The Impact of Microbiota-Immunity-Hormone Interactions on Autoimmune Diseases and Infection.

Autoimmune diseases are complex multifactorial disorders, and a mixture of genetic and environmental factors play a role in their onset. In recent years, the microbiota has gained attention as it helps to maintain host health and immune homeostasis and is a relevant player in the interaction between our body and the outside world. Alterations (dysbiosis) in its composition or function have been linked to different pathologies, including autoimmune diseases. Among the different microbiota functions, there is the activation/modulation of immune cells that can protect against infections. However, if dysbiosis occurs, it can compromise the host's ability to protect against pathogens, contributing to the development and progression of autoimmune diseases. In some cases, infections can trigger autoimmune diseases by several mechanisms, including the alteration of gut permeability and the activation of innate immune cells to produce pro-inflammatory cytokines that recruit autoreactive T and B cells. In this complex scenario, we cannot neglect critical hormones' roles in regulating immune responses. Different hormones, especially estrogens, have been shown to influence the development and progression of autoimmune diseases by modulating the activity and function of the immune system in different ways. In this review, we summarized the main mechanisms of connection between infections, microbiota, immunity, and hormones in autoimmune diseases' onset and progression given the influence of some infections and hormone levels on their pathogenesis. In detail, we focused on rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

Fashioning esophagogastric anastomosis in robotic Ivor-Lewis esophagectomy: a multicenter experience.

BACKGROUND: The aim of the present study is to compare outcomes of the robotic hand-sewn, linear- and circular-stapled techniques performed to create an intrathoracic esophagogastric anastomosis in patients who underwent Ivor-Lewis esophagectomy. METHODS: Patients who underwent a planned Ivor-Lewis esophagectomy were retrospectively analysed from prospectively maintained databases. Only patients who underwent a robotic thoracic approach with the creation of an intrathoracic esophagogastric anastomosis were included in the study. Patients were divided into three groups: hand-sewn-, circular stapled-, and linear-stapled anastomosis group. Demographic information and surgery-related data were extracted. The primary outcome was the rate of anastomotic leakages (AL) in the three groups. Moreover, the rate of grade A, B and C anastomotic leakage were evaluated. In addition, patients of each group were divided in subgroups according to the characteristics of anastomotic fashioning technique. RESULTS: Two hundred and thirty patients were enrolled in the study. No significant differences were found between the three groups about AL rate (p = 0.137). Considering the management of the AL for each of the three groups, no significant differences were found. Evaluating the correlation between AL rate and the characteristics of anastomotic fashioning technique, no significant differences were found. CONCLUSIONS: No standardized anastomotic fashioning technique has yet been generally accepted. This study could be considered a call to perform ad hoc high-quality studies involving high-volume centers for upper gastrointestinal surgery to evaluate what is the most advantageous anastomotic technique.

Perineural invasion score system and clinical outcomes in resected pancreatic cancer patients.

BACKGROUND/OBJECTIVES: Perineural invasion (PNI), classified according to its presence or absence in tumor specimens, is recognized as a poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC) patients. Herein, we identified five histological features of PNI and investigated their impact on survival outcomes of PDAC resected patients. METHODS: Five histopathological features of PNI (diameter, number, site, sheath involvement, and mitotic figures within perineural invasion) were combined in an additional final score (ranging from 0 to 8), and clinical data of PDAC patients were retrospectively analyzed. PNI + patients were stratified in two categories according to the median score value (<6 and ≥ 6, respectively). Impact of PNI on disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: Forty-five patients were enrolled, of whom 34 with PNI (PNI+) and 11 without PNI (PNI-). The DFS was 11 months vs. not reached (NR) (p = 0.258), while the OS was 19 months vs. NR (p = 0.040) in PNI+ and PNI- patients, respectively. A ≥6 PNI was identified as an independent predictor of worse OS vs. <6 PNI + patients (29 vs. 11 months, p < 0.001) and <6 PNI+ and PNI- patients (43 vs. 11 months, p < 0.001). PNI ≥6 was an independent negative prognostic factor of DFS vs. <6 PNI+ and PNI- patients (13 vs. 6 months, p = 0.022). CONCLUSIONS: We report a PNI scoring system that stratifies surgically-treated PDAC patients in a graded manner that correlates with patient prognosis better than the current dichotomous (presence/absence) definition. However, further and larger studies are needed to support this PNI scoring system.

