Paving the Path for Immune Enhancing Nutrition in Colon Cancer: Modulation of Tumor Microenvironment and Optimization of Outcomes and Costs.

INTRODUCTION: Published evidence suggests that immunonutrition has the potential to decrease postoperative complications and reduce length of stay in patients undergoing surgery for colorectal cancer. However, only a few studies have analyzed the effects of immunonutrition on tumor microenvironment and evaluated its prognostic impact. MATERIAL AND METHODS: This is a single center retrospective study enrolling 50 patients undergoing elective surgery for colorectal cancer managed with immunonutrition and 50 patients managed with standard nutrition for comparison. Tumor microenvironment was analyzed before (on the biopsy at the time of diagnosis) and after (on the matched surgical specimen) administration of immunonutrition. Immune function related indicators, including cytotoxic T-lymphocytes, helper T-cells, antigen presenting cells, natural killer cells, T-exhausted lymphocytes, T-regulatory cells, M1 and M2 tumor associated macrophages and PD-L1 expression were assessed by immunohistochemistry. For both groups, clinicopathological data were collected and a 5-year follow-up was available. RESULTS: We found that immunonutrition significantly activated the T-cell response against cancer, alter tumor microenvironment phenotype towards M2 polarization and inhibits the PD1/PD-L1 axis. A lower rate of postoperative complications and a shorter length of stay (p = 0.04) were observed in the immune nutrition group. Compared to standard nutrition group, patients managed wit immune nutrition showed a higher 5-year overall survival (p = 0.001). Finally, immune nutrition allowed to reduce the hospital care costs. CONCLUSIONS: Immunonutrition modulates tumor microenvironment by improving immune function and could prolong survival in patients undergoing elective surgery for colorectal cancer. Further studies are needed to optimize IN protocols and confirm their prognostic impact.

Neoadjuvant Treatment in Muscle-Invasive Bladder Cancer: From the Beginning to the Latest Developments.

Urothelial carcinoma of the bladder is one of the most prevalent cancers worldwide, diagnosed as muscle invasive in 25% of cases. Although several studies have demonstrated an overall 5% absolute survival benefit at 5 years with cisplatin-based combination neoadjuvant treatment, administration of chemotherapy prior to radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC) patients is still a matter of debate. This may be due to the perceived modest survival benefit, cisplatin-based chemotherapy ineligibility, or fear of delaying potentially curative surgery in non-responders. However, immunotherapy and novel targeted therapies have shown to prolong survival in advanced disease and are under investigation in the neoadjuvant and adjuvant settings to reduce systemic relapse and improve cure rates. Genomic characterization of MIBC could help select the most effective chemotherapeutic regimen for the individual patient. Large cohort studies on neoadjuvant treatments with immune checkpoint inhibitors (ICIs) and molecular therapies, alone or combined with chemotherapy, are ongoing. In this review, we trace the development of neoadjuvant therapy in MIBC and explore recent advances that may soon change clinical practice.

Histopathology and Molecular Genetics in Systemic Mastocytosis: Implications for Clinical Management.

The diagnosis of systemic mastocytosis (SM) is based on various clinical, dermatological, serological, and hematological findings but essentially relies on histological evidence of an abnormal increase in tissue-localized mast cells (MCs). The extra-cutaneous organ most frequently affected is the bone marrow (BM), and therefore, histological examination of trephine biopsy specimens of the iliac crest is mandatory on suspicion of SM. At microscopic examination, neoplastic MCs show aberrant morphology, usually with prominent spindling. Immunohistochemistry is a useful tool in the diagnosis of SM because mast cell (MC) infiltrates may be slight and scarce, in a mixed background of lymphohistiocytic cells, eosinophils, and plasma cells. Moreover, neoplastic MCs exhibit an aberrant phenotype. Recent evidence, largely derived from molecular genetics, has enhanced the diagnostic capability of SM, also providing the basis for adequate prognostic and therapeutic evaluation. The cases herein reported illustrate the variable clinical manifestations and disease course of SM, focusing on diagnostic and therapeutic challenges. In accordance with the World Health Organization (WHO) classification and the International Consensus Classification (ICC) systems, our findings emphasize the importance of an integrated diagnostic approach for SM, with proper application of diverse assessment methodologies in order to improve SM classification and treatment effectiveness.

