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Hereditary breast and ovarian cancer syndrome is caused by germline mutations in BRCA1/2 genes. These genes are very large and their mutations are heterogeneous and scattered throughout the coding sequence. In addition to the above-mentioned mutations, variants of uncertain/unknown significance (VUSs) have been identified in BRCA genes, which make more difficult the clinical management of the patient and risk assessment. In the last decades, several laboratories have developed different databases that contain more than 2000 variants for the two genes and integrated strategies which include multifactorial prediction models based on direct and indirect genetic evidence, to classify the VUSs and attribute them a clinical significance associated with a deleterious, high/low or neutral risk. This review provides a comprehensive overview of literature studies concerning the VUSs, in order to assess their impact on the population and provide new insight useful for the appropriate patient management in clinical practice.

Objective: An early diagnosis of pulmonary embolism (PE) improves outcome. Therefore, PE should be diagnosed in Emergency Care Units (ECU) at admission. Clinical algorithms support the clinician in this task, although performance is biased by differences in risk factors prevalent in different populations. The clinical conditions predictive of PE were evaluated in subjects from Southern Italy accessing ECU for dyspnea/chest pain.Methods: Retrospective clinical data were obtained by electronic retrieving from a hospital database. Data from 8177 patients (age 18-90 years, 54 with PE) were collected from years 2007-2013.Results: Previous history of PE, thrombosis and/or phlebitis, rheumatic diseases, respiratory failure, low blood pressure, pulse oxymetry rate (SpO2) and high heart rate were associated with PE diagnosis. High white blood count with neutrophilia, C reactive protein, D-dimer, NT-pro-BNP determinations, but not troponin T, were associated with PE. Recalibration of the GENEVA score and its modification, by inclusion of novel risk factors, improved the algorithm performance (GENEVA AROC=0.730, modified GENEVA AROC = 0.792, DeLong's test p=

The prognostic value of sentinel lymph node micrometastases in invasive breast cancer patients is still widely debated. Even if, in the absence of unequivocal guidelines, the axillary lynphadenectomy is not still performed in the routine clinical care of these patients.We have retrospectively analyzed 746 patients with operable invasive breast cancer and clinically negative axillary lymph nodes. These patients underwent conservative surgery or total mastectomy with sentinel lymph node biopsy. Patients with micrometastases in the sentinel lymph node treated with axillary dissection has been checked and the involvement of the remaining lymph nodes analyzed. Patients with micrometastases in the SLN not followed by axillary dissection have been checked as well and the incidence of recurrences has been evaluated in both groups.Micrometastases were found in 51 (6.83%) patients and isolated tumor cells in 8 (1.07%) patients at frozen section and confirmed at the final hystopathologic examination. Fifteen of these patients underwent complete axillary dissection: two of them (13.33%) had metastatic involvement of other axillary lymph nodes. The other 44 patients didn't receive further surgical axillary procedure. No axillary recurrences in these patients were found during a median follow up of 65.3±9.65 months (range 42-78 months).Based on the results and according to some recent randomized trials we can say that axillary lynphadenectomy can be avoided when micrometastases are found in sentinel lynph nodes. It should be performed anyway, depending on the analysis of the biomedical profile of the tumor.Breast carcinoma, Micrometases, Sentinel lymph node.Il significato prognostico delle micrometastasi nel linfonodo sentinella nelle pazienti affette da carcinoma della mammella è ancora ampiamente dibattuto. Anche se, in assenza di univoche linee guida, nella pratica clinica la linfadenectomia ascellare in queste pazienti non viene più eseguita di routine. Abbiamo condotto uno studio retrospettivo su 746 patienti affette da carcinoma invasivo della mammella con linfonodi ascellari negativi, sottoposte a chirurgia conservativa o a mastectomia totale con biopsia del linfonodo sentinella. Le pazienti in cui è stata diagnostica la presenza di micrometastasi del linfonodo sentinella sono state considerate in due diversi gruppi. In un primo gruppo, trattato con linfadenectomia ascellare totale è stata valutata l’incidenza di metastasi a carico dei rimanenti linfonodi ascellari. Un secondo gruppo non ha ricevuto alcun trattamento aggiuntivo dell’ascella e le pazienti sono state seguite con controlli periodici clinico strumentali. In entrambi i gruppi è stata valutata l’incidenza di eventuali recidive ascellari. All’esame istologico estemporaneo ed al successivo esame istologico definitivo del linfonodo sentinella, in 51 pazienti (6,83%) sono state evidenziate micrometastasi, in 8 pazienti (1,07%) erano presenti cellule tumorali isolate. Quindici di queste pazienti sono state sottoposte a linfadenectomia ascellare totale. Solo in 2 casi (13,33%) sono state ritrovate metastasi a carico dei rimanenti linfonodi ascellari. Quarantaquattro pazienti non hanno ricevuto alcun trattamento aggiuntivo dell’ascella. In queste pazienti nessuna recidiva ascellare è stata registrata durante un follow-up medio di 65,3±9,65 mesi (range 42-78 mesi). Sulla base dei risultati ottenuti in questo studio ed in linea con alcuni recenti trials randomizzati si ci sentiamo di concludere che la linfadenectomia ascellare può essere evitata nei casi con micrometastasi nel linfonodo sentinella. Una sua eventuale indicazione può essere valutata caso per caso considerando come fattori di rischio per la recidiva ascellare alcune caratteristiche biomorfologiche del tumore primitivo.

