CD39 is highly involved in mediating the suppression activity of tumor-infiltrating CD8+ T regulatory lymphocytes.

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (Treg). In this study, CD39 expression and function was analyzed in both CD8+ and CD4+CD25(hi) Treg from the peripheral blood of healthy donors as well as from tumor specimens. CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) Treg, and CD39 expression correlated with suppression activity mediated by CD8+ Treg. Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ Treg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function. Collectively, these findings, unveiling a new mechanism of action for CD8+ Treg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.

Alpha-fetoprotein has no prognostic role in small hepatocellular carcinoma identified during surveillance in compensated cirrhosis.

UNLABELLED: Alpha-fetoprotein is a tumor marker that has been used for surveillance and diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. The prognostic capability of this marker in patients with HCC has not been clearly defined. In this study our aim was to evaluate the prognostic usefulness of serum alpha-fetoprotein in patients with well-compensated cirrhosis, optimal performance status, and small HCC identified during periodic surveillance ultrasound who were treated with curative intent. Among the 3,027 patients included in the Italian Liver Cancer study group database, we selected 205 Child-Pugh class A and Eastern Cooperative Group Performance Status 0 patients with cirrhosis with a single HCC ≤ 3 cm of diameter diagnosed during surveillance who were treated with curative intent (hepatic resection, liver transplantation, percutaneous ethanol injection, radiofrequency thermal ablation). Patients were subdivided according to alpha-fetoprotein serum levels (i.e., normal ≤ 20 ng/mL; mildly elevated 21-200 ng/mL; markedly elevated >200 ng/mL). Patient survival, as assessed by the Kaplan-Meier method, was not significantly different among the three alpha-fetoprotein classes (P = 0.493). The same result was obtained in the subgroup of patients with a single HCC ≤ 2 cm (P = 0.714). An alpha-fetoprotein serum level of 100 ng/mL identified by receiver operating characteristic curve had inadequate accuracy (area under the curve = 0.536, 95% confidence interval = 0.465-0.606) to discriminate between survivors and deceased patients. CONCLUSION: Alpha-fetoprotein serum levels have no prognostic meaning in well-compensated cirrhosis patients with single, small HCC treated with curative intent.

CDKN2A is the main susceptibility gene in Italian pancreatic cancer families.

Background Most familial pancreatic cancer (FPC) remains unexplained. The identification of individuals with a high genetic risk of developing pancreatic adenocarcinoma (PC) is important to elucidate its biological basis and is critical to better define emerging strategies for the detection of early pancreatic neoplasms. Patients and methods A series of 225 consecutively enrolled patients with PC were tested for CDKN2A mutations. After personal and family cancer histories of all the patients had been reviewed, a subset of the patients were classified as FPC and were also tested for mutations in PALLD, PALB2, BRCA1 and BRCA2 as FPC candidate genes. Results The CDKN2A mutation rate in the 225 PC cases was 5.7%. The CDKN2A founder mutations, p.E27X and p.G101W, were predominant, but the mutation spectrum also included p.L65P, p.G67R and two novel, potentially pathogenic variants, promoter variant c.-201ACTC>CTTT and p.R144C. None of the patients with FPC harboured germline mutations in PALLD, PALB2 or BRCA2. One family was positive for the BRCA1 UV variant p.P727L. Strikingly, five of 16 patients with FPC (31%) carried CDKN2A mutations. Conclusion These findings suggest that a sizeable subset of Italian FPC families may carry CDKN2A mutations. This result may be of value for identifying the best candidates for future PC screening trials in Italy.

Completion thyroidectomy for differentiated thyroid cancer (results in a consecutive series of 68 patients).

INTRODUCTION: Completion thyroidectomy plays an important role in the management of patients with thyroid cancer. The aim of this study is to determine the indications for and timing of a second surgery, as well as surgical complications. MATERIAL AND METHODS: Operative reports, as well as the hospital and outpatient records of 686 consecutive patients, who had undergone surgery for differentiated thyroid cancer, were reviewed. Among these, 68 (9,9%) patient records of a completion thyroidectomy for cancer were analyzed. RESULTS: The mean time interval between the first and second operation was 3.6 months (range: 1-9). Post-operative complications occurred in 9 patients (12,9%). Among three patients with inferior laryngeal nerve palsy (4,4%) one had definitive palsy (1.4%). Hypoparathyroidism occurred in 6 patients (8,8%) being permanent in one of them (1.4%). No significant difference either for definitive inferior laryngeal nerve lesions (p = 0.9) or for definitive hypocalcemia (p = 1) was found between the groups of patients who had a completion thyroidectomy and those who had a one-step total thyroidectomy for cancer. CONCLUSIONS: Correct indications for re-operation, total lobectomy as a primary surgical procedure as well as lateral access to the residual thyroid gland could all reduce the high risks of complications related to this kind of surgery.