Surgical Techniques and Related Perioperative Outcomes After Robot-assisted Minimally Invasive Gastrectomy (RAMIG): Results From the Prospective Multicenter International Ugira Gastric Registry.

OBJECTIVE: To gain insight in global practice of RAMIG and evaluated perioperative outcomes using an international registry. BACKGROUND: The techniques and perioperative outcomes of robot-assisted minimally invasive gastrectomy (RAMIG) for gastric cancer vary substantially in literature. METHODS: Prospectively registered RAMIG-cases for gastric cancer (≥10 per center) were extracted from 25 centers in Europe, Asia and South-America. Techniques for the resection, reconstruction, anastomosis and lymphadenectomy were analyzed, and related to perioperative surgical and oncological outcomes. Complications were uniformly defined by the Gastrectomy Complications Consensus Group. RESULTS: Between 2020-2023, 759 patients underwent total (n=272), distal (n=465) or proximal (n=22) gastrectomy (RAMIG). After total gastrectomy with Roux-en-Y-reconstruction, anastomotic leakage rates were 8% with hand-sewn (n=9/111) and 6% with linear stapled anastomoses (n=6/100). After distal gastrectomy with Roux-en-Y (67%) or Billroth-II-reconstruction (31%), anastomotic leakage rates were 3% with linear stapled (n=11/433) and 0% with hand-sewn anastomoses (n=0/26). Extent of lymphadenectomy consisted of D1+ (28%), D2 (59%) or D2+ (12%). Median nodal harvest yielded 31 nodes [IQR 21-47] after total and 34 nodes [IQR 24-47] after distal gastrectomy. R0-resection rates were 93% after total and 96% distal gastrectomy. Hospital stay was 9 days after total and distal gastrectomy, and was 3 days shorter without perianastomotic drains versus routine drain placement. Postoperative 30-day mortality was 1%. CONCLUSIONS: This large multicenter study provided a worldwide overview of current RAMIG-techniques with their respective perioperative outcomes. These outcomes demonstrated high surgical quality, set a quality standard for RAMIG and can be considered an international reference for surgical standardization.

Microbiota Transplant and Gynecological Disorders: The Bridge between Present and Future Treatments.

Fecal microbiota transplantation (FMT) is a procedure that involves transferring fecal bacteria from a healthy donor to a patients' intestines to restore gut-immunity homeostasis. While FMT was primarily supposed to treat gastrointestinal disorders such as inflammatory bowel disease and irritable bowel syndrome-and especially Clostridium difficile infection (currently the only used as clinical treatment)-recent research has suggested that it may also become a potential treatment for gynecological disorders, including endometriosis and polycystic ovary syndrome (PCOS). On the contrary, vaginal microbiota transplantation (VMT) is a newer and less commonly used procedure than the FMT approach, and its potential applications are still being explored. It involves direct grafting of the entire vaginal microbiota of healthy women into the vaginal tract of patients to easily rebuild the local microbiota environment, restoring vaginal eubiosis and relieving symptoms. Like FMT, VMT is thought to have potential in treating different microbiota-related conditions. In fact, many gynecological disorders, such as bacterial vaginosis and vulvovaginal candidiasis, are thought to be caused by an imbalance in the vaginal microbiota. In this review, we will summarize the development, current challenges, and future perspectives of microbiota transplant, with the aim of exploring new strategies for its employment as a promising avenue for treating a broad range of gynecological diseases.

Parathyroid Retrospective Analysis of Neoplasms Incidence (pTRANI Study): An Italian Multicenter Study on Parathyroid Carcinoma and Atypical Parathyroid Tumour.

BACKGROUND: Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT). METHODS: All relevant information was collected about PC and APT patients treated between 2009 and 2021. RESULTS: Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates (p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%. CONCLUSIONS: Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs.

Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention. In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control. Accordingly, CAIX-high-expressing GC cells showed increased therapy resistance compared to low-expressing cells. Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT.