Peripancreatic paraganglioma: Lesson from a round table.

We described the case of a peripancreatic paraganglioma (PGL) misdiagnosed as pancreatic lesion. Surgical exploration revealed an unremarkable pancreas and a large well-defined cystic mass originating at the mesocolon root. Radical enucleation of the mass was performed, preserving the pancreatic tail. Histologically, a diagnosis of PGL was rendered. Interestingly, two previously unreported mutations, one affecting the KDR gene in exon 7 and another on the JAK3 gene in exon 4 were detected. Both mutations are known to be pathogenetic. Imaging and cytologic findings were blindly reviewed by an expert panel of clinicians, radiologists, and pathologists to identify possible causes of the misdiagnosis. The major issue was lack of evidence of a cleavage plane from the pancreas at imaging, which prompted radiologists to establish an intra-parenchymal origin. The blinded revision shifted the diagnosis towards an extra-pancreatic lesion, as the pancreatic parenchyma showed no structural alterations and no dislocation of the Wirsung duct. Ex post, the identified biases were the emergency setting of the radiologic examination and the very thin mesocolon sheet, which hindered clear definition of the lesion borders. Original endoscopic ultrasonography diagnosis was confirmed, emphasizing the intrinsic limit of this technique in detecting large masses. Finally, pathologic review favored a diagnosis of PGL due to the morphological features and immonohistochemical profile. Eighteen months after tumor excision, the patient is asymptomatic with no disease relapse evident by either radiology or laboratory tests. Our report strongly highlights the difficulties in rendering an accurate pre-operative diagnosis of PGL.

Surgery for ulcerative colitis complicated with colorectal cancer: when ileal pouch-anal anastomosis is the right choice.

Patients with ulcerative colitis (UC) are at risk of developing a colorectal cancer. The aim of this study was to examine our experience in the treatment of ulcerative Colitis Cancer (CC), the role of the ileal pouch-anal anastomosis (IPAA), and the clinical outcome of the operated patients. Data from 417 patients operated on for ulcerative colitis were reviewed. Fifty-two (12%) were found to have carcinoma of the colon (n = 43) or the rectum (n = 9). The indication to surgery, the histopathological type, the cancer stage, the type of surgery, the oncologic outcome, and the functional result of IPAA were examined. The majority of the patients had a mucinous or signet-ring carcinoma. An advanced stage (III or IV) was present in 28% of the patients. Early (stage I or II) CC was found in all except one patient submitted to surgery for high-grade dysplasia, low-grade dysplasia, or refractory colitis. Thirty-nine (75%) of the 52 patients underwent IPAA, 10 patients were treated with a total abdominal proctocolectomy with terminal ileostomy. IPAA was possible in 6/9 rectal CC. Cumulative survival rate 5 and 10 years after surgery was 61% and 53%, respectively. The survival rate was significantly lower for mucinous or signet-ring carcinomas than for other adenocarcinoma. No significant differences of the functional results and quality of life were observed between IPAA patients aged less than or more than 65 years. Failure of the pouch occurred in 5 of 39 (12.8%) patients for cancer of the pouch (2 pts) or for tumoral recurrence at the pelvic or peritoneal level. Early surgery must be considered every time dysplasia is discovered in patients affected by UC. The advanced tumoral stage and the mucous or signet-ring hystotype influence negatively the response to therapy and the survival after surgery. IPAA can be proposed in the majority of the patients with a functional result similar to that of UC patients not affected by CC. Failures of IPAA for peritoneal recurrence or metachronous cancer of the pouch can be observed when CC is advanced, moucinous, localized in the distal rectum, or is associated with primary sclerosing cholangitis.

Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives.

