Common and Rare Variants in TMEM175 Gene Concur to the Pathogenesis of Parkinson's Disease in Italian Patients.

Parkinson's disease (PD) represents the most common neurodegenerative movement disorder. We recently identified 16 novel genes associated with PD. In this study, we focused the attention on the common and rare variants identified in the lysosomal K+ channel TMEM175. The study includes a detailed clinical and genetic analysis of 400 cases and 300 controls. Molecular studies were performed on patient-derived fibroblasts. The functional properties of the mutant channels were assessed by patch-clamp technique and co-immunoprecipitation. We have found that TMEM175 was highly expressed in dopaminergic neurons of the substantia nigra pars compacta and in microglia of the cerebral cortex of the human brain. Four common variants were associated with PD, including two novel variants rs2290402 (c.-10C > T) and rs80114247 (c.T1022C, p.M341T), located in the Kozak consensus sequence and TM3II domain, respectively. We also disclosed 13 novel highly penetrant detrimental mutations in the TMEM175 gene associated with PD. At least nine of these mutations (p.R35C, p. R183X, p.A270T, p.P308L, p.S348L, p. L405V, p.R414W, p.P427fs, p.R481W) may be sufficient to cause the disease, and the presence of mutations of other genes correlated with an earlier disease onset. In vitro functional analysis of the ion channel encoded by the mutated TMEM175 gene revealed a loss of the K+ conductance and a reduced channel affinity for Akt. Moreover, we observed an impaired autophagic/lysosomal proteolytic flux and an increase expression of unfolded protein response markers in patient-derived fibroblasts. These data suggest that mutations in TMEM175 gene may contribute to the pathophysiology of PD.

A Quest for Optimization of Postoperative Triage After Major Surgery.

INTRODUCTION: Innovative strategies to reduce costs while maintaining patient satisfaction and improving delivery of care are greatly needed in the setting of rapidly rising health care expenditure. Intensive care units (ICUs) represent a significant proportion of health care costs due to their high resources utilization. Currently, the decision to admit a patient to the ICU lacks standardization because of the lack of evidence-based admission criteria. The objective of our research is to develop a prediction model that can help the physician in the clinical decision-making of postoperative triage. MATERIALS AND METHODS: Our group identified a list of index events that commonly grants admission to the ICU independently of the hospital system. We analyzed correlation among 200 quantitative and semiquantitative variables for each patient in the study using a decision tree modeling (DTM). In addition, we validated the DTM against explanatory models, such as bivariate analysis, multiple logistic regression, and least absolute shrinkage and selection operator. RESULTS: Unlike explanatory modeling, DTM has several unique strengths: tree models are easy to interpret, the analysis can examine hundreds of variables at once, and offer insight into variable relative importance. In a retrospective analysis, we found that DTM was more accurate at predicting need for intensive care compared with current clinical practice. DISCUSSION: DTM and predictive modeling may enhance postoperative triage decision-making. Future areas of research include larger retrospective analyses and prospective observational studies that can lead to an improved clinical practice and better resources utilization.

MRI-Based Apparent Diffusion Coefficient for Predicting Pathologic Response of Rectal Cancer After Neoadjuvant Therapy: Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study was to assess the use of apparent diffusion coefficient (ADC) during DWI for predicting complete pathologic response of rectal cancer after neoadjuvant therapy. MATERIALS AND METHODS: A systematic review of available literature was conducted to retrieve studies focused on the identification of complete pathologic response of locally advanced rectal cancer after neoadjuvant chemoradiation, through the assessment of ADC evaluated before, after, or both before and after treatment, as well as in terms of the difference between pretreatment and posttreatment ADC. Pooled mean pretreatment ADC, posttreatment ADC, and Δ-ADC (calculated as posttreatment ADC minus pretreatment ADC divided by pretreatment ADC and multiplied by 100) in complete responders versus incomplete responders were calculated. For each parameter, we also pooled sensitivity and specificity and calculated the area under the summary ROC curve. RESULTS: We found 10 prospective and eight retrospective studies. Overall, pathologic complete response was observed in 22.2% of patients. Pooled mean pretreatment ADC in complete responders was 0.84 × 10-3 mm2/s versus 0.89 × 10-3 mm2/s in incomplete responders (p = 0.33). Posttreatment ADC values were 1.51 × 10-3 mm2/s and 1.29 × 10-3 mm2/s, in complete and incomplete responders, respectively (p = 0.00001). The Δ-ADC percentages were also significantly higher in complete responders than in incomplete responders (59.7% vs 29.7%, respectively, p = 0.016). Pooled sensitivity, specificity, and AUC were 0.743, 0.755, and 0.841 for pretreatment ADC; 0.800, 0.737, and 0.782 for posttreatment ADC; and 0.832, 0.806, and 0.895 for Δ-ADC. CONCLUSION: Use of ADC during DWI is a promising technique for assessment of results of neoadjuvant treatment of rectal cancer.

