Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

Causes or Cures: What makes us think of attention issues as disorders?

Are attention issues disorders or not? Philosophers of medicine have tried to address this question by looking for properties that distinguish disorders from non-disorders. Such properties include deviation of a statistical norm, a loss of function or experienced suffering. However, attempts at such conceptual analysis have not led to a consensus on the necessary and sufficient conditions for the application of the concept of disorder. Recently, philosophers have proposed an experimental approach to investigate in which circumstances people think a specific concept is applicable. Here we present a quantitative vignette study investigating whether disorder attribution depends on the perceived cause and the perceived type of treatment for an attention problem. The results of our study indicate that the attribution of a disorder decreased when the attention problem was understood as caused by bullying (social environmental cause) or by an accident (non-social environmental cause) rather than a genetic cause. When prescribed a pill, attention problems were considered a disorder to a larger extent than when the child was prescribed an environmental treatment. Our study also suggests that whereas successful environmental treatments will not necessarily decrease the disorder attribution, successful pharmacological treatments will decrease the likelihood that a person is thought to still suffer from a disorder after receiving the treatment.

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.

BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. METHODS: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group. INTERPRETATION: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. FUNDING: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family.

BACKGROUND: Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1-3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer. CASE PRESENTATION: A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient's young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient's father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy. CONCLUSION: Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.

Novel biomarkers in cancer: The whole is greater than the sum of its parts.

The major issues hampering progress in the treatment of cancer patients are distant metastases and drug resistance to chemotherapy. Metastasis formation is a very complex process, and looking at gene signatures alone is not enough to get deep insight into it. This paper reviews traditional and novel approaches to identify gene signature biomarkers and intratumoural fluid pressure both as a novel way of creating predictive markers and as an obstacle to cancer therapy. Finally recently developed in vitro systems to predict the response of individual patient derived cancer explants to chemotherapy are discussed.

Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial.

BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. METHODS: In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1, intravenous cisplatin 60 mg/m2 on day 1, and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally (two doses of 625 mg/m2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). INTERPRETATION: Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. FUNDING: None.

Perspectives in chemosensitivity and chemoresistance assays and their implementation in head and neck cancer.

Therapeutic options for patients with head and neck squamous cell carcinoma include surgery, radiation and chemotherapy. The latter plays a major role in the treatment selection of recurrent, metastatic or therapy resistant tumours, these being some of the major challenges in head and neck oncology. For these patients, chemosensitivity and chemoresistance assays would be paramount to identify their individual therapy options. In this review, seven common assays will be described and discussed in the context of several studies. Further, a new assay will also be presented, currently being validated in a European Union funded project. Comparisons will be drawn to evaluate the sensitivity and specificity of these assays in identifying individual treatment options, and their potential implementation in head and neck malignancies will be discussed. There is an unmet demand for the development of ex vivo diagnostic tools that may predict response in head and neck cancer on the way towards an individualized treatment for these patients.

DEGRO practical guidelines for radiotherapy of non-malignant disorders: Part I: physical principles, radiobiological mechanisms, and radiogenic risk.

PURPOSE: Synopsis of the introductory paragraph of the DEGRO consensus S2e-guideline recommendations for the radiotherapy of benign disorders, including physical principles, radiobiological mechanisms, and radiogenic risk. MATERIALS AND METHODS: This work is based on the S2e-guideline recommendations published November 14, 2013. The basic principles of radiation physics and treatment delivery, evaluation of putative underlying radiobiological mechanisms, and the assessment of genetic and cancer risk following low-dose irradiation will be presented. RESULTS: Radiation therapy of benign diseases is performed according to similar physical principles as those governing treatment of malignant diseases in radiation oncology, using the same techniques and workflows. These methods comprise usage of orthovoltage X-ray units, gamma irradiation facilities, linear accelerators (LINACs), and brachytherapy. Experimental in vitro and in vivo models recently confirmed the clinically observed anti-inflammatory effect of low-dose X-irradiation, and implicated a multitude of radiobiological mechanisms. These include modulation of different immunological pathways, as well as the activities of endothelial cells, mono- and polymorphonuclear leukocytes, and macrophages. The use of effective dose for radiogenic risk assessment and the corresponding tumor incidence rate of 5.5%/Sv are currently controversially discussed. Some authors argue that the risk of radiation-induced cancers should be estimated on the basis of epidemiological data. However, such data are rarely available at present and associated with high variability. CONCLUSION: Current radiobiological studies clearly demonstrate a therapeutic effectiveness of radiation therapy used to treat benign diseases and implicate various molecular mechanisms. Radiogenic risks should be taken into account when applying radiation treatment for benign diseases.