Viewpoint: Virtual and Augmented Reality in Basic and Advanced Life Support Training.

The use of augmented reality (AR) and virtual reality (VR) for life support training is increasing. These technologies provide an immersive experience that supports learning in a safe and controlled environment. This review focuses on the use of AR and VR for emergency care training for health care providers, medical students, and nonprofessionals. In particular, we analyzed (1) serious games, nonimmersive games, both single-player and multiplayer; (2) VR tools ranging from semi-immersive to immersive virtual and mixed reality; and (3) AR applications. All the toolkits have been investigated in terms of application goals (training, assessment, or both), simulated procedures, and skills. The main goal of this work is to summarize and organize the findings of studies coming from multiple research areas in order to make them accessible to all the professionals involved in medical simulation. The analysis of the state-of-the-art technologies reveals that tools and studies related to the multiplayer experience, haptic feedback, and evaluation of user's manual skills in the foregoing health care-related environments are still limited and require further investigation. Also, there is an additional need to conduct studies aimed at assessing whether AR/VR-based systems are superior or, at the minimum, comparable to traditional training methods.

Tako-tsubo cardiomyopathy as initial presentation of pheocromocytoma. A clinical case.

INTRODUCTION: Tako-tsubo cardiomyopathy is a rapidly reversible form of acute heart failure triggered by stressful events that occur more frequently in postmenopausal women. A central role is supposed to be played by catecholamines and the association with pheocromocytoma is rare. CASE PRESENTATION: We describe a patient admitted for abdominal pain and suffering of hypertension pharmacologically treated. During hospitalization the patient presented cephalea and precordial pain with nausea and profuse sweating. ECG showed ST elevation and deep negative T wave. Blood tests were moderately elevated. Echo-cardiography reported a left ventricular apex akynesia and hyperkynesia of the base while coronarography was negative. As hypertension persisted the suspicion of pheocromocytoma arose. Urinary and blood catecholamines were mildly elevated and echography and Magnetic Resonance revealed a left adrenal gland mass. The diagnosis of pheocromocytoma was thus confirmed Left laparoscopic adrenalectomy was performed after adequate stabilization and preoperative pharmacological preparation by hydration, a-and f-blockers. Intraoperatively blood pressure was controlled by nitroprussiate, rapid half life beta-blockers (esmolol cloridrate). Post-operative course was uneventful and arterial pressure returned to normal as well as catecholamines values. Patient was discharged on the 5th post-operative day Five months afterwards the patient had normal arterial pressure without anti-hypertensive therapy and symptom free. CONCLUSION: The case confirmed that tako-tsubo cardiomyopathy could be the first manifestation of tumors secreting catecholamines and that pheocromocytoma should be considered in patients with hypertension and acute stress-induced cardiomiopathy without evidence of acute coronary disease and with negative coronarography.

Pheochromocytoma during pregnancy treated by surgery. A case report and the review of the literature.

INTRODUCTION: Prenatal diagnosis of pheocromocytoma, although rare, is important as it allows a reduction in both maternal mortality and foetal loss. Pheocromocytoma operated on in the first trimester of pregnancy with survival of both patient and foetus is rare in literature. Our case was operated on with success after a correct and early diagnosis was obtained despite a chronic hypertension which existed long before pregnancy. Our case study well illustrates that a correct multidisciplinary approach involving endocrinologists, anesthesiologists, surgeons and gynecologists is fundamental for a positive outcome. CASE REPORT: The case of a white caucasian pregnant woman at 13th weeks of gestation with pheocromocytoma and severe and unstable hypertension that could not be pharmacologically controlled is described. Morphological diagnosis was safely obtained by Magnetic Resonance Imaging (MRI) without intravenous medium contrast agent. Pre-operative treatment consisted of therapy with alpha-blockers and rehydration. Adrenalectomy was performed through a laparotomy. Postoperative treatment consisted of rehydration and ephedrine continued until the fourth post-operative day. The post-operative period was uneventful and a new ultrasound (US) scan confirmed foetal vitality. The patient was discharged seven days after surgery. A live newborn was physiologically delivered after a nine-month pregnancy. CONCLUSION: A correct diagnosis in all pregnant women with severe hypertension particularly those not screened for secondary hypertension and a multidisciplinary management are mandatory to obtain optimal results and avoid deleterious effects at delivery.