In recent years digital videofluorography (VFG) with water siphon test (WST) has been proposed just for diagnosing hiatal hernia and/or gastroesophageal reflux. PATIENTS AND METHODS: Fifteen patients undergone Laparoscopic Nissen (LN) for complicated GERD associated to hiatal hernia, were referred for VFG and WST in order to evaluate the functional results of surgery. At one-month videofluorographic control thirteen patients had just a minimal prolonged esophageal transit time but only six of these had an early postoperative dysphagia, whereas at six months control the prolonged esophageal transit time was present in three patients two of which complained a very light dysphagia. One patient at one month control had a severe dysphagia, her videofluorography showed a very prolonged esophageal transit time and she had to redo surgery. She had a complete resolution of dyspagia and at the six months videofluorographic control she had a normal esophageal and esophagogastric transit time. One patient, underwent surgery in another hospital, complained a persistent and moderate dysphagia and at one month videofluorografic control was evident a malposition of wrap around the upper part of the stomach and a WST positive for reflux and at six months control clinical finding was worst. He will be evaluated for further endoscopic or surgical treatment. CONCLUSIONS: In our experience we believe that VFG is a valid test to identificate the postoperative outcomes giving the surgeons a visual evaluation of their work.

The sentinel node is the first lymph node reached by metastasising cells from a primary tumour. Numerous studies have confirmed and demonstrated the reliability of the sentinel node biopsy hypothesis, on account of the high identification rate and overall accuracy of dye-guided and radio-guided procedures. It is remarkable that the concept of lymphatic mapping was not introduced until the end of the twentieth century. The development of the dynamic technique of intraoperative lymphatic mapping in the 1990s resulted in general acceptance of the sentinel node theory. The current literature suggests that sentinel node biopsy may eventually replace axillary dissection as the nodal staging procedure of choice in early breast cancer. This report describes the history and validation of the sentinel node biopsy technique, with particular reference to breast cancer.

the Autthors report a case of localised perianal Paget's disease consisting of an eczematous lesion unresponsive to steroid anal treatment subsequently treated with local excision. the patient after 20 months is alive and presents no further signs of disease. The Authors therefore point out that in elderly patients with stage I perianal Paget's disease local wide excision is considered the best therapeutical choice.

The prognostic value of sentinel lymph node (SLN) micrometastases in invasive breast cancer patients is still widely debated. Even if, in the absence of unequivocal guidelines, the axillary lynphadenectomy is not still performed in the routine clinical care of these patients.We have retrospectively analyzed 897 patients with operable invasive breast cancer and clinically negative axillary lymph nodes underwent conservative surgery or total mastectomy with SLN biopsy. Two groups of patients with SLN micrometastases and isolated tumor cells (ITC) were considered, the first one treated with completion axillary dissection, the second one not followed by further surgical axillary procedure. The incidence of axillary recurrences has BEEN evaluated in both groups and only in the first group of patients the involvement of the remaining lymph nodes was analyzed.Micrometastases were found in 67 (7.4%) patients and ITC in 8 (0,9%) patients. 14 (20.9%) patients with micrometastases and 1 (12.5%) patient with ITC underwent completion axillary dissection. 53 (79.1%) patients with micrometastases and 7 (87.5%) with ITC didn't receive further surgical axillary procedure. No axillary recurrences were found during a median follow up of 65.7±8.69 months in both groups of patients.Based on the results and according to some recent randomized trials we can say that completion axillary dissection can be safely avoided when micrometastases are found in sentinel lymph nodes. It should be performed anyway, depending on the analysis of the biomedical profile of the tumor.Breast Carcinoma, Micrometastases Axillary Lymphonode Dissection, Sentinel Lymphonode.Il significato prognostico delle micrometastasi nel linfonodo sentinella nelle pazienti affette da carcinoma della mammella è ancora ampiamente dibattuto. Anche se, in assenza di univoche linee guida, nella pratica clinica la linfadenectomia ascellare in queste pazienti non viene più eseguita di routine. Abbiamo condotto uno studio retrospettivo su 897 pazienti affette da carcinoma invasivo della mammella con linfonodi ascellari negativi, sottoposte a chirurgia conservativa o a mastectomia totale con biopsia del linfonodo sentinella. Le pazienti in cui è stata diagnostica la presenza di micrometastasi del linfonodo sentinella sono state considerate in due diversi gruppi. In un primo gruppo, trattato con linfadenectomia ascellare totale è stata valutata l’incidenza di metastasi a carico dei rimanenti linfonodi ascellari. Un secondo gruppo non ha ricevuto alcun trattamento aggiuntivo dell’ascella e le pazienti sono state seguite con controlli periodici clinico strumentali. In entrambi i gruppi è stata valutata l’incidenza di eventuali recidive ascellari. All’esame istologico estemporaneo ed al successivo esame istologico definitivo del linfonodo sentinella, in 51 pazienti (6,83%) sono state evidenziate micrometastasi, in 8 pazienti (1,07%) erano presenti cellule tumorali isolate. Quindici di queste pazienti sono state sottoposte a linfadenectomia ascellare totale. Solo in 2 casi (13,33%) sono state ritrovate metastasi a carico dei rimanenti linfonodi ascellari. Quarantaquattro pazienti non hanno ricevuto alcun trattamento aggiuntivo dell’ascella. In queste pazienti nessuna recidiva ascellare è stata registrata durante un follow-up medio di 125,7±9,65 mesi (range 42- 102 mesi). Sulla base dei risultati ottenuti in questo studio ed in linea con alcuni recenti trials randomizzati si ci sentiamo di concludere che la linfadenectomia ascellare può essere evitata nei casi con micrometastasi nel linfonodo sentinella. Una sua eventuale indicazione può essere valutata caso per caso considerando come fattori di rischio per la recidiva ascellare alcune caratteristiche biomorfologiche del tumore primitivo.

