Palliative surgery: state of the science and future directions.

Palliative surgical procedures are operations that aim to alleviate symptoms in a patient with serious, life-limiting illness. They are common, particularly within the field of surgical oncology. However, few high-quality studies have attempted to measure the durability of improvements in symptoms and quality of life after palliative surgery. Furthermore, many of the studies that do exist are outdated and employ highly inconsistent definitions of palliative surgery. Consequently, the paucity of robust and reliable evidence on the benefits, risks, and trade-offs of palliative surgery hampers clinical decision-making for patients and their surgeons. The evidence for palliative surgery suggests that, with effective communication about goals of care and careful patient selection, palliative surgery can provide symptomatic relief and reduce healthcare burdens for certain seriously ill patients.

Impact of COVID-19 on presentation, management, and outcomes of acute care surgery for gallbladder disease and acute appendicitis.

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic has significantly disrupted both elective and acute medical care. Data from the early months suggest that acute care patient populations deferred presenting to the emergency department (ED), portending more severe disease at the time of presentation. Additionally, care for this patient population trended towards initial non-operative management. AIM: To examine the presentation, management, and outcomes of patients who developed gallbladder disease or appendicitis during the pandemic. METHODS: A retrospective chart review of patients diagnosed with acute cholecystitis, symptomatic cholelithiasis, or appendicitis in two EDs affiliated with a single tertiary academic medical center in Northern California between March and June, 2020 and in the same months of 2019. Patients were selected through a research repository using international classification of diseases (ICD)-9 and ICD-10 codes. Across both years, 313 patients were identified with either type of gallbladder disease, while 361 patients were identified with acute appendicitis. The primary outcome was overall incidence of disease. Secondary outcomes included presentation, management, complications, and 30-d re-presentation rates. Relationships between different variables were explored using Pearson's r correlation coefficient. Variables were compared using the Welch's t-Test, Chi-squared tests, and Fisher's exact test as appropriate. RESULTS: Patients with gallbladder disease and appendicitis both had more severe presentations in 2020. With respect to gallbladder disease, more patients in the COVID-19 cohort presented with acute cholecystitis compared to the control cohort [50% (80) vs 35% (53); P = 0.01]. Patients also presented with more severe cholecystitis in 2020 as indicated by higher mean Tokyo Criteria Scores [mean (SD) 1.39 (0.56) vs 1.16 (0.44); P = 0.02]. With respect to appendicitis, more patients were diagnosed with a perforated appendix at presentation in 2020 [20% (36) vs 16% (29); P = 0.02] and a greater percentage were classified as emergent cases using the emergency severity index [63% (112) vs 13% (23); P < 0.001]. While a greater percentage of patients were admitted to the hospital for gallbladder disease in 2020 [65% (104) vs 50% (76); P = 0.02], no significant differences were observed in hospital admissions for patients with appendicitis. No significant differences were observed in length of hospital stay or operative rate for either group. However, for patients with appendicitis, 30-d re-presentation rates were significantly higher in 2020 [13% (23) vs 4% (8); P = 0.01]. CONCLUSION: During the COVID-19 pandemic, patients presented with more severe gallbladder disease and appendicitis. These findings suggest that the pandemic has affected patients with acute surgical conditions.

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection.

The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1ß-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The γδ T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-γ, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus-induced γδ T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant Vγ5+ dendritic epidermal T cells. However, this T cell receptor γ (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGV5 and TRGV6, indicating clonotypic expansion. TNF- and IFN-γ-producing γδ T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded γδ T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections.

Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation.

BACKGROUND: Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. OBJECTIVE: Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. METHODS: We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. RESULTS: Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FcεRI-mediated proximal and distal signaling, as well as reduced degranulation. CONCLUSION: This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others.