Defining features of hereditary lobular breast cancer due to CDH1 with magnetic resonance imaging and tumor characteristics.

Women with germline pathogenic variants in CDH1, which encodes E-cadherin protein, are at increased lifetime risk of invasive lobular carcinoma (ILC). The associated tumor characteristics of hereditary lobular breast carcinoma (HLBC) in this high-risk population are not well-known. A single-center prospective cohort study was conducted to determine the imaging and pathologic features of HLBC compared to population-based ILC using Surveillance, Epidemiology, and End Results (SEER) data. One hundred fifty-eight women with CDH1 variants were evaluated, of whom 48 (30%) also had an ILC diagnosis. The median age at CDH1 diagnosis was 45 years [interquartile range, IQR 34-57 years] whereas the median age at diagnosis of CDH1 with concomitant ILC (HLBC) was 53 [IQR 45-62] years. Among women with HLBC, 83% (40/48) were identified with CDH1 mutation after diagnosis of ILC. Among 76 women (48%, 76/158) undergoing surveillance for ILC with breast magnetic resonance imaging (MRI), 29% (22/76) had an abnormal MRI result with available biopsy data for comparison. MRI detected ILC in 7 out of 8 biopsy-confirmed cases, corresponding with high sensitivity (88%), specificity (75%), and negative predictive value (98%); however, false-positive and false-discovery rates were elevated also (25% and 68%, respectively). HLBC was most frequently diagnosed at age 40-49 years (44%, 21/48), significantly younger than the common age of diagnosis of ILC in SEER general population data (most frequent age range 60-69 years, 28%; p < 0.001). HLBC tumors were smaller than SEER-documented ILC tumors (median 1.40 vs. 2.00 cm; p = 0.002) and had a higher incidence of background lobular carcinoma in situ (88% vs. 1%; p < 0.001) as well as progesterone receptor positivity (95% vs. 81%, p = 0.032). These findings suggest that HLBC is often detected via conventional screening methods as an early-stage hormone receptor-positive tumor, thus the clinical benefit of intensive screening with MRI may be limited to a subset of women with germline CDH1 variants.

Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study.

BACKGROUND: Loss of function variants in CDH1 are the most frequent cause of hereditary diffuse gastric cancer. Endoscopy is regarded as insufficient for early detection due to the infiltrative phenotype of diffuse-type cancers. Microscopic foci of invasive signet ring cells are pathognomonic of CDH1 and precede development of diffuse gastric cancer. We aimed to assess the safety and effectiveness of endoscopy for cancer interception in individuals with germline CDH1 variants, particularly in those who declined prophylactic total gastrectomy. METHODS: In this prospective cohort study, we included asymptomatic patients aged 2 years or older with pathogenic or likely pathogenic germline CDH1 variants who underwent endoscopic screening and surveillance at the National Institutes of Health (Bethesda, MD, USA) as part of a natural history study of hereditary gastric cancers (NCT03030404). Endoscopy was done with non-targeted biopsies and one or more targeted biopsy and assessment of focal lesions. Endoscopy findings, pathological data, personal and family cancer history, and demographics were recorded. Procedural morbidity, gastric cancer detection by endoscopy and gastrectomy, and cancer-specific events were assessed. Screening was defined as the initial endoscopy and all subsequent endoscopies were considered surveillance; follow-up endoscopy was at 6 to 12 months. The primary aim was to determine effectiveness of endoscopic surveillance for detection of gastric signet ring cell carcinoma. FINDINGS: Between Jan 25, 2017, and Dec 12, 2021, 270 patients (median age 46·6 years [IQR 36·5-59·8], 173 [64%] female participants, 97 [36%] male participants; 250 [93%] were non-Hispanic White, eight [3%] were multiracial, four [2%] were non-Hispanic Black, three [1%] were Hispanic, two [1%] were Asian, and one [<1%] was American Indian or Alaskan Native) with germline CDH1 variants were screened, in whom 467 endoscopies were done as of data cutoff (April 30, 2022). 213 (79%) of 270 patients had a family history of gastric cancer, and 176 (65%) reported a family history of breast cancer. Median follow-up was 31·1 months (IQR 17·1-42·1). 38 803 total gastric biopsy samples were obtained, of which 1163 (3%) were positive for invasive signet ring cell carcinoma. Signet ring cell carcinoma was detected in 76 (63%) of 120 patients who had two or more surveillance endoscopies, of whom 74 had occult cancer detected; the remaining two individuals developed focal ulcerations each corresponding to pT3N0 stage carcinoma. 98 (36%) of 270 patients proceeded to prophylactic total gastrectomy. Among patients who had a prophylactic total gastrectomy after an endoscopy with biopsy samples negative for cancer (42 [43%] of 98), multifocal stage IA gastric carcinoma was detected in 39 (93%). Two (1%) participants died during follow-up, one due to metastatic lobular breast cancer and the other due to underlying cerebrovascular disease, and no participants were diagnosed with advanced stage (III or IV) cancer during follow-up. INTERPRETATION: In our cohort, endoscopic cancer surveillance was an acceptable alternative to surgery in individuals with CDH1 variants who declined total gastrectomy. The low rate of incident tumours (>T1a) suggests that surveillance might be a rational alternative to surgery in individuals with CDH1 variants. FUNDING: Intramural Research Program, National Institutes of Health.