Pre-surgery age-adjusted Charlson Comorbidity Index is associated with worse outcomes in acute cholecystitis.

BACKGROUND: Beneficial effects of cholecystectomy in acute cholecystitis (AC) might be weakened by complications. The age-adjusted Charlson Comorbidity Index (CCI) assesses disease relevance in the prediction of one-year mortality. AIMS: To evaluate whether age-adjusted CCI predicted complications (including surgical complications, intensive care unit [ICU] admission, and in-hospital death) among patients undergoing cholecystectomy for AC. Associations between age-adjusted CCI and the length of hospital stay have been also evaluated. METHODS: 271 patients were enrolled at Ospedale Policlinico San Martino (Genoa, Italy) between 2005 and 2013. Clinical data and blood samples were collected. RESULTS: Patients' median age was 67 years. They underwent more frequently video-laparoscopic cholecystectomy with a limited rate of conversion to open cholecystectomy. Surgical complications occurred in 23 patients (8.5%). 6 patients (2.2%) needed ICU admission, while death occurred in 4 patients (1.5%). According to the cut-off point identified by ROC curve, an age-adjusted CCI cut-off value of 5 was found predictive for in-hospital complications also when confounders were considered (OR 1.35, 95% CI 1.02-1.79, p = 0.035). No association between adjusted CCI and the length of hospital stay was found. CONCLUSIONS: In patients surgically treated for AC, age-adjusted CCI could represent an additional tool, along with available risk scores, to help surgeons in choosing the best therapeutic option.

Rectal hepatoid carcinoma with liver metastases in a patient affected by ulcerative colitis.

BACKGROUND: Hepatoid tumors (HTs) are rare extra-hepatic neoplasms with the histological features, biochemical profile and, sometimes, even clinical course of hepatocellular carcinoma. We present a case of rectal hepatoid adenocarcinoma with metachronous liver metastases. METHODS: Four months after total procto-colectomy for a rectal adenocarcinoma (Astler-Coller C2), a 42-year-old man with ulcerative colitis showed hypoechoic masses in the hepatic parenchyma by abdominal ultrasonography. Carcinoembryonic antigen was normal, but alpha-fetoprotein was 32,000 microg/L. Fine-needle biopsy revealed that liver masses were positive for hepatocellular carcinoma. The patient underwent left hepatectomy and alcoholisation of a small deep nodule in segment 8. RESULTS: Immunohistochemistry and albumin mRNA in situ hybridization suggested that the nodules were metastases of a HT. The patient was well during the first 6 months and refused any adjuvant chemotherapy. He died from liver failure 19 months after initial diagnosis. CONCLUSIONS: HT is a rare colon cancer. The preoperative diagnosis of this tumor requires a high degree of suspicion, the availability of a panel of immunohistochemical markers, and a certain amount of luck. The prognosis is poor despite an aggressive and multimodal therapeutic strategy. So far, none of the hypotheses proposed about the origin and the biology of these tumors is convincing.

Surgery to Treat Symptomatic Mobile Cecum Syndrome Is Safe and Associated with Good Recovery Outcomes.

The mobile cecum syndrome includes a spectrum of conditions. The cecal volvulus represents the acute form, with typical feature of a bowel obstruction that needs immediate operative treatment. On the other hand, a chronic form of mobile cecum syndrome which is the most common form reported a history of intermittent crampy abdominal pain, distension, and constipation. In this study, five patients came to our attention during the last ten years, presenting different symptoms due to a mobile cecum. All patients were investigated by several diagnostic techniques according to the specific clinical setting. All patients were found to have the cecum and ascending colon unattached to the posterior peritoneum. Surgery was the treatment of choice. In our experience, the best diagnostic technique was computed tomography scan, especially if performed in the Trendelenburg position. We also propose virtual colonoscopy as a good option for diagnosis (in patients with chronic syndrome) and follow-up after surgery. In conclusion, laparoscopic approach guaranteed a good result, with no symptoms of recurrence, in both acute and elective treatments. The diagnosis of mobile cecum needs a high index of suspicion and a targeted radiological investigation. Surgery, especially laparoscopic cecopexy and appendectomy, is the recommended treatment.

The bowel cleansing for colonoscopy. A randomized trial comparing three methods.