Assessment of attenuation properties for SLA and SLS 3D-printing materials in X-ray imaging and nuclear medicine.

In recent years, access to 3D printers has become increasingly affordable. Alongside industrial and private applications, the significance of 3D printing in the clinical context is also growing. For instance, 3D printing processes enable the production of individual anatomical models that can be used to support patient communication or aid in surgical planning. While filament 3D printing is common, stereolithography (SLA) and selective laser sintering (SLS) printing processes offer higher precision. For the use of 3D printing materials in radiology, understanding their attenuation properties concerning ionizing radiation is crucial. Polymethyl methacrylate (PMMA) serves as an important reference material for radiological applications in this regard. In this research, linear- and mass attenuation coefficients of 38 SLA-/SLS-materials from Formlabs (Somerville, Massachusetts, USA) and PMMA will be determined through intensity measurements in nuclear medicine for the radionuclides technetium-99 m and iodine-131, as well as for X-ray imaging in the range of 60 kVp - 110 kVp tube voltage. Based on the mass attenuation coefficients, correction factors in respect to PMMA will be calculated for each material. A significant number of materials exhibit a deviance within approximately ±5% in respect to PMMA regardless of radiation energy. However, certain materials from the dental and industrial application show deviances up to +500% at the lower end of radiation energy spectrum. In conclusion, most materials can be considered equivalent to PMMA with only minor adjustments required. Materials with high deviances can be utilized as high-contrast materials in custom X-ray phantoms.

The vices and virtues of medical models of obesity.

Despite numerous public health organizations supporting the pathologization of obesity and considering recent obesity rates a health crisis, many researchers in the humanities, social sciences, and even in the health sciences remain unconvinced. In this paper, we address a set of arguments coming from these academic fields that criticize medical models of obesity for their supposedly flawed diagnostic categories that shift focus onto individuals and support moralizing judgements. Clarifying some key claims in these models and explicating the view of obesity in terms of energy dysregulation, we aim to tease apart misunderstandings and argue that not only do these models not say what they are often accused of saying, but their apparent vices may actually be virtues in helping to combat stigma. Building on the social psychology of stigma and disease labeling, we then suggest that current medical models are largely supportive of many moral and political aims promoted by critics of these models.

Why we essentialize mental disorders.

Essentialism is one of the most pervasive problems in mental health research. Many psychiatrists still hold the view that their nosologies will enable them, sooner or later, to carve nature at its joints and to identify and chart the essence of mental disorders. Moreover, according to recent research in social psychology, some laypeople tend to think along similar essentialist lines. The main aim of this article is to highlight a number of processes that possibly explain the persistent presence and popularity of essentialist conceptions of mental disorders. One such process is the general tendency of laypeople to essentialize conceptual structures, including biological, social, and psychiatric categories. Another process involves the allure of biological psychiatry. Advocating a categorical and biological approach, this strand of psychiatry probably reinforced the already existing lay essentialism about mental disorders. As such, the question regarding why we essentialize mental disorders is a salient example of how cultural trends zero in on natural tendencies, and vice versa, and how both can boost each other.

[Splenic surgery in hematological diseases : Indications and surgical technique]. / Chirurgie der Milz bei hämatologischen Erkrankungen : Indikationen und operative Technik.