AIM: Transanal Endoscopic Video Assisted (TEVA) excision using a Single Incision Laparoscopic Surgery SILSTM-Port represents a safe and complete technique to remove benign lesions of the rectum not treatable by endoscopy and malignant rectal lesions at early stage. It is a valid alternative to transanal endoscopic microsurgery (TEM), to conventional transanal surgery and to transabdominal resection. METHODS: In our operating Unit we performed a resection of 8 voluminous adenoma in the rectal ampulla with SILSTM-Port. RESULTS: The mean age of the patients was of 51.1 years, the mean BMI was 23. There were not intra or post-operative complications nor conversions to conventional transanal excision or major resective surgery. The postoperative course was normal. The average time of hospitalization was 3 days. CONCLUSIONS: TEVA is easier to perform than TEM and does not require a long training and specific and expensive material as the TEM does. TEVA might go to replace completely TEM.

Background The association between Hashimoto’s thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a controversial question that is still under debate, its pathological significance and the eventual clinical implications of this association remaining unclear. Methods The data regarding 305 patients were retrospectively analyzed. The patients were divided in two different groups. A first group made up of 142 patients undergoing surgery for differentiated thyroid carcinoma was compared to a control group of 142 analogous subjects operated for normofunctioning goiter. A second group was made up of 163 patients who had undergone total thyroidectomy (TT) with pre-operative diagnosis of HT. Results In the first group of patients an association with HT was found in 28,6% of the patients with final histopathological diagnosis of PTC versus 7,7% of the patients with histopathological diagnosis of multinodular goiter, which was a significant difference (p

Background: The aim of this study was to evaluate the effect of a single early administration of dexamethasone and escin after loss of signal (LOS) during a neuromonitored total thyroidectomy. Methods: A retrospective analysis of results concerning consecutive patients undergoing total thyroidectomy was performed. Patients included in the study were divided into two groups: Group 1 for which a “wait and see” strategy was used; Group 2, receiving dexamethasone and escin immediately after LOS detection. Results: Overall 37 patients were included in Group 1 and 35 in Group 2. LOS recovery occurring in 29.7% of cases (n. 11) versus 65.7% (n. 23) respectively (p < 0.001). Postoperative fibrolayngoscopy for patients without LOS recovery showed normal cord function in 4 out of 26 cases (15.4%) in Group 1 and in 7 out of 12 (58.3%) in Group 2 (p < 0.001). Conclusions: The early administration of dexamethasone and escin after LOS detection may achieve greater EMG signal recovery than a “wait and see” strategy.

The authors present their experience of treating anti-cancer drug extravasation by means of a composite surgical technique that consists of infiltration with physiological solution and hyaluronidase and subsequent manual aspiration of solutes alternated with profuse irrigation of the infiltrated area. In the immediate post-op we carry out a medical therapy that consists of calciparine and topic antibiotic and/or steroid creams. Since the year 2000 this technique has been used on 25 patients. We have had neither complications nor scars. Copyright 2005 Wiley-Liss, Inc Surgical treatment of extravasation injuries. Napoli P, Corradino B, Badalamenti G, Tripoli M, Vieni S, Furfaro MF, Cordova A, Moschella F. Source Chirurgia Plastica e Ricostruttiva, Dipartimento di Discipline Chirurgiche ed Oncologiche, Università degli Studi di Palermo, Italy. pietronapoli@libero.it Abstract The authors present their experience of treating anti-cancer drug extravasation by means of a composite surgical technique that consists of infiltration with physiological solution and hyaluronidase and subsequent manual aspiration of solutes alternated with profuse irrigation of the infiltrated area. In the immediate post-op we carry out a medical therapy that consists of calciparine and topic antibiotic and/or steroid creams. Since the year 2000 this technique has been used on 25 patients. We have had neither complications nor scars.

Purpose Local neck symptoms (LNS) may be related to goiter, but are also reported by patients suffering from laryngeal–pharyngeal reflux (LPR). The aim of this study was to investigate whether LPR could play a role in the persistence of some LNS after total thyroidectomy (TT). Methods A consecutive case series of 160 patients with multinodular goiter (MNG) candidate for TT were included in this study. Each patient was closely studied for both the thyroid pathology and reflux disease before and 6 months after surgery to assess the persistence of LNS after surgery. Results Only throat discomfort showed a significant improvement (p = 0.031) after surgery. On the other hand, swallowing and voice disorders persisted after surgery in 82.3% and 77.3% of patients, respectively (p = 0.250 and p = 0.062), such as the correlated reflux laryngopharyngitis (p = 0.5). Conclusions LPR can be considered a predisposing factor or an important concurrent causa to the persistence of LNS after TT, in particular for swallowing disorders and voice disorders. In patients with non-toxic MNG who complain of local neck symptoms, the investigation of a possible coexistence of a reflux disease is appropriate before surgery. Patients should be informed about the possibility that some symptoms can persist even after removal of the goiter.

MUTYH gene is involved in the base excision repair (BER) mechanism and its pathogenic alterations are associated with colorectal polyposis and cancer. MUTYH-associated polyposis (MAP) is a condition which is inherited in an autosomal recessive manner. MAP patients, beyond colorectal cancer (CRC), may develop other types of tumors, including duodenal, breast, ovarian, pancreatic, bladder and skin cancers. Carriers of biallelic MUTYH likely pathogenic/pathogenic variants exhibit a high lifetime risk of CRC, though cancer risk evidence becomes less clear when monoallelic carriers and extraintestinal tumors are considered. However, several studies recently reported an increased genetic susceptibility to cancer also for carriers of germline monoallelic MUTYH mutations. Moreover, experimental evidence highlighted the MUTYH involvement in many other biological functions. In future, MUTYH mutation carriers might benefit from new target therapies involving the use of PD-1 or KRAS inhibitors. Therefore, "MUTYH-associated tumor syndrome" might be the most appropriate term, due to the multiplicity of tumors observed in MAP patients and different biological contexts in which MUTYH acts as a "playmaker". In this Review, we will investigate the impact of germline mono- and biallelic MUTYH mutations on cancer risk, providing a proposal for clinical surveillance of mutation carriers.