INTRODUCTION: Colonoscopy is the procedure of choice for the detection and ablation of small lesions o the colonic mucosa. A proper bowel cleansing is mandatory. So far several regimens have been proposed but rather none has shown a clear-cut advantage over the others. Aim of this study was to compare cleansing ability and patients' compliance of three oral regimens. PATIENTS AND METHODS: Two-hundred and seventy-three patients were block randomised into three groups. Group A (92 patients) received tablets containing senna 12 mg and Magnesium Sulphate 15 mg the day before colonoscopy. Group B (98 patients) received a Polyethylene Glycol-based solution of two litres plus 4 tablets of Bisacodyl the day before the exam. Group C (83 patients) received Sodium Phosphate 40 milliliters the day before and the day of colonoscopy. Results of 265 patients were available for the analysis. Eight patients were excluded because inability to follow prescription. The lower incidence of constipation in group C was not significant. The other parameters were homogeneously distributed in the three groups. RESULTS: The 79 patients of the group C achieved a better bowel cleansing as compared with the 90 of group A (p = 0.0003) and the 96 of group B (p = 0.034). Constipated patients had a significantly better cleansing with Sodium Phosphate preparation compared with senna plus Magnesium Sulphate (p = 0.017), but not significantly better compared with Golytely solution. Compliance and rate of total colonoscopy performed were not statistically different in the three groups. CONCLUSIONS: Sodium Phosphate solution gave better bowel preparation, with the same compliance, than either senna or Polyethylene solution. In constipated patients Sodium Phosphate showed good efficacy resulting in good cleansing rates similar to that of non-constipated patients. The poor results obtained by Polyethylene were related to the little amount of solution taken even if associated to Bisacodyl.

Pancreatic metastasis from mycosis fungoides mimicking primary pancreatic tumor.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that can undergo local progression with possible systemic dissemination. We report a case of a patient affected by MF with a pancreatic mass that was a diagnostic challenge between primitive tumor and pancreatic metastasis from MF. Clinical setting findings and imaging studies raised the suspicion of a pancreatic primary neoplasm. A diagnostic clue was provided by the combined histomorphologic/immunohistochemical study of pancreatic and cutaneous biopsies, which revealed a pancreatic localization of MF. Considering the rarity of metastatic localization of MF to the pancreas, we next investigated whether chemokine-chemokine receptor interactions could be involved in the phenomenon to provide new insight into the possible mechanisms underlying metastatic localization of MF to the pancreas. Histological analyses of archival pancreatic tissue demonstrated that glucagon-secreting cells of the pancreatic islets expressed the CCL27 chemokine, which may have attracted in our case metastatic MF cells expressing the complementary receptor CCR10.

Gastrointestinal stromal tumors: clinical pathological review of a personal series.

The Authors report their experience on the management of gastrointestinal stromal tumors (GISTs). In addition to recent cases immediately diagnosed as GISTs, a pathological review of stored material from non-epithelial tumors of the gastrointestinal tract operated on over the past 20 years was performed. Twenty-three out of a total of 31 cases were shown to be positive for the immunophenotypic characteristics (CD117/CD34) of GISTs. Most cases (approximately 60%) were symptomatic, with hemorrhage being the most common presenting sign, followed by occlusion, pain and perforation. Asymptomatic cases were detected incidentally during procedures for other conditions. Diagnostic techniques (ultrasound, endoscopy, endoscopic ultrasound, X-ray, CT, MRI) allowed only the detection of wall (extraluminal) involvement. Apart from differentiating between benign and malignant, preoperative biopsy was seldom valuable. All cases were treated surgically, with intervention tailored to location and anatomical/surgical and anatomical/pathological features. Long-term follow-up was conducted in all patients and for most is still ongoing: five patients died from recurrent disease at varying intervals after surgery (from 17 to 102 months). Relationships between observed aggressiveness and risk were studied. Parameters that may prove useful for the early detection and appropriate management of these lesions are discussed.

Metastases to the thyroid gland from renal cancer.

