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Gastric cancer heterogeneity represents a barrier to disease management. We generated a comprehensive single-cell atlas of gastric cancer (>200,000 cells) comprising 48 samples from 31 patients across clinical stages and histologic subtypes. We identified 34 distinct cell-lineage states including novel rare cell populations. Many lineage states exhibited distinct cancer-associated expression profiles, individually contributing to a combined tumor-wide molecular collage. We observed increased plasma cell proportions in diffuse-type tumors associated with epithelial-resident KLF2 and stage-wise accrual of cancer-associated fibroblast subpopulations marked by high INHBA and FAP coexpression. Single-cell comparisons between patient-derived organoids (PDO) and primary tumors highlighted inter- and intralineage similarities and differences, demarcating molecular boundaries of PDOs as experimental models. We complemented these findings by spatial transcriptomics, orthogonal validation in independent bulk RNA-sequencing cohorts, and functional demonstration using in vitro and in vivo models. Our results provide a high-resolution molecular resource of intra- and interpatient lineage states across distinct gastric cancer subtypes.Significance:We profiled gastric malignancies at single-cell resolution and identified increased plasma cell proportions as a novel feature of diffuse-type tumors. We also uncovered distinct cancer-associated fibroblast subtypes with INHBA–FAP-high cell populations as predictors of poor clinical prognosis. Our findings highlight potential origins of deregulated cell states in the gastric tumor ecosystem.This article is highlighted in the In This Issue feature, p. 587

Supplementary Data from Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer

Purpose:Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability.Patients and Methods:We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2.Results:This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively.Conclusions:The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases.See related commentary by de Jong et al., p. 1830

Mean concentration-time profiles of pressurized intraperitoneal aerosol chemotherapy (PIPAC) oxaliplatin (n = 14) in plasmatot (A) and ultrafiltrate (B)

The area under the curve(AUC) ratio (Ultrafiltrate(UF) vs Plasmatot) at different dose levels

Study timeline

Supplementary tables and figures

Gastric cancer heterogeneity represents a barrier to disease management. We generated a comprehensive single-cell atlas of gastric cancer (>200,000 cells) comprising 48 samples from 31 patients across clinical stages and histologic subtypes. We identified 34 distinct cell-lineage states including novel rare cell populations. Many lineage states exhibited distinct cancer-associated expression profiles, individually contributing to a combined tumor-wide molecular collage. We observed increased plasma cell proportions in diffuse-type tumors associated with epithelial-resident KLF2 and stage-wise accrual of cancer-associated fibroblast subpopulations marked by high INHBA and FAP coexpression. Single-cell comparisons between patient-derived organoids (PDO) and primary tumors highlighted inter- and intralineage similarities and differences, demarcating molecular boundaries of PDOs as experimental models. We complemented these findings by spatial transcriptomics, orthogonal validation in independent bulk RNA-sequencing cohorts, and functional demonstration using in vitro and in vivo models. Our results provide a high-resolution molecular resource of intra- and interpatient lineage states across distinct gastric cancer subtypes. Significance: We profiled gastric malignancies at single-cell resolution and identified increased plasma cell proportions as a novel feature of diffuse-type tumors. We also uncovered distinct cancer-associated fibroblast subtypes with INHBA–FAP-high cell populations as predictors of poor clinical prognosis. Our findings highlight potential origins of deregulated cell states in the gastric tumor ecosystem. This article is highlighted in the In This Issue feature, p. 587

Objective:To explore motivations, self-regulation barriers and strategies in a multi-ethnic Southeast Asian population with overweight and obesity.Design:Qualitative design using semi-structured face-to-face and videoconferencing interviews. Data were analysed using thematic framework analysis and constant comparison method.Setting:Specialist weight management clinic.Participants:Twenty-two participants were purposively sampled from 13 April to 30 April 2021. Median age and BMI of the participants were 37·5 (interquartile range (IQR) = 13·3) and 39·2 kg/m2 (IQR = 6·1), respectively. And 31·8 % were men, majority had a high intention to adopt healthy eating behaviours (median = 6·5; IQR = 4·8–6·3) and 59 % of the participants had a medium level of self-regulation.Results:Six themes and fifteen subthemes were derived. Participants were motivated to lose weight by the sense of responsibility as the family’s pillar of support and to feel ‘normal’ again. We coupled self-regulation barriers with corresponding strategies to come up with four broad themes: habitual overconsumption – mindful self-discipline; proximity and convenience of food available – mental tenacity; momentary lack of motivation and sense of control – motivational boosters; and overeating triggers – removing triggers. We highlighted six unique overeating triggers namely: trigger activities (e.g. using social media); eating with family, friends and colleagues; provision of food by someone; emotions (e.g. feeling bored at home, sad and stressed); physiological condition (e.g. premenstrual syndrome); and the time of the day.Conclusions:Future weight management interventions should consider encompassing participant-led weight loss planning, motivation boosters and self-regulation skills to cope with momentary overeating triggers.