Open vs robotic gastrectomy with D2 lymphadenectomy: a propensity score-matched analysis on 1469 patients from the IMIGASTRIC prospective database.

BACKGROUND: Comparative data on D2-robotic gastrectomy (RG) vs D2-open gastrectomy (OG) are lacking in the Literature. Aim of this paper is to compare RG to OG with a focus on D2-lymphadenectomy. STUDY DESIGN: Data of patients undergoing D2-OG or RG for gastric cancer were retrieved from the international IMIGASTRIC prospective database and compared. RESULTS: A total of 1469 patients were selected for inclusion in the study. After 1:1 propensity score matching, a total of 580 patients were matched and included in the final analysis, 290 in each group, RG vs OG. RG had longer operation time (210 vs 330 min, p < 0.0001), reduced intraoperative blood loss (155 vs 119.7 ml, p < 0.0001), time to liquid diet (4.4 vs 3 days, p < 0.0001) and to peristalsis (2.4 vs 2 days, p < 0.0001), and length of postoperative stay (11 vs 8 days, p < 0.0001). Morbidity rate was higher in OG (24.1% vs 16.2%, p = 0.017). CONCLUSION: RG significantly expedites recovery and reduces the risk of complications compared to OG. However, long-term survival is similar.

Ileostomy versus colostomy: impact on functional outcomes after total mesorectal excision for rectal cancer.

AIM: Even if a defunctioning stoma mitigates the serious consequences of anastomotic leakage after total mesorectal excision (TME) for rectal cancer, the presence of a temporary stoma or having a stoma for a prolonged period of time may also be a determining factor for further morbidities and poor bowel function. The aim of this study was to evaluate the impact of diverting stomas on clinical and functional outcomes after TME, comparing ileostomy or colostomy effects. METHODS: All consecutive patients who underwent TME for rectal cancer between March 2017 and December 2020 in three Italian referral centres were enrolled in the present study. For every patient sex, age, stage of the tumour, neoadjuvant therapy, surgical technique, anastomotic technique, the presence of a diverting stoma, perioperative complications and functional postoperative status were recorded. Considering the diverting stoma, the kind of stoma, length of time before closure and stoma related complications were evaluated. RESULTS: During the study period 416 consecutive patients (63% men) were included. Preoperative neoadjuvant therapy was performed in 79%. A minimally invasive approach was performed in >95% of patients. Temporary stoma was performed during the operation in 387 patients (93%) (ileostomy 71%, colostomy 21%). The stoma was closed in 84% of patients. The median time from surgery to stoma closure was 145 days. No difference was found between ileostomy and colostomy in overall morbidity after stoma creation and closure. Moreover, increased postoperative functional disturbance seemed to be significantly proportional to the attending time for closure for ileostomy. CONCLUSION: The presence of a defunctioning stoma seems to have a negative impact on functional bowel activity, especially for delayed closure for ileostomy. This should be considered when the kind of stoma (ileostomy vs. colostomy) is selected for each patient.

Effects of the learning curve on operative time and lymph node harvesting during robotic gastrectomy.

BACKGROUND: Gastric cancer is the fifth most frequent cancer globally. The introduction of minimally invasive surgery for gastric cancer aimed at reducing post-operative morbidity and hospital length of stay. Although the role of laparoscopic gastrectomy has been established, robotic gastric surgery has only recently gained popularity. The purpose of this study was to evaluate, with a multidimensional analysis, the learning curve of a single surgeon with extensive experience in laparoscopic gastrectomy. METHODS: We prospectively collected data from 104 gastric cancer patients who underwent surgery with a robotic approach from June 2015 to June 2019 by a single surgeon. We performed 21 total gastrectomies (TGs) and 83 subtotal gastrectomies (STGs). A D2 lymphadenectomy was performed in all the patients. Proximal and distal resection margins were tumoour-free in all patients. There were no intraoperative complications, and no conversions occurred. RESULTS: The plateau of the learning curve based on harvesting lymph nodes and operative time was not reached for TG. The learning curve of operative time for STG could be divided into three different phases: an early or learning phase from 1 to 27 cases, an intermediate or proficiency phase from 28 to 48 cases, and a late or mastery phase from 49 to 83 cases. The learning curve for harvesting lymph nodes was achieved after 41 cases in the STG group. CONCLUSION: This study shows that robotic gastrectomy is a complex procedure with a significant multiphasic learning curve. Nevertheless, the robotic learning curve seems to be more rapid than that of conventional laparoscopy. Most importantly, our results suggest that the robotic technique can provide oncological adequacy in terms of lymph node harvesting even in the very first phase of the learning curve.

