR-TKI. Gefitinib, followed by chemotherapy and finally erlotinib resulted in prolonged disease control, until multiple liver metastases were detected. After stopping EGFR-TKI, brain metastases with carcinomatous meningitis were diagnosed. A secondary T790M mutation, associated with resistance to EGFR-TKI, was found on the liver biopsy but not in the cerebrospinal fluid. Erlotinib was reintroduced and allowed a quick neurological improvement, even though the extra-cranial disease remained resistant to erlotinib. The present report underscores the interest of molecular monitoring in lung cancer. Persistent cerebral tyrosine kinase inhibitor sensitivity should be considered in patients presenting with an early central nervous system relapse after stopping epidermal growth factor receptor tyrosine kinase inhibitor, even with a T790M-resistant mutation in noncerebral metastases. Questions remain concerning the selection of sub-clones during epidermal growth factor receptor tyrosine kinase inhibitor therapy, which could differ according to metastatic sites, especially in the central nervous system.

Spontaneous cystic artery rupture: a rare cause of haemoperitoneum.

We report the case of a 74-year-old man who presented an acute haemoperitoneum further to the rupture of the cystic artery. The bleeding was successfully controlled using embolization. This procedure was complicated by ischaemic necrosis and perforation of the gall-bladder requiring laparoscopic cholecystectomy. Spontaneous rupture of intra-abdominal arteries is a rare event. This usually occurs in abnormal arteries, presenting pseudo-aneurysm or, weakened by arterial hypertension, diabetes or corticotherapy. In the case of a cystic artery rupture, embolization can be safely done as long as the arterial anastomotic network with hepatic parenchyma is sufficient to supply the gall-bladder.

A laparoscopic approach to left diaphragmatic rupture after blunt trauma.

Diaphragmatic rupture after blunt trauma is rare, but indicates a powerful external impact. Associated lesions are often life-threatening and require a rapid diagnosis and management. We report a case of a 24-year-old man, admitted to the emergency department after a serious car accident. He complained of a left sided thoraco-abdominal pain with breathing difficulties. Chest X-ray showed a left diaphragmatic elevation. Computed tomography demonstrated a left haemo-pneumothorax, herniation of the stomach in the chest and a haemoperitonium. Laparoscopically, herniated organs were re-integrated in the abdominal cavity ; the diaphragmatic tear was repaired by both direct suture and synthetic prosthesis. Closure of a small bowel perforation found during the laparoscopic exploration was also performed. We consider this therapeutic modality to be an excellent approach in the management of acute left side diaphragmatic rupture in haemodynamically stable patients. Firstly, it permits an inspection of the thoracic cavity through the diaphragmatic tear and secondly, an easy repair of damaged structures in the abdominal cavity.

[Iron deficiency anaemia, pancreatitis and epigastric mass in a young female: a rare presentation of a large gastric trichobezoar]. / Anémie ferriprive, pancréatite et masse epigastrique chez une jeune patiente: une présentation clinique rare d'un volumineux trichobézoard gastrique.

We report the case of a 15-year old girl presenting with a gastric fullness sensation. The biological examination showed iron deficiency anaemia and elevation of the pancreatic enzymes. At endoscopy, a huge trichobezoar is found in the stomach. The endoscopic removal is impossible due to the compacity of the mass. Surgical resection is therefore performed. The postoperative course is uneventful and the biologic anomalies are rapidly corrected. A throughout anamnesis revealed a trichotillomania with trichophagia, this behavioural trouble found its origin in a familial conflict.

[Acute and latent right side diaphragmatic rupture after blunt trauma: cases studies and review of the literature]. / Ruptures diaphragmatiques droites aiguës et latentes après traumatismes fermés: observations cliniques et revue de la littérature.

A right diaphragmatic rupture (RDR) after blunt trauma is rare. Diagnosis of this entity remains difficult due to the absence of a precise anamnesis and pathognomonic signs. We report two cases of acute and latent RDR respectively. Immediate laparotomy was performed in the first case and thoracotomy was done nine weeks after blunt trauma for the second one. After the hepatothorax reduction, diaphragmatic lesions were sutured and reinforced by prosthesis. Acute RDR evolve inevitably to a latent and obstructive phases. Then, the mainstay treatment is surgical repair of the diaphragmatic defect. At present, thoracotomy is recommended for latent RDR. In the acute phases, thoracic and/or abdominal approaches depend on associated lesions, hemodynamical patient stability and surgical competence of the practitioner.