Smoke generated by cautery devices used during surgery may contain infective particles and may cause transmission of airborne viruses. This study determines whether live viruses are present in surgical smoke and evaluates the effectiveness of several proposed methods of removal so as to improve safety of healthcare workers.

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability. Patients and Methods: We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2. Results: This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively. Conclusions: The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases. See related commentary by de Jong et al., p. 1830

Pressurised IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a novel surgical technique to administer aerosolized chemotherapy into the abdominal cavity as treatment for peritoneal metastasis from various cancers. As the surgery is unique and there are concerns about occupational hazards, specific anaesthetic setup and techniques are required. Notably, our institution’s experience with PIPAC has enlightened us that anaesthesia requirements during PIPAC are generally uncomplicated and that the majority of the patients undergoing PIPAC do not require invasive monitoring, advanced intra or postoperative analgesia like epidurals or PCA. The need for postoperative intensive unit care is also not required in routine PIPAC cases. We describe the anaesthetic considerations involved and the detailed preparation of staff, space, anaesthetic equipment and drugs to facilitate the appropriate modifications for anaesthesia monitoring and maintenance for an elective set up as well as our standard operating procedure for an emergency situation should it arise.

Background & Aims Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (PGC) transcript–expressing cells represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model. Methods We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/+ and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments and histologic and immunofluorescence staining. We further established Pgc-CreERT2;KrasG12D/+ mice and investigated whether PGC transcript–expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC transcript–expressing cells with activated Kras, inactivated Apc, and Trp53 signaling pathways, we crossed Pgc-CreERT2/+ mice with conditional KrasG12D, Apcflox, Trp53flox mice. Results Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;KrasG12D/+ mice, PGC transcript–expressing cells with KrasG12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven KrasG12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+;Apcflox/flox mice presented intramucosal dysplasia/carcinoma and Pgc-CreERT2;KrasG12D/+;Apcflox/flox;Trp53flox/flox mice presented invasive and metastatic gastric carcinoma. Conclusions The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development.

Introduction: A Dieulafoy lesion is a large tortuous submucosal arteriole protruding through a small mucosal defect.1 It is uncommon but potentially life threatening.2 Endoscopic hemostasi...

Enhanced recovery after surgery (ERAS) protocols have been successfully integrated into peri-operative management of different cancer surgeries such as colorectal cancer. Their value for gastric cancer surgery, however, remains uncertain. A search for randomized and observational studies comparing ERAS versus conventional care in gastric cancer surgery was performed according to PRISMA guidelines. Random-effects meta-analyses with inverse variance weighting were conducted, and quality of included studies was assessed using the Cochrane risk-of-bias tool and Newcastle-Ottawa scale (PROSPERO: CRD42017080888). Twenty-three studies involving 2686 patients were included. ERAS was associated with reduced length of hospital stay (WMD—2.47 days, 95% CI − 3.06 to − 1.89, P

Despite the high incidence of reflux esophagitis, there are few reports of antireflux modifications for minimally invasive Ivor-Lewis esophagectomy. We present the case of a 63-year-old man with mid-thoracic esophageal squamous cell carcinoma who underwent minimally invasive Ivor-Lewis esophagectomy after neoadjuvant chemoradiotherapy. Laparoscopic dissection, gastric tube creation, and mobilization was performed. Thoracoscopic esophageal dissection, subcarinal, paraesophageal and diaphragmatic lymphadenectomy were performed, followed by esophagogastric anastomosis with double seromuscular flap reconstruction to recreate the lower esophageal sphincter. The operation was completed in 618 minutes with 200 mL blood loss and the patient recovered uneventfully. A morphologic sphincter was seen on postoperative contrast study.

Highlights • Discussion on minimally invasive approaches to acute groin hernia surgery. • Technical ‘tips and tricks’ for emergency laparoscopic repair of femoral hernia. • Review of the current literature., Introduction Femoral hernias frequently present with incarceration, resulting in obstruction and strangulation. Laparoscopic groin hernia repairs have been shown in the elective setting to be an effective alternative to open repair. Acute incarceration of groin hernia with obstruction, though previously seen as a relative contraindication, has been increasingly repaired with minimally invasive techniques, with the potential benefit of avoiding the morbidity associated with a laparotomy. Presentation of case and discussion We describe a case of an acutely incarcerated femoral hernia with intestinal obstruction that was repaired using the totally extra-peritoneal approach. A releasing incision was performed to facilitate reduction of hernia prior to mesh repair. Diagnostic laparoscopy through a separate incision was then performed. Conclusion This modification of the TEP repair technique for the acutely incarcerated and obstructed femoral hernia serves to minimise potential contamination by keeping the pre-peritoneal plane strictly separate from the intra-peritoneal space.