Micronutrient Supplementation and Bone Health After Prophylactic Total Gastrectomy in Patients With CDH1 Variants.

INTRODUCTION: Patients with germline variants in CDH1 who undergo prophylactic total gastrectomy (TG) are at risk of altered nutrient and drug absorption due to modified gastrointestinal anatomy. Bone mineral density loss and micronutrient deficiencies have not been described previously in this patient population. METHODS: In this study we included 94 patients with germline CDH1 variants who underwent prophylactic TG between October 2017 and February 2022. We examined pre- and post-gastrectomy bone mineral density (BMD); serum biomarkers including calcium, phosphorus, alkaline phosphatase, and 25 (OH)-vitamin D; and postoperative adherence to calcium and multivitamin supplementation. RESULTS: Almost all patients (92/94, 98%) lost a substantial amount of weight post-TG, with an average weight loss of 26.5% at 12 months post-surgery. Serum biomarkers of mineral metabolism, namely calcium and phosphorus, did not change significantly after TG. However, average BMD was decreased in all patients at 12 months post-TG. Nonadherence to calcium supplementation was associated with a decrease in BMD. Nonadherence to multivitamin supplementation was associated with greater percent BMD loss in the femoral neck and total hip. CONCLUSIONS: Appropriate micronutrient supplementation and nutritional counseling pre- and postoperatively in patients undergoing prophylactic TG are important to mitigate the long-term effects of gastrectomy on bone health.

The Etiology, Diagnosis, and Management of Esophageal Perforation.

BACKGROUND: Esophageal perforation is a serious and potentially life-threatening medical emergency. Given multiple etiologies and varying clinical presentations of the perforated esophagus, the diagnosis is commonly delayed, complicating expeditious and optimal intervention. METHODS: We thoroughly reviewed the latest literature on the subject and herein describe the various treatment strategies in varying settings. RESULTS: Treatment depends on multiple factors including the cause and location of the perforation, the time interval between the inciting event and presentation to the managing clinician, the overall medical stability of the patient, comorbidities including pre-existent esophageal pathology or prior foregut operations, and both the location and extent of extra-esophageal fluid collections. Because of these various considerations, determining the best diagnostic and therapeutic approach requires considerable clinical experience and judgment on the part of the physician. Management principles include (1) adequate fluid resuscitation; (2) expeditious administration of appropriate broad-spectrum antibiotics; (3) repair, occlusion, exclusion, diversion, or exteriorization of the perforation site; (4) drainage of extraluminal fluid collections; (5) relief of distal obstruction; and (6) nutritional support. CONCLUSIONS: For decades, operative intervention has been the mainstay of therapy for esophageal perforation. More recently, endoscopic therapies, including stenting, clipping, suturing, or endoscopic vacuum therapy, have been introduced, expanding the clinician's therapeutic armamentarium while supplanting surgical approaches in many cases. With further experience and introduction of novel therapies, the management of esophageal perforation undoubtedly will continue to evolve.

