Laparoscopic management of colovesical fistula in different clinical scenarios.

INTRODUCTION: Colovesical fistula (CVF) is a condition with various aetiologies and presentations. Surgical treatment is necessary in most cases. Due to its complexity, open approach is preferred. However, laparoscopic approach is reported in the management of CVF due to diverticular disease. The aim of this study was to analyse the management and outcome of patients with CVF of different aetiologies treated with laparoscopic approach. PATIENTS AND METHODS: This was a retrospective study. We retrospectively reviewed all patients undergoing elective laparoscopic management of CVF from March 2015 to December 2019. STATISTICAL ANALYSIS USED: None. RESULTS: Nine patients underwent laparoscopic management of CVF. There were no intraoperative complications or conversions to open surgery. A sigmoidectomy was performed in eight cases. In one patient, a fistulectomy with sigmoid and bladder defect closure was performed. In two cases of locally advanced colorectal cancer with bladder invasion, a multi-stage procedure with temporary colostomy was chosen. In three cases, with no intraoperative leakage, we did not perform bladder suture. Four Clavien I-II complications were recorded. Two fragile patients died in the post-operative period. No patients required re-operation. At a median follow-up of 21 months (interquartile range: 6-47), none of the patients had recurrence of fistula. CONCLUSIONS: CVF can be managed with laparoscopic approach by skilled laparoscopic surgeons in different clinical scenarios. Bladder suture is not necessary if leakage is absent. Informed counselling to the patient must be guaranteed concerning the risk of major complications and mortality in case of CVF due to malignant disease.

Management of colovesical fistula: a systematic review.

INTRODUCTION: Colovesical fistulas (CVFs) account for approximately 95% enterovesical fistulas (EVFs). About 2/3 CVF cases are diverticular in origin. It mainly presents with urological signs such as pneumaturia and fecaluria. Diagnostic investigations aim at confirming the presence of a fistula. Although conservative management can be chosen for selected individuals, most patients are mainly treated through surgical interventions. CVF represents a challenging condition, which records high rates of morbidity and mortality. Our systematic review aimed at achieving deeper knowledge of both indications, in addition to short- and long-term outcomes related to CVF management. EVIDENCE ACQUISITION: We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Pubmed/MEDLINE, Embase, Scopus, Cochrane Library and Web of Science databases were used to search all related literature. EVIDENCE SYNTHESIS: The 22 included articles covered an approximately 37 years-study period (1982-2019), with a total 1365 patient population. CVF etiology was colonic diverticulitis in most cases (87.9%). Pneumaturia (50.1%), fecaluria (40.9%) and urinary tract infections (46.6%) were the most common symptoms. Abdomen computed tomography (CT) scan (80.5%), colonoscopy (74.5%) and cystoscopy (55.9%) were the most frequently performed diagnostic methods. Most CVF patients underwent surgery (97.1%) with open approach (63.3%). Almost all patients had colorectal resection with primary anastomosis with or without ostomy and 53.2% patients underwent primary repair or partial/total cystectomy. Four percent anastomotic leak, 1.8% bladder leak and 3.1% reoperations rates were identified. In an average 5-68-month follow-up, overall morbidity, overall mortality and recurrences rates recorded were 8-49%, 0-63% and 1.2%, respectively. CONCLUSIONS: CVF mainly affects males and has diverticular origin in almost all cases. Pneumaturia, fecaluria and urinary tract infections are the most characteristic symptoms. Endoscopic tests and imaging are critical tools for diagnostic completion. Management of CVFs depends on the underlying disease. Surgical treatment represents the final approach and consists of resection and reanastomosis of offending intestinal segment, with or without bladder closure. In many cases, a single-stage surgical strategy is selected. Perioperative and long-term outcomes prove good.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic-Pathologic Correlations.

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic-pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables.

Immunotherapy targeting the PD-1-PD-L1 axis yielded good results in treating different immunologically ''hot'' tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11-41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in <200 cases. The PD-L1 positivity rate was usually higher in tumors than benign tissues. It was higher in non-tissue microarray specimens (41-50% vs. 15%), as PC cells frequently showed heterogenous or focal PD-L1-staining. PD-L1 was expressed by immune or stromal cells in 12% and 69% cases, respectively. Tumor heterogeneity, inter-institutional preanalytics, and inter-observer interpretation variability may account for result biases.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 4: Experimental Treatments in Pre-Clinical Studies (Cell Lines and Mouse Models).