Mushroom extracts are a rich source of natural compounds with antimicrobial properties, which are able to prevent, to some extent, the growth of foodborne pathogens. The aim of this study was to investigate the potential of extracts from albino Grifola frondosa (GF), commonly known as maitake, to inhibit the growth of some bacteria and the biofilm production by Staphylococcus aureus. We obtained not only a significant reduction of OD score between biofilm and biofilm plus albino G. frondosa extract group, but also a reduction of category of biofilm. In addition, we observed a significant presence of isolates with strong category for the biofilm group and a significant presence of isolates with absent category for the biofilm plus albino G. frondosa extract group. These results confirm that the use of albino G. frondosa extract reduces in significant way the presence of biofilm. Our results suggest and confirm that albino G. frondosa extracts could be employed as functional food and could be used as a natural additive for food process control and food safety.

Background Sentinel lymph node biopsy is the gold standard surgical technique for axillary staging in patients with clinically node-negative. However, it is still uncertain what is the optimal number of sentinel lymph nodes (SLNs) to be removed to reduce the false-negative rate. The aim of this study was to investigate whether patients with a single negative SLN have a worse prognosis than those with two or more negative SLNs. Methods A retrospective review was conducted on a large series of SLN-negative breast cancer patients. Survival outcomes and regional recurrence rate were evaluated according to the number of removed SLNs. Secondly, the contribution of different adjuvant therapies on disease-free survival was explored. Statistical analysis included the chi-square, Wilcoxon–Mann–Whitney test, and Kaplan–Meier survival analysis. Results A total of 1080 patients were included in the study. A first group consisted of 328 patients in whom a single SLN was retrieved, and a second group consisted of 752 patients in whom two or more SLNs were retrieved. There was no relevant difference in median DFS (64.9 vs 41.4) for SLN = 1 vs SLN > 1 groups (HR 0.76, CI 95% 0.39–1.46; p = 0.38). A statistically significant difference in mDFS was showed only for HT-treated patients who were SLN = 1 if compared to SLN > 1 (100.6 months versus 35.3 months). Conclusions There is likely a relationship between the number of resected SNL and mDFS. Our results, however, showed no relevant difference in median DFS for SLN = 1 vs SLN > 1 group, except for a subset of the patients treated with hormone therapy.

Background The aim of this study was to evaluate the reliability of intraoperative neuromonitoring through recurrent laryngeal nerve stimulation and simultaneous laryngeal palpation (NSLP) in predicting postoperative vocal cord palsy and in providing useful information in the decision to perform a staged surgery in initially planned total thyroidectomy. Materials and Methods A retrospective review was performed involving 552 patients for whom a total thyroidectomy was planned. In all patients, preoperative and postoperative laryngoscopy was performed. The incidence of vocal cord palsy was calculated on 1104 nerves at risk. Results Sensitivity and specificity of NSLP were 0.9411 and 0.9925 respectively. The positive predictive value was 0.7804, the negative predictive value was 0.9981, the false positive rate was 0.8%. In 41 patients (7.4%) the initial surgical strategy was changed into a staged procedure. Nine patients (21.9%) were false positive, 32 patients (78.1%) were true positive. Finally, a two-stage thyroidectomy was performed in 27 of 41 patients. Conclusions High sensitivity and specificity confirm the validity of NSLP in predicting postoperative vocal cord palsy and in driving a possible staged thyroidectomy, both in benign thyroid disease and in differentiated thyroid carcinoma.

Copyright © 2020 Murugaiah, Agostinis, Varghese, Belmonte, Vieni, Alaql, Alrokayan, Khan, Kaur, Roberts, Madan, Bulla and Kishore. Human surfactant protein D (SP-D) belongs to the family of collectins that is composed of a characteristic amino-terminal collagenous region and a carboxy-terminal C-type lectin domain. Being present at the mucosal surfaces, SP-D acts as is a potent innate immune molecule and offers protection against non-self and altered self-such as pathogens, allergens, and tumour. Here, we examined the effect of a recombinant fragment of human SP-D (rfhSP-D) on a range of breast cancer lines. Breast cancer has four molecular subtypes characterised by varied expression of oestrogen (ER), progesterone (PR) and EGF receptors (HER2). The cell viability of HER2 over-expressing (SKBR3) and triple-positive (BT474) breast cancer cell lines (but not of triple-negative cell line (BT20), was reduced following rfhSP-D treatment at 24h. Upregulation of p21/p27 cell cycle inhibitors and p53 phosphorylation (Ser15) in rfhSP-D-treated BT474 and SKBR3 cell lines signified G2/M cell cycle arrest. Cleaved caspase 9 and 3 were detected in rfhSP-D- treated BT474 and SKBR3 cells, suggesting an involvement of intrinsic apoptosis pathway. However, rfhSP-D-induced apoptosis was nullified in the presence of hyaluronic acid whose increased level in breast tumor microenvironment is associated with malignant tumor progression and invasion. rfhSP-D bound to solid-phase HA and promoted tumor cell proliferation. rfhSP-D-treated SKBR3 cells in the presence of hyaluronic acid showed decreased transcriptional levels of p53 when compared to SKBR3 cells treated with rfhSP-D only. Thus, hyaluronic acid appears to negate the anti-tumorigenic properties of rfhSP-D against HER2-over-expressing and triple-positive breast cancer cells. King Saud University, Riyadh, International Scientific Partnership Program (ISPP) ISPP-145; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy, RC20/16 and 5MILLE15D.

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor–positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24− cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268–79. ©2017 AACR.