AIMS AND BACKGROUND: Metastases to the thyroid gland from renal cancer pose a challenge to physicians, due in part to the rarity of the phenomenon, the prolonged time interval between removal of the primary renal cancer and the appearance of metastases, the difficulty in diagnosis, and the uncertainty regarding long-term prognosis. We report our experience with diagnosis and management of patients affected by thyroid metastases from renal clear cell carcinoma. STUDY DESIGN: We report herein three clinical cases of thyroid metastases from renal clear cell carcinoma. We also present a review of the literature and examine common features of clinical presentation and management recommendations. RESULTS: Over the past 17 years, 918 patients underewent surgery for thyroid cancer in our institution. Histological examination demonstrated a thyroid secondary malignancy from kidney cancer in 3 cases. Two patients underwent total thyroidectomy, whereas in the third patient a palliative right lobectomy with homolateral latero-cervical lymphoadenectomy was performed. At a 5-year follow-up, only one patient survived and was disease-free. CONCLUSIONS: Thyroid metastases from renal clear cell carcinoma are a rare occurrence but should be taken into consideration in the differential diagnosis of a thyroid nodule. Preoperative diagnosis is often difficult. Nevertheless, an extensive diagnostic workup is recommended because the subsequent therapy must be tailored on the basis of the local extension of metastases. Surgical treatment of solitary thyroid metastases is recommended. However, patients with disseminated disease have a poor prognosis, and palliative care is the indicated recommendation. In these patients and in surgically untreatable patients, prolonged survival may be achieved by adjuvant medical therapy.

Immunosuppressive cells and tumour microenvironment: focus on mesenchymal stem cells and myeloid derived suppressor cells.

Tumours have been compared to unhealed wounds that produce large amounts of inflammatory mediators, including cytokines, chemokines, and growth factors. These molecules participate in the formation of a rich and heterogeneous microenvironment by attracting non malignant cells that promote tumour progression and dissemination. Tumour infiltrating cells include macrophages, myeloid-derived suppressor cells (MDSCs), mesenchymal stromal cells (MSCs) and TIE2-expressing monocytes. Most of them are bone marrow-derived, although MSC are present in virtually every tissue. This review focuses on MDSCs and MSCs, both of which can exert pro-tumorigenic effects through negative regulation of immune responses. MDSCs represent a heterogeneous population of cells of myeloid origin that are expanded and activated in response to growth factors and cytokines released by tumours. Once MDSCs are activated, they accumulate in lymphoid organs and tumours where they exert T cell immunosuppression. Like MDSCs, MSCs can be mobilized from the bone marrow into the bloodstream and home in the tumour stroma, where they either help or hinder tumour growth. Here, we will discuss the origin, the functions and the mechanisms of action of MSCs and MDSCs, as well as the strategies to target these cells for the therapeutic benefit of cancer patients.

Cytokines in neuroblastoma: from pathogenesis to treatment.

Cytokines released by cancer cells or by cells of the tumor microenvironment stimulate angiogenesis, act as autocrine or paracrine growth factors for malignant cells, promote tumor cell migration and metastasis or create an immunosuppressive microenvironment. These tumor-promoting effects of cytokines also apply to neuroblastoma (NB), a pediatric neuroectodermal malignancy with frequent metastatic presentation at diagnosis and poor prognosis. IL-6 and VEGF are the best characterized cytokines that stimulated tumor growth and metastasis, while others such as IFN-γ can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis. On the other hand, cytokines are part of the anti-NB therapeutic armamentarium, as exemplified by IL-2 and granulocyte-macrophage colony stimulating factor that potentiate the activity of anti-NB antibodies. These recent results raise hope for more efficacious treatment of this ominous pediatric malignancy.

Anal metastasis from recurrent breast lobular carcinoma: a case report.

We report a case of isolated gastrointestinal metastasis from breast lobular carcinoma, which mimicked primary anal cancer. In July 2000, an 88-year-old woman presented with infiltrating lobular cancer (pT1/G2/N2). The patient received postoperative radiotherapy and hormonal therapy. Four years later, she presented with an anal polypoid lesion. The mass was removed for biopsy. Immunohistochemical staining suggested a breast origin. Radiotherapy was chosen for this patient, which resulted in complete regression of the lesion. The patient died 3 years after the first manifestation of gastrointestinal metastasis. According to the current literature, we consider the immunohistochemistry features that are essential to support the suspicion of gastrointestinal breast metastasis, and since we consider the gastrointestinal involvement as a sign of systemic disease, the therapy should be less aggressive and systemic.

Intestinal radiation-induced stricture favours small bowel obstruction by phytobezoar: report of a case.

Bezoars represent the fifth most frequent cause of acute small bowel obstruction. Phytobezoar is the most common type of bezoar. It is a concretion of undigestible fibers derived from ingested vegetables and fruits. We report a case of a woman with a 1-year history of recurrent epigastric and periumbilical abdominal pain with intermittent vomiting caused by phytobezoar of the terminal ileum. After careful investigation of the case and review of literature, we identified the factor involved in bezoar formation as radiation-induced ileal stenosis due to previous treatment for a pelvic tumour. This report provides evidence to consider phytobezoar as a possible cause of small bowel obstruction in patients previously treated with abdominal radiotherapy.