Calcific Aortic Valve Disease (CAVD) is the most common valvular heart disease in developed countries and in the ageing population. It is strongly correlated to median age, affecting up to 13% of the population over the age of 65. Pathophysiological analysis indicates CAVD as a result of an active and degenerative disease, starting with sclerosis and chronic inflammation and then leaflet calcification, which ultimately can account for aortic stenosis. Although CAVD has been firstly recognized as a passive event mostly resulting from a degenerative aging process, much evidences suggests that calcification arises from different active processes, involving both aortic valve-resident cells (valve endothelial cells, valve interstitial cells, mesenchymal stem cells, innate immunity cells) and circulating cells (circulating mesenchymal cells, immunity cells). Moreover, a role for the cell-derived "matrix vesicles" and extracellular matrix (ECM) components has also been recognized. The aim of this work is to review the cellular and molecular alterations occurring in aortic valve during CAVD pathogenesis, focusing on the role of ECM in the natural course of the disease.

Empagliflozin prevents doxorubicin-induced myocardial dysfunction.

BACKGROUND: Empagliflozin showed efficacy in controlling glycaemia, leading to reductions in HbA1c levels, weight loss and blood pressure, compared to standard treatment. Moreover, the EMPA-REG OUTCOME trial demonstrated a 14% reduction of major adverse cardiovascular events (MACE), a 38% reduction in cardiovascular (CV) death and a 35% reduction in the hospitalization rate for heart failure (HF). These beneficial effect on HF were apparently independent from glucose control. However, no mechanistic in vivo studies are available to explain these results, yet. We aimed to determine the effect of empagliflozin on left ventricular (LV) function in a mouse model of doxorubicin-induced cardiomyopathy (DOX-HF). METHODS: Male C57Bl/6 mice were randomly assigned to the following groups: controls (CTRL, n = 7), doxorubicin (DOX, n = 14), DOX plus empagliflozin (DOX + EMPA, n = 14), or DOX plus furosemide (DOX + FURO group, n = 7). DOX was injected intraperitoneally. LV function was evaluated at baseline and after 6 weeks of treatment using high-resolution echocardiography with 2D speckle tracking (Vevo 2100). Histological assessment was obtained using Haematoxylin and Eosin and Masson's Goldner staining. RESULTS: A significant decrease in both systolic and diastolic LV function was observed after 6 weeks of treatment with doxorubicin. EF dropped by 32% (p = 0.002), while the LS was reduced by 42% (p < 0.001) and the CS by 50% (p < 0.001). However, LV function was significantly better in the DOX + EMPA group, both in terms of EF (61.30 ± 11% vs. 49.24 ± 8%, p = 0.007), LS (- 17.52 ± 3% vs. - 13.93 ± 5%, p = 0.04) and CS (- 25.75 ± 6% vs. - 15.91 ± 6%, p < 0.001). Those results were not duplicated in the DOX + FURO group. Hearts from the DOX + EMPA group showed a 50% lower degree of myocardial fibrosis, compared to DOX mice (p = 0.03). No significant differences were found between the DOX + FURO and the DOX group (p = 0.103). CONCLUSION: Empagliflozin attenuates the cardiotoxic effects exerted by doxorubicin on LV function and remodelling in nondiabetic mice, independently of glycaemic control. These findings support the design of clinical studies to assess their relevance in a clinical setting.

Environment and urinary bladder cancer. A historical perspective.

Our understanding of aetiological factors associated with urinary bladder cancer has radically improved over the last decades. Cigarette smoking is considered the most important risk factor, even in the industrialised world, while various occupational and environmental exposures to chemicals are also held responsible. The link between bladder cancer and schistosomiasis, highly prevalent in sub-Saharan Africa, Sudan, Egypt, and Yemen, provides input for investigating and potentially preventing bladder carcinogenesis. Growing concern regarding environmental diseases prompts investigation into the historical milestones that have helped disentangle the relationships between health and environment.

Identification of mesothelial cells in intraoperative blood salvage.