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1.

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment.

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-ß, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

Toxoplasma cyst detection in Piringer-Kuchinka lymphadenitis. Report of two cases and literature review.

The diagnosis of acute toxoplasmic lymphadenitis is traditionally based on the combination of lymph node excisional biopsy with specific tests. The classic triad (marked follicular hyperplasia, small irregular clusters of epithelioid histiocytes in germinal centers, and sinusoidal distension by monocytoid B lymphocytes) is considered diagnostic of the so-called Piringer-Kuchinka lymphadenitis. Toxoplasma gondii organisms have been exceptionally disclosed in such histopathological setting, establishing the diagnosis of toxoplasmic lymphadenitis. Two cases of Piringer-Kuchinka lymphadenitis with toxoplasma cyst demonstration are reported, along with a complete review of the literature.

Laparoscopic Partial Splenectomy: A Critical Appraisal of an Emerging Technique. A Review of the First 457 Published Cases.

Background: Laparoscopic partial splenectomy (LPS) may allow avoiding total splenectomy (TS) complications and maximizing the advantages of mini-invasive approach. The objective of this review is to assess feasibility and safety of LPS, to compare this approach with alternative options. Materials and Methods: A literature review of articles reporting LPS is performed. Several parameters, including age, indication, surgical technique, devices used for splenic section/hemostasis, adverse outcomes, including morbidity/mortality, conversions to open surgery, conversions to TS, operative time (OT), and hospital stay (HS), are analyzed. Articles comparing LPS' results with those of open partial splenectomy and laparoscopic TS are also analyzed. Results: Fifty-nine articles reporting 457 LPS were included. Patients' characteristics varied widely, concerning age and indications, including hematological disease (hereditary spherocytosis, drepanocytosis), splenic focal masses, and trauma. Several technical options are reported. Mean OT and HS are 128 ± 43.7 minutes and 4.9 ± 3.8 days, respectively. No mortality and 5.7% morbidity are reported. Conversion rates to open surgery and to TS are 3.9% and 3.7%, respectively. Conclusions: In conclusion LPS is feasible and safe, with no mortality, low morbidity, and low conversion rates to laparotomy and to TS. LPS may be accomplished by various techniques and tools. Major complications are sporadically reported, thus potential risks should not be underestimated.

Damage control surgery for the treatment of perforated acute colonic diverticulitis: A systematic review.

BACKGROUND: Acute colonic diverticulitis (ACD) complications arise in approximately 8% to 35% patients and the most common ones are represented by phlegmon or abscess, followed by perforation, peritonitis, obstruction, and fistula. In accordance with current guidelines, patients affected by generalized peritonitis should undergo emergency surgery. However, decisions on whether and when to operate ACD patients remain a substantially debated topic while algorithm for the best treatment has not yet been determined. Damage control surgery (DCS) represents a well-established method in treating critically ill patients with traumatic abdomen injuries. At present, such surgical approach is also finding application in non-traumatic emergencies such as perforated ACD. Thanks to a thorough systematic review of the literature, we aimed at achieving deeper knowledge of both indications and short- and long-term outcomes related to DCS in perforated ACD. METHODS: We performed a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines. Pubmed/MEDLINE, Embase, Scopus, Cochrane Library, and Web of Science databases were used to search all related literature. RESULTS: The 8 included articles covered an approximately 13 years study period (2006-2018), with a total 359 patient population. At presentation, most patients showed III and IV American Society of Anesthesiologists (ASA) score (81.6%) while having Hinchey III perforated ACD (69.9%). Most patients received a limited resection plus vacuum-assisted closure at first-look while about half entire population underwent primary resection anastomosis (PRA) at a second-look. Overall morbidity rate, 30-day mortality rate and overall mortality rate at follow-up were between 23% and 74%, 0% and 20%, 7% and 33%, respectively. Patients had a 100% definitive abdominal wall closure rate and a definitive stoma rate at follow-up ranging between 0% and 33%. CONCLUSION: DCS application to ACD patients seems to offer good outcomes with a lower percentage of patients with definitive ostomy, if compared to Hartmann's procedure. However, correct definition of DCS eligible patients is paramount in avoiding overtreatment. In accordance to 2016 WSES (World Society of Emergency Surgery) Guidelines, DCS remains an effective surgical strategy in critically ill patients affected by sepsis/septic shock and hemodynamical unstability.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract: a tricky diagnosis of a gastric case.