This article was updated to correct Do Joong Park’s name: Do Joong (given name) Park (family name).

BackgroundPressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel laparoscopic intraperitoneal chemotherapy technique, with advantages such as homogeneous distribution of aerosol and deeper tissue penetration. Thus far, PIPAC oxaliplatin has been administered at an arbitrary dose of 92 mg/m2.AimWe aim to determine the dose-related safety profile and tolerability of PIPAC oxaliplatin using an evidence-based approach. The secondary aim is to evaluate clinic-pathologic response and the pharmacokinetic profile.MethodsThis is a phase I 3+3 dose escalation study for gastric and colorectal cancer with predominant peritoneal metastasis starting at a dose of 45 mg/m2. Safety is assessed according to Clavien-Dindo Classification and Common Terminology Criteria for Adverse Events (version 4.0). Clinico-pathologic response is assessed using the Peritoneal Regression Grading Score, Peritoneal Cancer Index, and Response Evaluation Criteria In Solid Tumour criteria (version 1.1). Pharmacokinetic analysis is performed using Inductively Coupled Plasma-Mass Spectrometry assay. This trial is registered on ClinicalTrials.gov (NCT03172416).ConclusionsThis phase I study can provide the scientific basis to identify the optimal dose for PIPAC with oxaliplatin such that the benefits of this novel and promising intraperitoneal chemotherapy delivery technique can be maximized.

Background Per-Oral Endoscopic Myotomy (POEM) has been adopted as a treatment option for Achalasia, with similar efficacy and safety profile as laparoscopic Heller Myotomy. However, issues of acid reflux and reflux oesophagitis have often plagued these patients. We aim to evaluate the clinical outcomes and resolution of reflux disease among individuals post-POEM. Methods A prospective review was performed for all patients who have undergone POEM from January 2014 to December 2017, with individuals analysed at the 1 year mark post-POEM. Subjective assessment of reflux was performed using self-administered questionnaires, with 24h pH impedence test and high resolution manometry providing objective correlation. Results Forty-three individuals underwent POEM during the 4 year period. The median age was 52 years (range, 24–78), with half being males (53.5%). The individuals had a median ASA score of 2 (range, 1–3). Majority of the individuals had type II achalasia (58.1%) followed by type I (34.9%) and type III (7%). Patients presented with dysphagia (88.4%) and reflux (10%); symptomatic for a median of 36 months (range, 3–540). One-third required the use of proton pump inhibitors (PPI) for symptomatic relief, with 35% receiving prior interventions for achalasia. These patients had a median Integrated Relaxation Pressure (IRP) of 23.6 mmHg (range, 4.6–160) and a median Eckardt score of 6 (range, 1 -11). One-third developed complications such as mucosal injury (18.6%), carbon dioxide pneumoperitoneum (16.3%) and bleeding (4.7%). The median length of stay was 3 days (range, 1–6). At the 1 year mark, 86% reported improvement in dysphagia (p: 0.043) with 66% having reduction in ratings for their severity (p: 0.002) and frequency (p: 0.05) of reflux. The median IRP (23 vs 13 mmHg) was also significantly lower (p: 0.005). However, only 38.5% correlated with a normal acid exposure on the impedence test (p: 0.592). Conclusion POEM is a promising solution in the management of achalasia given good clinical response for dysphagia and reflux. However, excessive lower oesophageal acid exposure may still be present in almost half of these patients, which may be alleviated with the use of long term use of PPI. Disclosure All authors have declared no conflicts of interest.

Peritoneal recurrence after gastrectomy for gastric cancer is common and the prognosis is dismal. Recent evidence suggests that extensive peritoneal lavage with large volume of normal saline after surgery before abdominal closure can reduce the risk of peritoneal recurrence and improve overall survival. This study aims to evaluate the benefit of extensive intraoperative peritoneal lavage. This is a prospective, open-label, multicentre randomised controlled trial involving 15 international centres in China, Korea, Japan, Malaysia and Singapore. Patients with cT3/4 stomach cancer undergoing curative resection are randomised to either extensive peritoneal lavage (10 l of saline) or standard lavage (≤2 l of saline). The primary outcome is overall survival and secondary outcomes include disease-free survival and peritoneal recurrence. The minimum sample size is 600 subjects with 300 per arm completing 3 years follow-up. The data will be analysed on an intention-to-treat basis, assuming a two-sided test with a 5% level of significance.