Intraoperative auto-transfusion with the use of cell saver systems is routinely used to reduce the rate of packed red blood transfusion in major surgery. Nevertheless some concerns have been raised on possible risks of coagulation disorders. The aim of the study was to analyze the blood processed by the cell saver, ready to be re-infused to the patient, in order to individuate unexpected cellular components, that can favor coagulopathy. We tested the blood processed by the cell saver in thirteen patients undergoing coronary bypass surgery with Cellsearch®, ScreenCell®, Cytology and Immunofluorescence. Those four methods allowed us to look for the presence of unexpected cells, quantify and characterize them. Furthermore, the blood processed by the cell saver was mixed with the patient's peripheral blood and analyzed with the ROTEM® thromboelastography. The Cellsearch® revealed and counted a mean number of 1241 unexpected cells/7.5 ml in the blood processed by the cell saver. The ScreenCell® and Cytology confirmed the presence of non-hematological cells. Immunofluorescence showed positivity for Calretinin and WT-1, confirming the mesothelial origin. Moreover we detected a peculiar arrangement of the platelets around the mesothelial cells in a "cloud" form, suggesting platelet activation. The ROTEM® analysis showed a significantly longer clot formation time, smaller clot amplitude and maximum clot firmness, compared to controls. In conclusion we demonstrated the presence of mesothelial cells in the cell saving blood, ready to be auto-transfused. This finding can contribute to develop a platelet depletion coagulopathy, with coagulation factors consumption.

Snail immunohistochemical overexpression correlates to recurrence risk in non-muscle invasive bladder cancer: results from a longitudinal cohort study.

The current WHO/ISUP classification and grading system subdivides urothelial tumours into prognostically distinct categories. Understanding the molecular pathways involved in bladder cancer development can improve patient stratification and management. This study aims to investigate the relationship between Snail, Slug and E-cadherin expressions and clinico-pathological features of non-muscle invasive bladder carcinoma (NMIBC). All patients attending the same urological centre from January to May 2002, who were pathologically diagnosed with NMIBC, were enrolled in this longitudinal cohort study. E-cadherin, Snail and Slug protein expressions were assessed by immunohistochemical analysis and compared with follow-up data. The main outcome measures were recurrence and progression rates. The cohort under investigation included 43 patients (38 men and 5 women, mean age 67.7 ± 10.6 years). High-grade (HG) carcinomas were 20/43, with 10 invasive cases (pT1). Low-grade (LG) carcinomas were 23/43, with no invasive cases (pTa). Among the eight HGpTa cases with recurrence, strong Snail expression was detected in six (75%). Out of the 17 LGpTa patients who experienced recurrence, 12 (70.6%) showed strong positivity for Snail. Among the 10 HGpT1 cases, recurrence was observed in 4, of which, 3 (75%) stained intensely for Snail. The Kaplan-Meier curves showed significantly different recurrence rates for patients with strong or weak Snail reactivity (p = 0.027). E-cadherin and Slug expression did not correlate with any of the parameters considered. On multivariate analysis, Snail expression was recognised as an independent prognostic factor for tumour recurrence (p = 0.003). In our study population, Snail immunohistochemical overexpression proved to be related to tumour recurrence in patients affected by NMIBC.

Cystic parathyroid glands in MEN1: A rare entity?

Approximately 300 cases of sporadic parathyroid cyst (PCs) have been reported to date. Only two cases have been described in MEN1 so far. Detection by imaging could be challenging, especially in multiglandular primary hyperparathyroidism (HPT) and clinical outcome could be different. During the period 1990-2014, 71 MEN1 patients were operated for primary hyperparathyroidism in our centre. We report three cases of PCs in MEN1 patients affected by HPT, who underwent a total or subtotal parathyroidectomy with transcervical thymectomy. In our series, all three patients had an unsatisfactory postoperative course, at variance with the high percentage (over 90 %) of long-term success in MEN1 patients operated at our centre. One patient affected by cystic degeneration of all the four parathyroid glands reported persistent hypoparathyroidism, despite autografts of parathyroid tissue. For the other two cases, surgery failed to cure hyperparathyroidism, perhaps because of the presence of undetected ectopic parathyroid tissue. In the context of a multiglandular disease such as MEN1 syndrome, PCs seem rare but our experience shows about a 4 % incidence. Furthermore their presence, even in expert hands, could affect the preoperative identification of the parathyroid glands due to the difficult differential diagnosis between PC and other cystic lesions of the neck, and intraoperative detection of the glands as well as the postoperative outcome.