Background The accuracy of axillary ultrasound (AUS) with fine-needle aspiration with varying patient body mass index (BMI) is still unclear. The aim of our study was to evaluate whether the US features of axillary lymph nodes changes with BMI of patients. Patients and methods A retrospective review was performed involving 144 out of 270 patients with early breast cancer who underwent breast surgery with sentinel lymph node biopsy. Diagnostic efficacy of AUS in preoperative axillary nodal staging was assessed in relation to BMI. Results Negative predictive values of AUS for the overweight and obese groups were statistically significantly lower compared to the normal/underweight group (p=0.02 and p=0.003, respectively). Additionally, Spearman's correlation coefficient R between BMI and positive sentinel lymph node biopsy was 0.257, suggesting a significantly positive linear relationship between the two variables in the cohort overall. Conclusion Our results demonstrate how in our cohort the negative predictive value of AUS was significantly influenced by adipose tissue and that the selection of the most suitable instrumental diagnostic technique might contribute to improving heterogeneous results.

Inflammatory bowel disease (IBD) remains a global health problem with a significant percentage of patients progressing to chronic inflammation and colitis-associated cancer (CAC). Whether or not γδ T cells contribute to initiation and maintenance of inflammation in IBD and in the development of CAC is not known. We have evaluated the frequency, phenotype, and functions of γδ T cells among tissue-infiltrating lymphocytes in healthy donors and IBD and CAC patients. Results show that Vδ1 T cells are the dominant γδ T-cell population in healthy tissue, whereas Vδ2 T significantly abound in chronic IBD. Vδ2 T cells produce more IFN-γ, TNF-α, and IL-17 than Vδ1 T cells in chronic inflamed IBD. In CAC patients no significant cytokine production was detected in tissue-resident Vδ1 T cells, but Vδ2 T cells produced remarkable amounts of IFN-γ and TNF-α; these data were confirmed by the analysis of an independent cohort of IBD transcriptomes. Moreover, transcriptomes of IBD patients revealed a clear-cut clusterization of genes related with the maintenance of the inflammatory status. In conclusion, our results demonstrating that Vδ2 T cells have a proinflammatory profile in chronic IBD are suggestive of their participation in IBD and CAC pathogenesis.

Recently, immunotherapy has been shown to be an effective and helpful therapeutic option for the treatment of advanced non-small-cell lung cancer (NSCLC). The activity of antitumor T cells may be restored through the checkpoint blockade using anti-programmed death 1 or anti-programmed death ligand 1 (PD-L1) antibodies, showing, in several cancer patients, an increased progression-free survival and overall survival compared with classical chemotherapy. As recently shown by several studies, the PD-L1 expression levels in tumors may offer a selection criterion for patients to predict their immunotherapy response. In particular, NSCLC patients with high tumor PD-L1 levels (proportional score ≥ 50% for first-line therapy and ≥ 1% for second-line treatment, respectively) showed better response rates to immunotherapy and longer survival in first-line therapy compared with conventional chemotherapy. PD-L1, whose expression is evaluated by using immunohistochemistry analysis, is currently the only biomarker approved for clinical use in the first- and second-line monotherapy setting and therefore plays a central role in treatment decision-making for patients with advanced NSCLC. In this review we will discuss the key role of PD-L1 as a predictive biomarker of response to pembrolizumab therapy in NSCLC patients by describing the appropriate techniques and methodologies for immunohistochemical evaluation of PD-L1 expression and providing an overview of the clinical studies supporting its predictive significance.

Background and objectives The Axillary Lymph Node Dissection (ALND) is the standard treatment in patients with invasive breast cancer and sentinel node metastasis, but in 60% of the cases there is no further axillary neoplastic involvement, so this invasive intervention represents an overtreatment. The purpose of the study is to identify patients with low risk of additional nodal metastases, to omit ALND. Methods The MSKCC Additional nodal metastasis nomogram was applied on a sample of 175 patients with invasive breast cancer who underwent ALND after detection of macrometastasis with the extemporaneous examination of the sentinel lymph node. Patients were classified as "low risk" when the result of the nomogram was ≤50%. Sensitivity, specificity, positive and negative predictive values and AUC (Area Under Curve) of the ROC curve of the nomogram were then calculated. Results A cut-off by 50% yielded 92.3% sensitivity, 81,4% specificity, 80% positive predictive value and 92.9% negative predictive value. The ROC curve AUC in these patients was 0.885. Conclusions The MSKCC nomogram has proven to be an effective tool in estimating the axillary lymph node status and it can potentially be used to better select the patients with sentinel node macrometastasis who can actually benefit from ALND.

Dietary restrictions, including fasting (or long-term starvation), calorie restriction (CR), and short-term starvation (STS), are considered a strong rationale that may protect against various diseases, including age-related diseases and cancer. Among dietary approaches, STS, in which food is not consumed during designed fasting periods but is typically not restricted during designated feeding periods, seems to be more suitable, because other dietary regimens involving prolonged fasting periods could worsen the health conditions of cancer patients, being they already naturally prone to weight loss. Until now, the limited amount of available data does not point to a single gene, pathway, or molecular mechanism underlying the benefits to the different dietary approaches. It is well known that the healthy effect is mediated in part by the reduction of nutrient-related pathways. The calorie restriction and starvation (long- and short-term) also suppress the inflammatory response reducing the expression, for example, of IL-10 and TNF-α, mitigating pro-inflammatory gene expression and increasing anti-inflammatory gene expression. The dietary restriction may regulate both genes involved in cellular proliferation and factors associated to apoptosis in normal and cancer cells. Finally, dietary restriction is an important tool that may influence the response to chemotherapy in preclinical models. However, further data are needed to correlate dietary approaches with chemotherapeutic treatments in human models. The aim of this review is to discuss the effects of various dietary approaches on the cancer progression and therapy response, mainly in preclinical models, describing some signaling pathways involved in these processes.

