Major adverse cardiac events and cardiovascular toxicity with PARP inhibitors-based therapy for solid tumors: a systematic review and safety meta-analysis.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) provided significant antitumor activity in various tumors, mainly carrying deleterious mutations of BRCA1/BRCA2 genes. Only few data are available regarding the cardiac and vascular safety profile of this drug class. We carried out a meta-analysis for assessing the incidence and relative risk (RR) of major adverse cardiovascular events (MACEs), hypertension, and thromboembolic events in patients with solid tumors treated with PARPi-based therapy. METHODS: Prospective studies were identified by searching the Medline/PubMed, Cochrane Library, and ASCO Meeting abstracts. Data extraction was conducted according to the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) statement. Combined odds ratios (ORs), RRs, and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods, depending on studies heterogeneity. RevMan software for meta-analysis (v.5.2.3) was used to carry out statistical analyses. RESULTS: Thirty-two studies were selected for the final analysis. The incidence of PARPi-related MACEs of any and high grade was 5.0% and 0.9%, respectively, compared with 3.6% and 0.9% in the control arms, corresponding to a significant increased risk of MACEs of any grade (Peto OR 1.62; P = 0.0009) but not of high grade (P = 0.49). The incidence of hypertension of any grade and high grade was 17.5% and 6.0% with PARPi, respectively, compared with 12.6% and 4.4% in the controls. Treatment with PARPi significantly increased the risk of hypertension of any grade (random-effects, RR = 1.53; P = 0.03) but not of high grade (random-effects, RR = 1.47; P = 0.09) compared with controls. Finally, PARPi-based therapies significantly increased the risk of thromboembolic events of any grade (Peto OR = 1.49, P = 0.004) and not of high grade (Peto OR = 1.31; P = 0.13) compared with controls. CONCLUSIONS: PARPi-based therapy is associated with a significantly increased risk of MACEs, hypertension, and thromboembolic events of any grade compared with controls. The lack of a significant increased risk of high-grade events together with the absolute low incidence of these adverse events led not to consider routine cardiovascular monitoring as recommended in asymptomatic patients.

The cell division control protein 42-Src family kinase-neural Wiskott-Aldrich syndrome protein pathway regulates human proplatelet formation.

Essentials The role of the cytoskeleton during megakaryocyte differentiation was examined. Human megakaryocytes are derived from in vitro cultured CD34+ cells. Cell division control protein 42 (CDC42) positively regulates proplatelet formation (PPF). Neural Wiskott-Aldrich syndrome protein, the main effector of CDC42 with Src positively regulates PPF. SUMMARY: Background Cytoskeletal rearrangements are essential for platelet release. The RHO small GTPase family, as regulators of the actin cytoskeleton, play an important role in proplatelet formation (PPF). In the neuronal system, CDC42 is involved in axon formation, a process that combines elongation and branching as for PPF. Objective To analyze the role of CDC42 and its effectors of the Wiskott-Aldrich syndrome protein (WASP) family in PPF. Methods Human megakaryocytes (MKs) were obtained from CD34+ cells. Inhibition of CDC42 in MKs was performed with the chemical inhibitor CASIN or with an active or a dominant-negative form of CDC42. The knock-down of N-WASP was obtained with a small hairpin RNA strategy Results Herein, we show that CDC42 activity increased during MK differentiation. The use of the chemical inhibitor CASIN or of an active or a dominant-negative form of CDC42 demonstrated that CDC42 positively regulated PPF in vitro. We determined that N-WASP, but not WASP, regulated PPF. We found that N-WASP knockdown led to a marked decrease in PPF, owing to a defect in the demarcation membrane system (DMS). This was associated with RHOA activation, and a concomitant augmentation in the phosphorylation of mysosin light chain 2. Phosphorylation of N-WASP, creating a primed form of N-WASP, increased during MK differentiation. Phosphorylation inhibition by two Src family kinase inhibitors decreased PPF. Conclusions We conclude that N-WASP positively regulates DMS development and PPF, and that the Src family kinases in association with CDC42 regulate PPF through N-WASP.

Clinical validity of tumor-infiltrating lymphocytes analysis in patients with triple-negative breast cancer.

