Enhanced angiogenesis in the 3D dynamic responsive implant for inguinal hernia repair {ProFlor}{ extregistered}

Biologic response to hernia prostheses represents a continuous source of debate. Conventional hernia meshes, in their typical static, passive configuration have been used for decades to reinforce the herniated abdominal wall. These flat implants, mainly fixated with sutures or tacks, induce poor quality fibrotic ingrowth that shrinks the mesh. In groin hernia repair, flat meshes are applied in the delicate inguinal surrounding where uncontrolled development of a scar plate can impair movement and may incorporate the sensitive nerves crossing this area. Complications deriving from mesh fixation and nerve entrapment are frequent and unpleasant for patients. To remedy these problems, a multilamellar shaped 3D device with a dynamic responsive behavior has recently been developed to repair inguinal hernia. Its inherent dynamic compliance during inguinal movements has shown to induce enhanced biological response with ingrowth of newly formed connective tissue, muscle fibers, and nerves. The function of these highly specialized tissue structures is supported by the contextual development of newly formed arteries and veins. The scope of the study was to assess quantity and quality of vessels, which had ingrown in the 3D hernia device in the short-term, medium-term, and long-term post-implantation, in biopsy specimens gathered from inguinal hernia patients operated with the 3D device. Starting from an early stage, widespread angiogenesis was evident within the 3D structure. Arteries and veins increased in quantity showing progressive development until full maturation of all specific vascular components throughout the mid-term, to long-term, post-implantation. High quality biologic ingrowth in hernia prosthetics needs an adequate vascular support. The broad network of mature arteries and veins evidenced herewith seems to confirm the enhanced biological features of the dynamic responsive 3D device whose features resemble a regenerative scaffold, an ideal feature for the treatment of the degenerative source of inguinal hernia disease

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in combination with standard of care chemotherapy in primarily untreated chemo naïve upper gi-adenocarcinomas with peritoneal seeding - a phase II/III trial of the AIO/CAOGI/ACO.

Peritoneal metastasis is a common and dismal evolution of several gastrointestinal (GI) tumors, including gastric, colorectal, hepatobiliary, pancreatic, and other cancers. The therapy of peritoneal metastasis is largely palliative; with the aim of prolonging life and preserving its quality. In the meantime, a significant pharmacological advantage of intraperitoneal chemotherapy was documented in the preclinical model, and numerous clinical studies have delivered promising clinical results

Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma - A randomized phase II/III trial of the German AIO and Italian GOIM

: This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared to FLOT alone (A:82% B:96%; p=0.009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, p=0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, p=0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade≥3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted. This article is protected by copyright. All rights reserved

The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction – a phase III trial of the German AIO/CAO-V/CAOGI

Abstract Background Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases. Methods This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled. Discussion If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention. Trial registration The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368 ; EudraCT: 2014–002665-30

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/m2on day 1, intravenous cisplatin 60 mg/m2on day 1, and either fluorouracil 200 mg/m2as continuous intravenous infusion or capecitabine 1250 mg/m2orally (two doses of 625 mg/m2per 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/m2as 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.</p

Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency

Abstract T-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT04954469) in 54 patients with congenital or acquired B-cell deficiency receiving one subcutaneous CoVac-1 dose. Immunogenicity in terms of CoVac-1-induced T-cell responses and safety are the primary and secondary endpoints, respectively. No serious or grade 4 CoVac-1-related adverse events have been observed. Expected local granuloma formation has been observed in 94% of study subjects, whereas systemic reactogenicity has been mild or absent. SARS-CoV-2-specific T-cell responses have been induced in 86% of patients and are directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4+ T cells. CoVac-1-induced T-cell responses have exceeded those directed to the spike protein after mRNA-based vaccination of B-cell deficient patients and immunocompetent COVID-19 convalescents with and without seroconversion. Overall, our data show that CoVac-1 induces broad and potent T-cell responses in patients with B-cell/antibody deficiency with a favorable safety profile, which warrants advancement to pivotal Phase III safety and efficacy evaluation. ClinicalTrials.gov identifier NCT04954469

Supplementary Figures 1-12 from Colorectal Cancer Organoid–Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses

Supplementary Figure S1 shows light microscopic images of CRC organoids and CAFs. Supplementary Figure S2 shows immunostaining and RNA sequencing analysis of cultured CAFs. Supplementary Figure S3 shows chromosomal copy number changes in tumors and matched organoids. Supplementary Figure S4 shows the transcriptional variation among tumors and organoids. Supplementary Figure S5 shows the classification of cancer intrinsic subtypes (CRIS) in tumors, matched organoids and xenotransplants. Supplementary Figure S6 shows the tissue microarray analysis of the of tumor samples from the colorectal cancer organoid-stroma biobank cohort. Supplementary Figure S7 shows the association of growth characteristics with molecular features of colorectal cancer organoid-stroma biobank. Supplementary Figure S8 shows the shows CMS and CRIS classifications of tumors and of matched organoids in different contexts. Supplementary Figure S9 describes the establishment of a drug screening workflow in 3D organoid-stroma co-cultures. Supplementary Figure S10 describes the development of a dual luciferase assay to study cell viability simultaneously in organoids and CAFs. Supplementary Figure S11 demonstrates that the MET inhibitor BAY-474 sensitizes Gefitinib resistant co-cultures. Supplementary Figure S12 shows the association of identified sensitivity and resistance signatures with gene expression and prognosis in different CMS.</p

Supplementary Tables 1-12 from Colorectal Cancer Organoid–Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses

Supplementary Table S1 shows the clinical data of the CRC organoid-stroma cohort. Supplementary Table S2 shows the inventory of available materials and molecular analyses. Supplementary Table S3 shows the selected variant types for whole exome analysis. Supplementary Table S4 summarizes the genetic characterization of CRC models. Supplementary Table S5 shows the classification according to the consensus molecular subtypes (CMS). Supplementary Table S6 shows classification according to the CRC intrinsic subtypes (CRIS). Supplementary Table S7 summarizes the functional data in mono- and co-cultures. Supplementary Table S8 shows drug sensitivity of CRC organoids in co-culture with autologous and heterologous fibroblasts. Supplementary Table S9 show the drug sensitivity in all biobank models in mono- and co-culture. Supplementary Table S10 shows the cell viability data of the chemogenomic library screens in resistant co-culture models. Supplementary Table S11 shows the identified drug sensitivity and resistance signatures. Supplementary Table S12 lists all antibodies and primer sequences used in this study.</p