A Critical Appraisal of Late Complications of Prepectoral versus Subpectoral Breast Reconstruction Following Nipple-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomy (NSM) offers improved aesthetics without compromising oncologic safety. Subpectoral breast reconstruction has long been standard practice, although prepectoral reconstruction has recently resurged in popularity. Due to this recent paradigm shift, studies comparing long-term outcomes by reconstructive plane are lacking. METHODS: A retrospective review was conducted on consecutive NSMs with implant-based reconstruction in either the prepectoral or subpectoral plane from 2014 to 2018. Patient demographics, implant specifications, and operative details were collected to evaluate primary outcomes of prosthetic failure and unplanned reoperations by reconstructive plane. Secondary outcomes included animation deformity, capsular contracture, rippling, plane change, and minor revisions, including fat grafting. Bivariate and multivariate analyses were performed to assess outcomes. RESULTS: Overall, 405 NSMs were performed on 228 women (subpectoral = 202, prepectoral = 203), with a mean follow-up of 2.1 years (standard deviation 1.1). During the study period (2014-2018), a shift from subpectoral to predominantly prepectoral mastectomies occurred in 2017. Prepectoral reconstructions were more often direct-to-implant (DTI) compared with subpectoral (73.9% vs. 33.2%, p < 0.001). Prepectoral reconstruction demonstrated significantly reduced prosthetic failure (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.14-0.65) and unplanned reoperations (OR 0.43, 95% CI 0.24-0.77) compared with subpectoral reconstruction after controlling for implant characteristics and other possible confounders. Prepectoral patients experienced decreased animation deformity overall (19.7% vs. 0.0%, p < 0.001), with plane changes seen in 10.6% of subpectoral reconstructions for animation deformity correction. Prepectoral patients experienced an increase in rippling (15.3% vs. 6.1%, p = 0.003) without a significant increase in fat grafting (subpectoral = 11.6% vs. prepectoral = 12.3%, p = 0.829). CONCLUSIONS: This single-institution experience compares late complications of prepectoral and subpectoral implant-based reconstruction following NSM. Prepectoral reconstruction can be safely performed with improved understanding of mastectomy planes, readily affords DTI reconstruction, and reduces animation deformity at the expense of rippling.

Are electronic cigarettes and vaping effective tools for smoking cessation? Limited evidence on surgical outcomes: a narrative review.

The rising popularity of e-cigarettes and vaping, particularly in youth populations, has prompted the scientific community to ocassionally recommend their use as alternative to smoking or as a modality for smoking cessation. Media also tends to portray them as stylish, smoking cessation tools. We first studied the current literature to better understand whether they are viable options for surgeons to use prior to surgery as part of their armamentarium and their efficacy in attaining smoking abstinence. Next, we performed a comprehensive review of the literature to study the impact of e-cigarette and vaping on lung pathophysiology, surgical outcomes, and postoperative complications. After a thorough search, we found limited evidence suggesting that e-cigarettes and vaping are effective smoking cessation tools, and indeed may increase the propensity of dual smoking, contrary to e-cigarette advertisements. Many potential biases and limitations exist due to self-reporting when investigating e-cigarettes and vaping. While there is controversial data in the literature about e-cigarettes and vaping not leading to lung cancer, there are chemicals in these products that compromise lung hemostasis, negatively affect the immune system, and have detrimental inflammatory effects on wound healing. Studies are warranted to elucidate objective data regarding short and long-term effects of these products on surgical outcomes, and given the current data, they should not be utilized as viable smoking cessation tools.

Therapeutic Application of Cannabis in Medicine and Its Relevance to Thoracic Surgery.

BACKGROUND: Cannabis is the most commonly used illicit substance in the United States. As cannabis use rises in popularity and its legalization continues to expand, the scientific community must address the controversy between beneficial and adverse effects of cannabis consumption. METHODS: We performed a comprehensive literature review to study the medicinal and pathologic effects of cannabis use, with emphasis on its association with cancer pathophysiology and thoracic surgery. RESULTS: We found evidence that cannabis products often contain carcinogenic materials and that their use is associated with the development of certain head and neck cancers, but not lung cancer. Indeed, several in vitro and in vivo studies have demonstrated that cannabis may have a therapeutic role in cancer given the antiproliferative effects of its active compounds such as δ-9-tetrahydrocannabinol. Cannabis-derived products have also been shown to be effective treatments for chronic pain, neuropathy, spasticity, and as antiemetics. CONCLUSIONS: We acknowledge that additional studies are required to elucidate the long-term effects of cannabis products and that many potential biases and limitations exist in the literature due to self-reporting and limited survey studies. Appropriate stewardship over cannabis use among our patient population will likely determine its full implications in both oncologic and perioperative outcomes.

Management of anastomotic leaks after esophagectomy and gastric pull-up.