BACKGROUND: Splenic surgery in hematological disorders requires a well-weighted decision on the indications because the medical treatment has rapidly changed in recent years due to new pharmaceutical approaches. OBJECTIVE: Summary of the indications, surgical procedures and perioperative management regarding operative interventions on the spleen in hematological disorders. MATERIAL AND METHODS: Selective literature search and summary of reviews and guideline recommendations. RESULTS: In hematological disorders surgical procedures of the spleen (splenectomy and partial splenectomy) are an important part of the repertoire in the treatment. In recent years the indications for surgery have become narrower because of new forms of medicinal treatment. Especially in hereditary spherocytosis, immune thrombocytopenia and symptomatic splenomegaly and hypersplenism it is still of importance. The minimally invasive splenectomy is regarded as the gold standard. The spleen has an important immune and sequestration function, therefore preoperative and postoperative infectious and thromboembolic events have to be anticipated and prevented. A close interdisciplinary cooperation with hematologists is essential for an optimal outcome of patients. CONCLUSION: The minimally invasive splenectomy and partial splenectomy are part of the surgical repertoire in the diagnostics and treatment of hematological disorders. Because of novel medicinal approaches the therapeutic protocols are continuously changing. A close cooperation with hematologists is important for the optimal evaluation of the indications and the perioperative management.

Questionable research practices in competitive grant funding: A survey.

There has been a surge of interest in research integrity over the last decade, with a wide range of studies investigating the prevalence of questionable research practices (QRPs). However, nearly all these studies focus on research design, data collection and analysis, and hardly any empirical research has been done on the occurrence of QRPs in the context of research funding. To fill this gap, we conducted a cross-sectional pre-registered survey of applicants, reviewers and panel members from the Research Foundation-Flanders (FWO), one of the main funding agencies in Belgium. We developed a bespoke survey and further refined it through feedback from experienced researchers and a pilot study. We asked how often respondents had engaged in a series of QRPs over the last ten years. A total of 1748 emails were sent, inviting recipients to participate in the survey, complemented by featuring the survey in the FWO newsletter. This resulted in 704 complete responses. Our results indicate that such QRPs are remarkably prevalent. Of the 496 participants who answered both the applicant and reviewer track, more than 60% responded that they engaged regularly in at least one of such practices, and around 40% indicated that they engaged at least occasionally in half of the QRPs queried. Only 12% reported not to have engaged in any of the QRPs. Contrary to our hypotheses, male respondents did not self-report to engage in the QRPs more often than female respondents, nor was there an association between the prevalence of QRPs and self-reported success rate in grant funding. Furthermore, half of the respondents indicated that they doubted the reliability of the grant peer review process more often than not. These results suggest that preventive action is needed, and provide new reasons to reconsider the practice of allocating research money through grant peer review.

Broadening the horizon: potential applications of CAR-T cells beyond current indications.

Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström's macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

Targeted hyperactivation of AKT through inhibition of ectopic expressed SHIP1 induces cell death in colon carcinoma cells and derived metastases.

Current therapeutic approaches for colorectal cancer (CRC) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the PI3K/AKT-signaling may lead to trigger CRC cell death. Recently we found that hematopoietic SHIP1 is ectopically expressed in CRC cells. Here we show that SHIP1 is more strongly expressed in metastatic cells than in the primary cancer cells, which allows for an increase in AKT signaling in metastatic cells, giving them an advantage from an evolutionary point of view. Mechanistically, the increased SHIP1 expression reduces the activation of the PI3K/ AKT signaling to a value that is below the threshold that leads to cell death. This mechanism gives the cell a selection advantage. We show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SHIP1, induces acute cell death in CRC cells, because of excessive accumulation of reactive oxygen species. Our results demonstrate that CRC cells critically depend on mechanisms to fine-tune PI3K/AKT activity and show SHIP1 inhibition as an unexpectedly promising concept for CRC therapy.