Nissen versus Toupet fundoplication: results of a randomized and multicenter trial.

BACKGROUND: Laparoscopic Toupet fundoplication (TF) is reported to be as effective as Nissen (NF), but to be associated with fewer unfavorable postoperative side-effects. This study evaluates the one- and three-year clinical outcome of 140 randomized patients after a laparoscopic NF or TF. PATIENTS AND METHODS: Inclusion criteria included patients over 16 years old with complications of gastro-oesophageal reflux disease (GORD) and persistence or recurrence of symptoms after three months of treatment. Subjects with a previous history of gastric surgery or repeated fundoplication, brachy-oesophagus or severe abnormal manometry results were excluded. Seventy-seven NF and 63 TF were performed. The severity of symptoms was assessed before and after the procedure. RESULTS: One hundred and twenty-one of the 140 patients after one year, and 118 after three years, were evaluated and no statistically significant clinical difference was observed. The level of satisfaction concerning the outcome of the operation remained high after one or three years regardless of the type of fundoplication performed. CONCLUSIONS: Functional complications after NF are not avoided with TF.

Long-term results of laparoscopic extended surgery in advanced gastric cancer: a series of 101 patients.

BACKGROUND/AIMS: The objective of our paper is to report on the remote results of patients with gastric cancer treated by mini-invasive surgery as a surgical tool with the "intention to treat with laparoscopy". METHODOLOGY: Between June 1993 and January 2004, 101 patients comprising 72 men and 29 women with gastric adenocarcinoma were prospectively selected by two hospitals based on prior agreement (the CHU Charleroi, Belgium, and Zumárraga Hospital, the Basque Country, Spain). Patients with adenocarcinoma of the cardia were excluded. Average age of the patients was 67 (37-83). RESULTS: Postoperative mortality within 60 days of operation was of 5 patients; 87 patients were therefore properly followed-up for an average of 41 months (7-129). Average survival time for 10 non-resected patients was 4.5 months. Average survival rate of the 10 palliatively resected patients was 7.1 months. Actuarial 5-year survival rate RO-type surgery was 34%. The global actuarial 5-year survival rate after resective surgery was 29%. CONCLUSIONS: Laparoscopic gastrectomy with any kind of lymphadenectomy is a heavy but safe operation, and produces acceptable mortality and morbidity rates in patients with advanced gastric cancer in a general poor condition. Laparoscopic gastrectomies for locally advanced cancers are equivalent to those reported by laparotomy as far as long-term oncological results are concerned.

Stromal tumour of the rectum: laparoscopic approach of a rare localization of GIST.

The authors present the case of a 60 year-old man known for a rectal polyp which was diagnosed in 1994 and since then followed-up by means of a colonoscopy associated with periodic biopsies. Recently, the results of a biopsy revealed positive markers for the diagnosis of Gastro-Intestinal Stromal Tumor (GIST). Despite the absence of malignant criteria, an anterior resection of the rectum was performed by laparoscopy and the patient rapidly recovered. Epidemiology, diagnosis and management of this rare location of GIST's are discussed.

Spontaneous renal artery dissection in an otherwise healthy male.

Dissection of a renal artery is rare and, in most cases, associated with underlying arterial diseases. Spontaneous renal artery dissection (RAD) is exceptional. We report the case of a young and otherwise healthy man with an isolated dissection of the right renal artery without any obvious origin. Diagnosis was made by angiography. He received medical treatment and rapidly recovered. Renal artery dissection can be misdiagnosed because its clinical presentation may be confusing. Selective renal angiography is essential to evaluate the extent of the dissection and the suitability for repair. Control of the hypertension and renal function preservation are the two main goals of the treatment. The place of surgical repair remains unclear because of the poor results on hypertension improvement and high complication rate.