Acute Localized Exanthematous Pustulosis (ALEP): Review of Literature with Report of Case Caused by Amoxicillin-Clavulanic Acid.

Acute localized exanthematous pustulosis (ALEP) is a localized form of acute generalized exanthematous pustulosis, characterized by acute onset of multiple nonfollicular, pinhead-sized, sterile pustules following drug administration. Antibiotics, especially ß-lactams and macrolides, have been implicated in the majority of cases, although eruption after nonsteroidal antiinflammatory drugs and many other medications has also been reported. Skin reaction arises quickly within a few hours, resolving rapidly within a few days without treatment, and it is usually accompanied by fever and neutrophilic leukocytosis. We report herein all cases of ALEP described in literature, adding the case of a 35-year-old woman admitted to our hospital with outbreak of erythematous pustules on her face, neck, and chest after amoxicillin-clavulanic acid treatment.

Can axillary node dissection be safely omitted in the elderly? A retrospective study on axillary management of early breast cancer in older women.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) is a minimally invasive technique to stage the axillary lymph node status. The burden of nodal metastasis is of great concern, as the clinical relevance and therapeutic implications of pN1mi and pN0(i+) in the sentinel lymph node (SLN) remain a matter of debate. MATERIALS AND METHODS: We examined the pathological features of 901 patients above the age of 65 presenting with clinical T1-T2 N0M0 breast tumours (<3 cm), detecting tumours related to llary non-sentinel node (NSN) metastases when the SLN was minimally involved. RESULTS: A total of 270 patients underwent complete axillary lymph node dissection (cALND) after their SLNB specimen tested positive for macrometastasis, micrometastasis and isolated tumour cells (ITCs). Seventy-six patients were diagnosed with micrometastatic disease pN1mi (27.5%), whilst ITCs (pN0i+) were detected in seven patients (2.5%). NSNs were found to be involved in two patients (2.6%) with micrometastases at the SLN. No further metastatic disease was detected in NSNs when the SLN contained ITCs. At a median follow-up period of 5.8 years, no axillary recurrence was observed among pN1mi and pN0(i+) patients. Lobular histotype, multicentricity and lymphovascular invasion were found to be associated with NSN involvement. DISCUSSION: The results from our case series are supported by IBCSG 23-01 level 1 evidence, which demonstrated a local recurrence rate of 1% in 'minimally involved not-surgical treated axilla'. CONCLUSIONS: Based on current evidence, we spare well-informed and consenting patients from further axillary surgery when the SLN is minimally involved in early breast cancer within an agreed protocol, whilst scheduling adjuvant treatment based on the patients' primary tumour characteristics.

Minimally invasive radioguided parathyroid surgery: A literature review.

The minimally invasive approach to parathyroid glands represents an important field of application of radioguided surgery. As always happens, in all cases pertaining to hyper-specialized skills, scientific production has long been the prerogative of a few Authors, but the ever increasing technological diffusion, combined with excellent results often achieved, increases the interest in this technique. This is particularly true in the era of minimally invasive surgery. The Authors realize a review of the existing literature to allow an overall view of current knowledge on this particular topic and to guide future research.

Adrenocortical carcinoma: what the surgeon needs to know. Case report and literature review.

Adrenocortical carcinoma is a rare and aggressive cancer and its prognosis is frequently unsatisfactory. Due to its rarity there's a lack of prospective randomized studies. Without experience in the approach of this kind of tumor, managing becomes challenging and, moreover, we have only few recommendations, based on weak evidence. We report a case that has some peculiarities and is an excellent food for thought. Then we deal with a literature review to highlight and summarize most significant aspects of epidemiology, clinic, diagnosis, therapy and prognosis in an exquisitely surgical point of view.