Purpose To compare magnetic resonance imaging (MRI) findings with gadoxetic acid and gadobenate dimeglumine for the diagnosis of hepatic hemangiomas. Materials and Methods In this retrospective study, we included 26 hemangiomas (mean size was 14 mm ± 10 mm) in 19 patients (mean age 60 ± 14 years) scanned with both gadobenate dimeglumine MRI and gadoxetic acid MRI. For each patient, we collected multiple lesion variables including location, number, size and enhancement pattern on arterial, portal venous, 3-minute and hepatobiliary phases with both gadoxetic acid and gadobenate dimeglumine. The enhancement pattern with the two contrast agents was then compared. Results The typical enhancement pattern of hepatic hemangiomas was more common—though not statistically significant—with gadobenate dimeglumine compared to gadoxetic acid (57% [15 of 26] vs 42% [11 of 26], respectively; P = 0.4057 for both peripheral globular discontinuous enhancement in the arterial phase and centripetal fill-in in the portal venous phase). A significantly higher number of hemangiomas showed centripetal fill-in or hyperintensity in the 3-minute phase with gadobenate dimeglumine compared to gadoxetic acid (88% [23 of 26) vs 58% [15 of 26]; P = 0.0266). A pseudo washout sign in the 3-minute phase was detected in one of the 5 flash-filling hemangiomas with gadoxetic acid, but not gadobenate dimeglumine. All hemangiomas were hypointense in the hepatobiliary phase with both gadobenate dimeglumine and gadoxetic acid. Conclusions The enhancement pattern of hepatic hemangiomas may vary depending on the hepatobiliary agent, with more frequent lack of the typical pattern with gadoxetic acid compared to gadobenate dimeglumine.

Research on longevity and healthy aging promises to increase our lifespan and decrease the burden of degenerative diseases with important social and economic effects. Many aging theories have been proposed, and important aging pathways have been discovered. Model organisms have had a crucial role in this process because of their short lifespan, cheap maintenance, and manipulation possibilities. Yeasts, worms, fruit flies, or mammalian models such as mice, monkeys, and recently, dogs, have helped shed light on aging processes. Genes and molecular mechanisms that were found to be critical in simple eukaryotic cells and species have been confirmed in humans mainly by the functional analysis of mammalian orthologues. Here, we review conserved aging mechanisms discovered in different model systems that are implicated in human longevity as well and that could be the target of anti-aging interventions in human.

γδ T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating γδ T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of γδ T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a highly variable rate of TILs (5–90%) and 4% γδ T cells on average, with the majority expressing Vδ1. Most Vδ1 and Vδ2 T cells showed a predominant effector memory phenotype and had reduced production of IFN- γ which was likely due to yet unidentified inhibitory molecules present in cancer stem cell secretome. Transcriptome analyses revealed that patients containing abundant γδ T cells had significantly longer 5-year disease free survival rate, suggesting their efficacy in controlling tumor at very early stage.

Neuroendocrine carcinoma of the breast is an extremely rare tumor. A standard treatment has yet to be established because only a few cases have been reported in literature. The authors report five cases observed from January 2007 to December 2014 and a review of literature. Four patients underwent quadrantectomy and in two cases axillary nodal dissection and only one to mastectomy with axillary nodal dissection. Tumor size was from T1 to T2 with N0 to N1, according TNM classification. Pathological specimens were stained with hematoxylin and eosin and an immunohistochemical panel of antibodies (Neuron-specific enolase, Chromogranin, Synaptophysin, Estrogen and Progesterone receptors, c-erb and Ki-67). All cases showed markers positivity to Neuron-specific enolase, Chromogranin, Synaptophysin and Estrogen and Progesterone receptors were found. Ki-67 was higher than 40% in four patients. Adjuvant chemotherapy was administrated in patients with Ki-67 > 10%; every patients were treated with radiotherapy and with hormonal therapy too. Although Neuroendocrine breast tumor is considered a distinct entity, the best treatment seems to be correlate to the size of tumor and to the lymph node status and to Ki-67 index like the common breast cancer.

Background: the inhibition of EGFR kinase activity by tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, can result in improved response and prolonged progression-free survival (PFS) in NSCLC patients harboring sensitizing exon 19del and exon 21 L858R mutations. Unfortunately, almost all patients will develop resistance to EGFR-TKI, in particular T790M is the most frequent mutation. Nowadays, new methods are urgently needed for a rapid, cost-effective and non-invasive identification of biomarkers as a valuable tool for obtaining the genetic follow-up data during the course of the disease. Circulating microRNAs might represent a new precious biomarker for patients’ monitoring. The study aimed to verify the association between microRNAs expression and EGFR mutational status in adenocarcinoma wt and EGFR-TKI sensitive mutated (del19) cells. Methods: EGFR wt and mutated adenocarcinoma cells (A549, HCC827), were cultured in RPMI1640 and incubated at 37C in 5% CO2. Cell viability before treatment was evaluated by MTT assay and then cells were treated with Erlotinib at growing concentration. MicroRNAs were extracted by using miRNeasy mini kit (QIAGEN). Nucleic acids quantity and quality was evaluated through the NanoDrop ND-2100 Bioanalyzer whereas integrity through the 2100 Bioanalyzer. MicroRNAs after retrotranscription were profiled through TaqMan Array Human MicroRNA Cards v2.0. Results: microRNAs extracted from A549 (wild-type) and HCC827 (del19) were profiled and differential expression analyzed at basal conditions (no treatment) using the wt cell as control. The miRNAs analysis highlighted that among the up-regulated microRNAs (miR-7, miR-18a, miR-106b, miR-200b, miR-505, miR-625), the miR-7 expression levels were 10 times higher, whereas among the down-regulated miRNAs (let-7f, miR-10b, miR-192, miR-193, miR-194, miR-767, miR-801), let-7f was 12 times lower. This signature may represent a valid start point for studying variations of the aforementioned miRNAs levels during TKIs treatment in order to demonstrate their involvement in inducing resistance. Conclusions: to outline molecular mechanisms responsible for resistance onset as consequence of TKIs treatment, the hypotetical role of miRNAs has been studied. The preliminary data, obtained so far only in cultured cell lines at basal conditions, would acquire higher relevance, if their involvement may be confirmed also in TKI-treated cells.