Prognostic factors for the long term outcome after surgical celiac artery decompression in MALS.

BACKGROUND: The median arcuate ligament syndrome (MALS) is a rare disease caused by compression of the celiac artery (ORPHA: 293208). Surgical treatment of MALS aims to restore normal celiac blood flow by laparoscopic celiac artery decompression. However, surgical success rates vary widely between patients, therefore adequate selection of patients is essential to improve surgical outcome. Symptoms of MALS might also overlap with other chronic multi-system disorders such as mast cell activation syndrome (MCAS). So far, no clinical or radiological parameter was found to be predictive of the postoperative outcome. We, therefore, aim to study preclinical parameters in one of the largest MALS cohorts with the focus to identify patients that would benefit from surgical MAL release. RESULTS: By analyzing 20 MALS patients that underwent surgical celiac artery decompression, we found 60% of patients (12/20) had a postoperative relief of their symptoms and a simultaneous decrease of analgetic use. No demographic, radiologic or operative parameter was able to predict postoperative symptom relief. However, mast cell activation syndrome correlated significantly (p = 0.04) with persistent symptoms after the operation. CONCLUSIONS: Overall, laparoscopic MAL release can provide immediate symptomatic relief. Despite the missing predictive value of demographic and imaging data, our data show a correlation between persistent symptoms and a co-existing mast cell activation syndrome. This suggests that MCAS symptoms might be interpreted as MALS symptoms in the presence of celiac artery stenosis and therefore surgical treatment should be evaluated carefully. Overall, the selection of patients who are most likely to respond to surgical MAL release may best be accomplished by an interdisciplinary team of gastroenterologists, radiologists and surgeons.

Epidemiology and Characteristics of Gastric Carcinoma in Childhood-An Analysis of Data from Population-Based and Clinical Cancer Registries.

(1) Background: Gastric carcinoma is an exceptionally rare tumor in childhood. Little is known about the etiology, epidemiology, and clinical features of pediatric gastric carcinomas. This analysis aimed to fill this gap by increasing knowledge about the occurrence of gastric carcinoma in childhood. (2) Material and methods: Data from gastric carcinoma cases diagnosed between 2000 and 2017/2018 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) and the German Center for Cancer Registry Data. Data from patients <20 years of age were analyzed for patient- and tumor-related characteristics. In addition, clinical data from patients with gastric carcinoma registered in the German Registry for Rare Pediatric Tumors (STEP) were analyzed for diagnostics, therapy, and outcome. (3) Results: Ninety-one cases of gastric carcinoma, mainly in adolescents, were identified in the epidemiologic cancer registries. Among patients with recorded staging data, advanced tumor stages were common (66.7%). Within the follow-up period covered, 63.7% of patients with clinical follow-up data died. Eight pediatric patients with gastric carcinoma were enrolled in the STEP registry, among whom two were patients with hereditary CDH1 mutations and another was a patient with Peutz−Jeghers syndrome. Three patients were found to have distinctly decreased immunoglobulin concentrations. All four patients in whom complete resection was achieved remained in remission. Three of the other four patients died despite multimodal therapy. (4) Conclusions: A combination of Helicobacter pylori infection and tumor predisposition and/or immunodeficiency appears to promote the development of gastric carcinoma in childhood. While patients with localized disease stages have a good chance of achieving durable remission through complete resection, patients with stage IV carcinomas face a dismal prognosis, highlighting the need to develop new strategies such as mutation-guided treatments.

Philosophy of Science Can Prevent Manslaughter.

In September 2020, the surgeon Paulo Macchiarini, who used stem cell technology to enable the transplants of artificial and donor trachea, was charged with aggravated assault in Sweden. In this comment, we argue that the Ethics Council of the Karolinska Institute should have considered issues from philosophy of science when they were brought to their attention, rather than dismiss them as irrelevant to research ethics. We demonstrate how conceptual issues of a philosophy-of-science-kind about clinical research and medical practice should be integral to research ethics.