Anastomotic leak is one of the most feared complications of esophagectomy, leading to prolonged hospital stay, increased postoperative mortality, and additional cost both to the patient and the hospital. Historically, anastomotic leaks have been treated with several techniques including conservative measures, percutaneous or operative drainage, primary surgical repair with buttressing, T-tube drainage, or excision of the esophageal replacement conduit with end esophagostomy. With advances in treatment modalities, including endoscopic stenting, clips and suturing, endoluminal vacuum-assisted closure (EVAC), such leaks increasingly are being managed without operative re-intervention and with salvage of the esophageal replacement conduit. For the purposes of this review, we identified studies analyzing the management of postoperative leak after esophagectomy. We then compared the efficacy of the various newer modalities for closure of anastomotic leaks and gastric conduit defects. We found both esophageal stent and EVAC sponges are effective treatments for closure of anastomotic leak. The chosen treatment modality for salvage of the esophageal replacement conduit is entirely dependent on the patient's clinical status and the surgeon's preference and experience. Emerging endoscopic and endoluminal therapies have increased the armamentarium of tools the esophageal surgeon has to facilitate successful resolution of anastomotic leaks following esophagectomy with reconstruction. While some literature suggests that EVACs have a slightly superior result in conduit success, we question this endorsement as EVACs mostly are utilized for contained leaks, many of which may have healed with conservative measures. This poses a challenge as there is clearly a bias given patient selection.

Characterization and expression analysis of Galnts in developing Strongylocentrotus purpuratus embryos.

Mucin-type O-glycosylation is a ubiquitous posttranslational modification in which N-Acetylgalactosamine (GalNAc) is added to the hydroxyl group of select serine or threonine residues of a protein by the family of UDP-GalNAc:Polypeptide N-Acetylgalactosaminyltransferases (GalNAc-Ts; EC 2.4.1.41). Previous studies demonstrate that O-glycosylation plays essential roles in protein function, cell-cell interactions, cell polarity and differentiation in developing mouse and Drosophila embryos. Although this type of protein modification is highly conserved among higher eukaryotes, little is known about this family of enzymes in echinoderms, basal deuterostome relatives of the chordates. To investigate the potential role of GalNAc-Ts in echinoderms, we have begun the characterization of this enzyme family in the purple sea urchin, S. purpuratus. We have fully or partially cloned a total of 13 genes (SpGalnts) encoding putative sea urchin SpGalNAc-Ts, and have confirmed enzymatic activity of five recombinant proteins. Amino acid alignments revealed high sequence similarity among sea urchin and mammalian glycosyltransferases, suggesting the presence of putative orthologues. Structural models underscored these similarities and helped reconcile some of the substrate preferences observed. Temporal and spatial expression of SpGalnt transcripts, was studied by whole-mount in situ hybridization. We found that many of these genes are transcribed early in developing embryos, often with restricted expression to the endomesodermal region. Multicolor fluorescent in situ hybridization (FISH) demonstrated that transcripts encoding SpGalnt7-2 co-localized with both Endo16 (a gene expressed in the endoderm), and Gcm (a gene expressed in secondary mesenchyme cells) at the early blastula stage, 20 hours post fertilization (hpf). At late blastula stage (28 hpf), SpGalnt7-2 message co-expresses with Gcm, suggesting that it may play a role in secondary mesenchyme development. We also discovered that morpholino-mediated knockdown of SpGalnt13 transcripts, results in a deficiency of embryonic skeleton and neurons, suggesting that mucin-type O-glycans play essential roles during embryonic development in S. purpuratus.

Fibronectin contributes to notochord intercalation in the invertebrate chordate, Ciona intestinalis.

BACKGROUND: Genomic analysis has upended chordate phylogeny, placing the tunicates as the sister group to the vertebrates. This taxonomic rearrangement raises questions about the emergence of a tunicate/vertebrate ancestor. RESULTS: Characterization of developmental genes uniquely shared by tunicates and vertebrates is one promising approach for deciphering developmental shifts underlying acquisition of novel, ancestral traits. The matrix glycoprotein Fibronectin (FN) has long been considered a vertebrate-specific gene, playing a major instructive role in vertebrate embryonic development. However, the recent computational prediction of an orthologous "vertebrate-like" Fn gene in the genome of a tunicate, Ciona savignyi, challenges this viewpoint suggesting that Fn may have arisen in the shared tunicate/vertebrate ancestor. Here we verify the presence of a tunicate Fn ortholog. Transgenic reporter analysis was used to characterize a Ciona Fn enhancer driving expression in the notochord. Targeted knockdown in the notochord lineage indicates that FN is required for proper convergent extension. CONCLUSIONS: These findings suggest that acquisition of Fn was associated with altered notochord morphogenesis in the vertebrate/tunicate ancestor.