P63 is a transcription factor belonging to the family of p53, essential for the development and differentiation of epithelia. In recent years, it has become clear that altered expression of the different isoforms of this gene can play an important role in carcinogenesis. The p63 gene encodes for two main isoforms known as TA and ΔN p63 with different functions. The role of these different isoforms in sustaining tumor progression and metastatic spreading however has not entirely been clarified. Here we show that breast cancer initiating cells express ΔNp63 isoform that supports a more mesenchymal phenotype associated with a higher tumorigenic and metastatic potential. On the contrary, the majority of cells within the tumor appears to express predominantly TAp63 isoform. While ΔNp63 exerts its effects by regulating a PI3K/CD44v6 pathway, TAp63 modulates this pathway in an opposite fashion. As a result, tumorigenicity and invasive capacity of breast cancer cells is a balance of the two isoforms. Finally, we found that tumor microenvironmental cytokines significantly contribute to the establishment of breast cancer cell phenotype by positively regulating ΔNp63 and CD44v6 expression.

Summary Over the last few years, there has been an enormous increase in the use of needle core biopsy (CB) for the histopathological characterisation of suspect lesions of the breast. The aim of this study was to verify the diagnostic reliability of CB by comparing the histological results obtained with the use of this technique with those obtained from the whole of the surgically resected specimen. We studied 198 out of 426 patients with clinically and/or radiologically suspect breast lesions. We found correspondence between the histological examination of the whole of the excised specimen and that of the CB in 94.9% of the cases of infiltrating carcinoma and in 71.4% of those involving ductal carcinomas in situ. The predictive value of CB was 98.9%, sensitivity was 96.1% and specificity 93.3%. These results confirmed that CB is an extremely reliable diagnostic tool in the definition of breast lesions.

Several studies report a higher rate of papillary thyroid carcinomas (PTC) in patients with Hashimoto thyroiditis (HT), indicating a possible correlation between the two diseases. We studied a group of 89 subjects undergoing surgery for thyroid carcinomas compared with a control group of 89 subjects operated on for normofunctioning goiter, and a second group of 47 patients undergoing total thyroidectomy for HT. Association with HT was found in 19 of the 71 PTC subjects (26.7%) and in 8 goiter patients (8.9%), which was a significant difference ( P < 0.02). Thirteen of the HT patients, mostly with the nodular form, showed coexistent PTC (27.6%). HT and PTC coexisted in several morphological, immunohistochemical, and biomolecular aspects; increased incidence of PTC in HT patients might therefore indicate that HT is a precursor of thyroid cancer. Further studies are required, however, in order to confirm this hypothesis; until then, HT patients should undergo careful clinical and technical follow-up.

Background Seroma formation frequently occurs in patients who have undergone axillary lymphadenectomy. The aim of the study was to evaluate the effect of fibrin glue in the prevention of seroma formation after axillary lymphadenectomy. Materials and Methods Hundred fifty-nine breast cancer patients about to undergo quadrantectomy or mastectomy plus axillary lymphadenectomy were enrolled in the study and randomized into two groups. Fibrin glue spray applied to the axillary fossa plus placement of closed suction drainage were used in 80 patients (group A); placement of closed suction drainage was only used in 79 patients (group B). Results Group A patients showed a slight advantage with regard to the mean duration of axillary drainage placement (4.5 ± 1.3 days in group A vs. 5.1 ± 1.6 days in group B) and number of seroma aspirations (6.3 ± 1.1 in group A vs. 6.7 ± 1.2 in group B). No statistically significant differences were observed between the two groups of patients regarding the mean volume of total axillary drainage and of total seroma volume. Conclusions The use of fibrin glue does not prevent seroma formation and does not reduce seroma magnitude and duration. The costs of the product involved do not justify its routine use in patients undergoing axillary dissection. J. Surg. Oncol. 2010; 101:600–603. © 2010 Wiley-Liss, Inc.

PURPOSE: In breast cancer staging, the need for intraoperative sentinel lymph node (SLN) evaluation has still not been adequately established. This study investigates the impact of intraoperative frozen section (FS) evaluation of SLN to avoid subsequent axillary lymph node dissection (ALND) in patients with positive SLN. METHODS: A retrospective review of 364 breast cancer patients undergoing SLN biopsy with intraoperative FS evaluation of SLN was performed. RESULTS: Sensitivity and accuracy of FS examination of SLN were 76.4% and 94.2%, respectively. The sensitivity was significantly higher in larger tumors (p < 0.01). No significant correlation was found between FS and histologic type. A second intervention was avoided in 83.9% of the patients with positive SLN. CONCLUSIONS: Intraoperative FS examination of the SLN is a useful predictor of axillary lymph node status in breast cancer patients. The majority of SLN-positive patients allows for immediate ALND in a one-stage surgical procedure.