Cellular signaling pathway alterations and potential targeted therapies for medullary thyroid carcinoma.

Parafollicular C-cell-derived medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular therapies that inhibit rearranged during transfection (RET) and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR) cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.

Expression of BMI1 and p16 in laryngeal squamous cell carcinoma.

BACKGROUND: The clinical evolution of laryngeal squamous cell carcinoma (SCC) is undetectable with the current staging criteria. To more completely understand the biology of laryngeal SCC, we assessed the expression of the proteins B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and p16. METHODS: We assessed immunohistochemically the expression of BMI1 and p16 in 25 laryngeal SCCs at different stages. RESULTS: High BMI1 expression was detected in 11.7% of glottic tumors and in 50% of supraglottic tumors. No significant differences were observed in the patients' clinical data after they were stratified by the tumor expression of p16. The expression of nuclear BMI1 in the absence of p16 immunoreactivity correlated significantly with the pN status of the primary tumors. CONCLUSION: Nuclear BMI1 expression in the absence of p16 expression seems to characterize a subset of patients with a high risk of developing lymph node metastasis.

Tryptase-positive mast cells and angiogenesis in keloids: a new possible post-surgical target for prevention.

Literature data indicate that mast cells (MCs) are involved in angiogenesis through the release of several pro-angiogenetic factors among which tryptase, a serine protease stored in MC granules, is one of the most active. However, no data are available concerning the role of MCs during keloids' angiogenesis. In this study, we evaluated the correlations of the number of MCs positive to tryptase (MCDPT) and microvascular density (MVD) within a series of 15 keloids and 10 normotrophic scars, by means of immunohistochemistry and image analysis methods. Data demonstrated a significant difference of MVD and MCDPT between keloids and normotrophic scars and a significant correlation between MVD and MCDPT in keloids. Our results suggest that tryptase-positive MCs might play a key role in keloids' angiogenesis. In this context, several tryptase inhibitors might be clinically evaluated as a possible new anti-angiogenetic approach to prevent keloid formation after surgery.

Multiple abscesses of the left brain hemisphere due to Listeria monocytogenes in an immunocompromised patient: a case report.

We describe a case of brain abscesses in a cirrhotic and diabetic 57-year-old woman showing fever, aphasia, right hemiparesis and seizures. Neuroradiological investigation revealed unilateral cerebritis evolving in multiple abscesses. From blood and surgical drainage samples Listeria monocytogenes grew in pure culture. Despite decompressive craniotomy, the patient died two months after hospital admission.

New evidence for a critical role of elastin in calcification of native heart valves: immunohistochemical and ultrastructural study with literature review.

AIMS: Calcific aortic stenosis is a progressive disease characterized by massive fibrosis andmineralization of the valve leaflets. The aim of this study was to determine whether the onset of native calcific aortic stenosis is associated primarily with matrix remodelling events, and particularly with elastin degradation. METHODS AND RESULTS: The immunohistochemical expression profile of matrix degradating enzymes and tenascin-C was investigated in both healthy and native calcified aortic valves. Collagen and elastic tissue were studied by light microscopy and electron microscopy. Immunophenotypic analysis of inflammatory cells was carried out by using monoclonal antibodies to macrophages, T and B lymphocytes. Immunoreactivity for tenascin-C and matrix metalloproteinase-12 (MMP-12) was associated with areas of dense mineralization, which were characterized by fibrosis, fragmentation and calcification of elastic fibres a positive reaction was also found around small islands of calcification. MMP-11 was not detected in the diseased valves. Osteopontin and osteonectin were also found at sites of mineralization. All calcified valves examined showed inflammatory cell infiltration. CONCLUSIONS: Our results demonstrate the direct involvement of MMP-12 in native aortic valve stenosis. MMP-mediated degradation of elastic fibres might contribute actively to valve mineralization by inducing calcium deposition onto fragmented elastin.