Surgery for Sporadic Primary Hyperparathyroidism: Evolution over the Last Twenty Years in a Monocentric Setting.

The sporadic parathyroid pathology of surgical interest is primarily limited to lesions that are the cause of hormonal hyperfunction (primary hyperparathyroidism). In recent years, parathyroid surgery has evolved significantly, and numerous minimally invasive parathyroidectomy techniques have been developed. In this study, we describe a single-center and well-documented case series of sporadic primary hyperparathyroidism, surgically treated by a single operator in the Endocrine Surgery Unit of the Surgical Clinic of the University of Florence-Careggi University Hospital, recorded and updated in a dedicated database that embraces the entire evolutionary timeframe of parathyroid surgery. From January 2000 to May 2020, 504 patients with a clinical and instrumental diagnosis of hyperparathyroidism were included in the study. The patients were divided into two groups, based on the application of intraoperative parathyroid hormone (ioPTH). The analysis shows that the use of ioPTH with the rapid method could be ineffective in helping surgeons in primary operations, especially when ultrasound and scintiscan are concordant. The advantages obtained by not using intraoperative PTH are not only economic. In fact, our data shows shorter operating and general anesthesia times and hospital stays, having an important impact on patient biological commitment. Furthermore, the significant reduction in operating time makes it possible to almost triple the volume of activity in the same unit of time available, with an undeniable advantage for the reduction of waiting lists. In recent years, minimally invasive approaches have allowed surgeons to reach the best compromise between invasiveness and aesthetic results.

Primary Tumour Treatment in Stage 4 Colorectal Cancer with Unresectable Liver and Lung Metastases and No Peritoneal Carcinomatosis-Current Trends and Attitudes in the Absence of Clear Guidelines.

BACKGROUND: The treatment of the primary tumour in colorectal cancer with unresectable liver and/or lung metastases but no peritoneal carcinomatosis is still a matter of debate. In the absence of clear evidence and guidelines, our survey was aimed at obtaining a snapshot of the current attitudes and the rationales for the choice of offering resection of the primary tumour (RPT) despite the presence of untreatable metastases. METHODS: An online survey was administered to medical professionals worldwide. The survey had three sections: (1) demographics of the respondent, (2) case scenarios and (3) general questions. For each respondent, an "elective resection score" and an "emergency resection score" were calculated as a percentage of the times he or she would offer RPT in the elective and in the emergency case scenarios. They were correlated to independent variables such as age, type of affiliation and specific workload. RESULTS: Most respondents would offer palliative chemotherapy as the first choice in elective scenarios, while a more aggressive approach with RPT would be reserved for younger patients with good performance status and in emergency situations. Respondents younger than 50 years old and those with a specific workload of fewer than 40 cases of colorectal cancer per year tend to be more conservative. CONCLUSIONS: In the absence of clear guidelines and evidence, there is a lack of consensus on the treatment of the primary tumour in case of colon cancer with unresectable liver and/or lung metastases and no peritoneal carcinomatosis. Palliative chemotherapy seems to be the first option, but more consistent evidence is needed to guide this choice.

Increased IL-17A Serum Levels and Gastric Th17 Cells in Helicobacter pylori-Infected Patients with Gastric Premalignant Lesions.