PURPOSE: LigaSure is a bipolar diathermy system, which achieves vessel sealing with reduced thermal spread. The device has been used successfully in abdominal operations and because of its features, it has been applied recently in thyroid surgery to minimize the risk of complications such as laryngeal nerve palsy and hypocalcemia, and also to reduce the operating time. METHODS: Between June and December 2005, we performed total thyroidectomy for various disorders in 105 patients. We used the LigaSure diathermy system in 53 patients and traditional hemostatic procedures in the other 52. We evaluated the demographic features, histopathological diagnosis, operating times, and relevant postoperative complications. RESULTS: The two study groups had similar demographic and histopathological features. The mean operating time +/- SD was not significantly shorter in the LigaSure group than in the traditional group (104 +/- 12.7 vs 110 +/- 15.6 min). None of the patients in either group suffered hemorrhage, definitive hypocalcemia, or definitive laryngeal nerve palsy. Transient hypocalcemia and transient laryngeal nerve palsy developed in 7.54% and in 1.88%, respectively, of the patients in the LigaSure group, and in 7.69% and 1.92%, respectively, of the patients in the traditional group; these differences were not significant. CONCLUSIONS: LigaSure is a safe and effective method of hemostasis control, but it did not reduce the incidence of complications or operating times compared with traditional hemostatic procedures; moreover, the operative costs were higher.

BACKGROUND: The aim of this study was to evaluate the feasibility and the accuracy of sentinel lymph node biopsy in multicentric breast cancer (MBC) performed by means of a subareolar (SA) injection of both 99Tc-labeled human albumin colloid and lymphazurin. METHODS: Between January 2002 and October 2007, 34 patients with MBC with clinically negative axilla underwent sentinel lymph node biopsy (SLNB) followed by total axillary node dissection (AD). Overall successful identification rate of SLN was 100%; there were no false negatives and overall accuracy rate was 100%. RESULTS: The mean number of sentinel lymph nodes (SLNs) identified was 1.8 +/- 0.88 (range = 1-4); the mean number of axillary lymph nodes examined was 21.4 +/- 5.76 (range = 8-36). CONCLUSIONS: The authors conclude that SA injection of the tracer is feasible and efficacious in the identification of the SLN. The accuracy of SLNB in MBC is comparable to that obtained in unifocal disease.

Background Secretory mammary carcinoma is a rare breast neoplasia originally described in children but sometimes also found in adults. It presents a more favourable outcome than more common histological types of breast carcinoma; published literature in fact reports only a few cases with axillary lymph node metastases and only four cases with distant metastases. Clinical presentation In this paper we report a rare case of secretory breast carcinoma with axillary lymph node metastases in a 33-year-old woman. To our knowledge, this is the first case of secretory carcinoma involving biopsy of the sentinel lymph node and investigation of the e-cadherin expression. We found positivity for e-cadherin, which would support the hypothesis that this type of tumour is a variant of the infiltrating ductal carcinoma. Conclusion After a careful analysis of reported data, we have come to the conclusion that the treatment of choice for patients with secretory breast carcinoma should be conservative surgery with sentinel lymph node biopsy, followed by accurate follow-up. We are of the opinion that while post-operative radiotherapy is indicated in adult patients who have undergone quadrantectomy, it should not be used in children. Although several cases of secretory carcinoma have been treated with adjuvant chemotherapy, there are still no reliable data regarding the real value of such a choice.

To prospectively evaluate the prognostic significance of TP53, H-, K-, and N-Ras mutations, DNA-ploidy and S-phase fraction (SPF) in patients affected by locally advanced laryngeal squamous cell carcinoma (LSCC). Eight-one patients (median follow-up was 71 months) who underwent resective surgery for primary operable locally advanced LSCC were analyzed. Tumor DNA was screened for mutational analysis by PCR/SSCP and sequencing. DNA-ploidy and SPF were performed by flow cytometric analyses. Thirty-six patients (44%) had, at least, a mutation in the TP53 gene. Of them, 22% (8/36) had double mutations and 3% (1/36) had triple mutations. In total, 46 TP53 mutations were observed. The majority (41%) of these occur in exon 5 (19/46), while the mutations in exons 6, 7, and 8 were represented in 14, 7, and 6 patients, respectively (31% 15%, and 16%). Five LSCC patients (6%) showed a mutation in H-Ras gene. Sixty-three percent of the cases (51/81) were DNA aneuploidy, 14% of these (7/51) were multiclonal. Thirty-nine patients (48%) had an high SPF value. At Univariate analysis, the DNA aneuploidy, high SPF (> 15.1%), TP53 mutations and, in particular, the mutations that occur in exons 5 and 8 were significantly related to quicker disease relapse and short OS. At Multivariate analysis, the major significant predictors for both disease relapse and death were high SPF and any TP53 mutations. While histological grade G3 was an independent factor only for relapse. In conclusions, any TP53 mutations and high SPF are important biological indicators to predict the outcome of LSCC patients.

Aims and background Gastrointestinal stromal tumors (GISTs), although rare, are the most common mesenchymal neoplasms affecting the gastrointestinal tract. We present our experience in the treatment of localized and metastatic disease and a review of literature. Patients and methods Nine patients were observed from April 2002 to July 2004. Eight tumors were in the gastric area and J was in the small bowel. In 5 cases, complete surgical removal was performed, and none of these patients underwent adjuvant therapy. The remaining 4 cases, with locally advanced or recurrent disease, were treated with imatinib. Results The patients with localized disease treated only by surgery did not relapse. In the patients with locally advanced or metastatic disease treated by imatinib, we observed 3 partial responses, and one case was not assessable because he had no measurable disease. In 2 of 3 responders, it was possible to perform a new radical surgery. Conclusions Our series is too small to draw any conclusion. According to our review of the literature, surgery remains the standard treatment for non-metastatic GISTs. Imatinib mesylate represents a major breakthrough in the treatment of advanced GISTs and is the first effective systemic therapy for the disease.