BACKGROUND: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is a rare low-grade clonal lymphoid proliferation, included as a provisional entity in the current World Health Organization classification. The disease is generally localized to the gastrointestinal tract, mainly small bowel and colon. Involvement of other organs is infrequently reported. The majority of patients show a protracted clinical course with persistent disease. A prolonged survival, even without treatment, is common. CASE PRESENTATION: A 28-year-old woman had a 2-year history of dyspepsia and lactose intolerance. Autoimmune diseases and celiac disease were excluded. No gross lesions were identified by endoscopy. Multiple gastric biopsies showed a small-sized lymphoid infiltrate, expanding the lamina propria, with a non-destructive appearance. The lymphoid cells were positive for CD3, CD4, CD5, CD7 and negative for CD20, CD8, CD56, CD103, PD1, CD30, ALK1, CD10, BCL6, perforin, TIA-1, Granzyme B and Epstein-Barr virus-encoded RNA. KI-67 index was low (5%). Molecular analysis revealed a clonal T-cell receptor γ rearrangement. Bone marrow was microscopically free of disease, but molecular testing identified the same T-cell receptor γ rearrangement present in the gastric biopsies. After the diagnosis of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, the patient received steroid therapy, only for 2 months. She is alive, with a stable disease restricted to the stomach, at 12 months from diagnosis. CONCLUSIONS: Indolent T-cell lymphoproliferative disorder is usually a disease of adulthood (median age: 51 yrs). The small bowel and colon are the sites most commonly involved. Our case occurred in a young woman and affected the stomach, sparing small intestine and colon. Clonality testing identified involvement of bone marrow, a site infrequently affected in this disease. Our aim is focusing on the main diagnostic issues. If appropriate immunostainings and molecular analysis are not performed, the subtle infiltrate may be easily overlooked. The risk of misdiagnosis as more aggressive lymphomas, causing patient overtreatment, needs also to be considered.

Acute Radiation Colitis after Preoperative Short-Course Radiotherapy for Rectal Cancer: A Morphological, Immunohistochemical and Genetic Study.

Preoperative radiotherapy is a widely accepted treatment procedure in rectal cancer. Radiation-induced changes in the tumor are well described, whereas less attention has been given to the non-neoplastic mucosa. Our aim is to provide a detailed analysis of the morphological features present in non-neoplastic mucosa that pathologists need to be familiar with, in order to avoid misdiagnosis, when evaluating rectal cancer specimens of patients preoperatively treated with radiotherapy, especially with short-course regimen. We compared 2 groups of 95 rectal cancer patients treated preoperatively with either short-course (45 patients) or long-course radiotherapy (50 patients). Depending on the type of protocol, different histopathological features, in terms of inflammation, glandular abnormalities and endocrine differentiation were seen in the non-neoplastic mucosa within the irradiated volume. Of note, features mimicking dysplasia, such as crypt distortion, nuclear and cytoplasmic atypia of glandular epithelium, were identified only in the short-course group. DNA mutation analysis, using a panel of 56 genes frequently mutated in cancer, and p53 immunostaining were performed on both tumor and radiation-damaged mucosa in a subset of short course cases. Somatic mutations were identified only in tumors, supporting the concept that tissues with radiation-induced "dysplastic-like" features are not genetically transformed. Pathologists should be aware of the characteristic morphological changes induced by radiation. The presence of features simulating dysplasia in the group treated with short-course radiotherapy may lead to serious diagnostic mistakes, if erroneously interpreted. Next generation sequencing (NGS) analysis further validated the morphological concept that radiation-induced abnormalities do not represent pre-neoplastic lesions.