TEM in the treatment of recurrent rectal cancer in elderly.

INTRODUCTION: Transanal microscopic surgery is an important application of minimally invasive surgery of rectum, allowing realization of complex transanal intervention. PATIENTS AND METHODS: During the period between January 2002 and December 2010, seven patients, five men and two women, average age 75 years, with early rectal cancer recurrence were selected for this type of surgical palliative procedure. The selection of the patients is made by: transrectal ultrasonography, colonoscopy and abdominal ultrasonografy, to rule out liver metastases, CT with and without enema, PET CT. Follow-up is approximately 12-30 months. RESULTS: The pathologic staging confirms the complete excision of recurrences. Then patients are referred for more complementary therapies. DISCUSSION: The significance of conservative treatment for local recurrence of rectum adenocarcinoma is still controversial because the recurrence is an expression of tumor spread not controlled by oncological surgical and radio/chemo therapy CONCLUSION: In selected subjects such as the elderly, based on equal oncological treatment, the reduction of surgical trauma, preservation of anatomical integrity and resolution of symptoms are important results.

TEM in the treatment of recurrent rectal cancer in elderly.

INTRODUCTION: Transanal microscopic surgery is an important application of minimally invasive surgery of rectum, allowing realization of complex transanal intervention. PATIENTS AND METHODS: During the period between January 2002 and December 2010, seven patients, five men and two women, average age 75 years, with early rectal cancer recurrence were selected for this type of surgical palliative procedure. The selection of the patients is made by: transrectal ultrasonografy, colonoscopy and abdominal ultrasonografy, to rule out liver metastases, CT with and without enema, PET CT. Follow-up is approximately 12-30 months. RESULTS: The pathologic staging confirms the complete excision of recurrences. Then patients are referred for more complementary therapies. DISCUSSION: The significance of conservative treatment for local recurrence of rectum adenocarcinoma is still controversial because the recurrence is an expression of tumor spread not controlled by oncological surgical and radio/chemo therapy. CONCLUSION: In selected subjects such as the elderly, based on equal oncological treatment, the reduction of surgical trauma, preservation of anatomical integrity and resolution of symptoms are important results.

Is 1 mm thickness sec. Breslow the correct cut-off for sentinel node biopsy in melanoma? Report of six cases of metastasis by thin melanoma.

AIM: To reassess selection criteria for Sentinel Lymph Node Biopsy (SLNB) in patients with thin melanoma (Breslow ≤ 1 mm). MATERIAL OF STUDY: Between January 2004 and November 2010 we observed 6 patients with lymph node metastasis from early melanoma (Breslow ranging from 0.3 mm to 0.9 mm, not ulcerated tumor, mitosis/ mmq < 1). Nobody had received a prior study of sentinel lymph node so all patients underwent enlarged lymphadenectomy of concerned lymphatic stations and cancer re-staging. RESULTS: The pathological examination of lymph nodes has always confirmed metastatic melanoma. The average followup is currently 51,5 months: 3 of 6 patients presented recurrence that in one case led to death. DISCUSSION: In the event of a thickness < 1 mm the probability of finding a positive sentinel lymph node is about 7%. Recent data have demonstrated a significant survival advantage to early therapeutic lymphadenectomy in melanoma. CONCLUSIONS: Our experience, supported by the cases described and the literature, leads to propose the technique of SLNB to all patients with melanoma thicker than 0.5 mm, given the low morbidity and the important prognostic role of the procedure, in addition to the possibility of reducing the incidence of lymph node metastases.

Early rectal cancer: local excision by Trans-anal Endoscopic Microsurgery (T.E.M.).

INTRODUCTION: The microscopic trans-anal surgery is an important application of the mininvasive surgery of the rectum. The evaluation of the linfonodular involvement represents a limit to the conservative procedure. PATIENTS AND METHODS: Between January 2004 to December 2010, 14 patients have been chosen and undergone surgery with mininvasive treatment for primary rectum cancer (early rectal cancer). RESULTS: After a follow-up of about 36 months (8-72) we encountered only one local recurrences on a patient with a T2 lesion, also treated with mininvasive treatment. CONCLUSION: The results obtained by us using the T.E.M. have been all around very encouraging for the treatment of early rectal cancer.