Background:Helicobacter pylori infection is characterized by an inflammatory infiltrate that might be an important antecedent of gastric cancer. The purpose of this study was to evaluate whether interleukin (IL)-17 inflammation is elicited by gastric T cells in Helicobacter pylori patients with gastric intestinal metaplasia and dysplasia (IM/DYS). We also investigated the serum IL-17A levels in Helicobacter pylori patients with gastric intestinal metaplasia and dysplasia, and patients with Helicobacter pylori non-atrophic gastritis (NAG). Methods: the IL-17 cytokine profile of gastric T cells was investigated in six patients with IM/DYS and Helicobacter pylori infection. Serum IL-17A levels were measured in 45 Helicobacter pylori-infected IM/DYS patients, 45 Helicobacter pylori-infected patients without IM/DYS and in 45 healthy controls (HC). Results: gastric T cells from all IM/DYS patients with Helicobacter pylori were able to proliferate in response to Helicobacter pylori and to produce IL-17A. The Luminex analysis revealed that IL-17A levels were significantly increased in Helicobacter pylori IM/DYS patients compared to healthy controls and to Helicobacter pylori gastritis patients without IM/DYS (452.34 ± 369.13 pg/mL, 246.82 ± 156.06 pg/mL, 169.26 ± 73.82 pg/mL, respectively; p < 0.01, p < 0.05). Conclusions: the results obtained indicate that Helicobacter pylori is able to drive gastric IL-17 inflammation in IM/DYS Helicobacter pylori-infected patients, and that IL-17A serum levels are significantly increased in Helicobacter pylori-infected patients with IM/DYS.

Perioperative Tailored Treatments for Gastric Cancer: Times Are Changing.

Resectable gastric or gastroesophageal (G/GEJ) cancer is a heterogeneous disease with no defined molecularly based treatment strategy. Unfortunately, nearly half of patients experience disease recurrence despite standard treatments (neoadjuvant and/or adjuvant chemotherapy/chemoradiotherapy and surgery). In this review, we summarize the evidence of potential tailored approaches in perioperative treatment of G/GEJ cancer, with a special focus on patients with human epidermal growth factor receptor-2(HER2)-positive and microsatellite instability-high (MSI-H) tumors. In patients with resectable MSI-H G/GEJ adenocarcinoma, the ongoing INFINITY trial introduces the concept of non-operative management for patients with complete clinical-pathological-molecular response, and this could be a novel and potential practice changing strategy. Other pathways involving vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), claudin18 isoform 2 (CLDN18.2), and DNA damage repair proteins are also described, with limited evidence until now. Although tailored therapy appears to be a promising strategy for resectable G/GEJ cancer, there are several methodological issues to address: inadequate sample size for pivotal trials, underestimation of subgroup effects, and choice of primary endpoint (tumor-centered vs. patient-centered endpoints). A better optimization of G/GEJ cancer treatment allows maximizing patient outcomes. In the perioperative phase, although caution is mandatory, times are changing and tailored strategies could introduce new treatment concepts. Overall, MSI-H G/GEJ cancer patients possess the characteristics to be the subgroup that could receive the most benefit from a tailored approach.

Duplication of the gallbladder in a patient with right colon cancer. A case report and review of the literature review.

AIM: Duplication of the gallbladder is a very rare congenital variant, showing an incidence of about 1 in 4000 in the population, occurring twice as often in women than in men. In the literature only a few cases of prenatal diagnosis are reported. The knowledge of the existence of this anatomical variable is very important in order to avoid complications and iatrogenic damage during interventional and surgical procedures involving the biliary tract or adjacent organs. CASE REPORT: A 79-year-old patient was admitted to our Hospital in May 2021 presenting abdominal pain. During hospitalization, a 5cm adenocarcinoma of the ascending colon was found. During surgery the known accessory gallbladder was found strongly adhering to the proximal transverse colon. The challenging viscerolysis maneuvers caused a lesion on one of the gallbladders, so we decided to proceed with cholecystectomy of both gallbladders. RESULTS AND DISCUSSION: Duplication of the gallbladder is a rare congenital anatomical variant and requires special attention to the biliary and arterial anatomy in order to avoid iatrogenic damage. This variant can complicate surgical treatment for complications that need urgent treatment, such as cholecystitis. Currently the technique of choice for the evaluation of the biliary tree is magnetic resonance cholangiography. Laparoscopic cholecystectomy is the treatment of choice. CONCLUSION: Surgeons should be aware of the different forms of presentation of gallbladder pathologies, also the ones that are not "the standard" of routine. Detailed preoperative study is essential to avoid a missed diagnosis. KEY WORDS: Gallbladder, Mininvasive surgery, Variant, Anatomical.