BACKGROUND: Although tumor-infiltrating lymphocytes (TILs) have been associated with a favorable prognosis in triple-negative breast cancer (TNBC) patients, this marker is not currently considered robust enough for entering the clinical practice. In the present study, we assessed the clinical validity of the guidelines recently issued by the International TIL Working Group in a large retrospective series of well-annotated TNBC patients. PATIENTS AND METHODS: TILs were evaluated in all the full-face H&E sections from 897 consecutive TNBC (i.e. tumors with <1% of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification) patients diagnosed and treated at the European Institute of Oncology between 1995 and 2010 (median follow-up 8.2 years, range 6 months to 18 years). All mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor, reported as a percentage value and treated as a continuous variable in survival analysis. RESULTS: The median percentage of TILs was 20%, and 21.9% of the cases had ≥50% (lymphocyte predominant breast cancer, LPBC) TILs. At univariable survival analysis, TILs were a significant predictor of better disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P < 0.0001). Multivariable analysis confirmed that each 10% increase in TILs strongly predicted better survival, independent of patients' age, lymph node status, tumor size, histological grade, peritumoral vascular invasion and Ki-67 labeling index. Patients with LPBC had a 10-year survival rate of 71%, 84% and 96% for DFS, DDFS and OS, respectively. Stratified analysis revealed a positive correlation between TILs and OS across all the subgroups analyzed. CONCLUSION: Our data support the analytical validity of the recently issued TILs evaluation guidelines in the clinical practice.

Long-term function of parathyroid subcutaneous autoimplantation after presumed total parathyroidectomy in the treatment of secondary hyperparathyroidism. A clinical retrospective study.

INTRODUCTION: Parathyroidectomy (PTx) is recommended in patients affected by secondary hyperparathyroidism (2HPT) of chronic kidney disease-mineral bone disorders (CKD-MBD), resistant to medical treatment. Analyzing total parathyroidectomy with muscular or subcutaneous autoimplantation (TPai) outcomes in hemodialysis (HD) 2HPT patients, and monitoring intact parathyroid hormone (iPTH) levels, we evaluated long-term functional results of subcutaneous parathyroid glandular tissue autoimplantation. METHODS: 40 HD 2HPT patients, resistant to medical treatment, and awaiting for renal transplantation, underwent total parathyroidectomy with subcutaneous autoimplantation of 9-12 fragments of not nodular hyperplasia parathyroid tissue in not dominant forearm. iPTH were analyzed 24 h, and 3-6-12-24 months after surgery. The 1.08-6.99 pmol/L range was taken as reference of normal iPTH level based on which eu- (1.08-6.99), hypo- (<1.08), aparathyroidism (0) and persistence or relapse (>6.99) of disease were determined. RESULTS: In every case PTai determined an extraordinary improvement of quality of life, associated with a notable reduction of iPTH serum level. Immediate normalization of iPTH was achieved in 50% of cases; hypoparathyroidism in 25% of cases and persistence of disease in 25% were observed. Long term follow-up showed a reduction of hypoparathyroidism and an increase of relapse rate up to 20%. Grafting resection was never performed. DISCUSSION: Subcutaneous autotrasplantation is a very simple and fast surgical technique. Nevertheless, similar success and recurrence rates were reported following muscular or subcutaneous grafting, as confirmed in our experience. CONCLUSIONS: Subcutaneous grafting was effective as muscular implantation, with comparable functional results, but avoiding its potential complications.

Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms.

Abexinostat is a pan histone deacetylase inhibitor (HDACi) that demonstrates efficacy in malignancy treatment. Like other HDACi, this drug induces a profound thrombocytopenia whose mechanism is only partially understood. We have analyzed its effect at doses reached in patient plasma on in vitro megakaryopoiesis derived from human CD34(+) cells. When added at day 0 in culture, abexinostat inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. These effects required only a short incubation period. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2/STAT signaling. When added later (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet (PPT) formation. Gene profiling from MK revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. DNA double-strand breaks were increased as attested by elevated γH2AX phosphorylation level. Moreover, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, and only partially the defect in PPT formation. These results suggest that HDACi induces a thrombocytopenia by a p53-dependent mechanism along MK differentiation and a p53-dependent and -independent mechanism for PPT formation.

Long-term outcomes following "presumed" total parathyroidectomy for secondary hyperparathyroidism of chronic kidney disease.

AIM: The most efficacious surgical treatment for renal hyperparathyroidism is still subject of research. Considering its low incidence rate of long-term relapse, "presumed" total parathyroidectomy without autotrasplantation (TP) may be indicated for secondary hyperparathyroidism (2HPT) in patients with chronic kidney disease (CKD), not eligible for kidney transplantation. The aim of this study was to analyse the TP long-term results in 2HPT haemodialysis (HD) patients. METHOD: Between January 2004 and October 2009, 25 2HPT HD patients, not eligible for kidney transplantation, underwent TP of at least four parathyroid glands. Clinical status and intact parathyroid hormone (iPTH) serum levels were assessed intraoperatively and during a 36-month follow-up. RESULTS: TP improved the typical clinical symptoms and a significant reduction of iPTH serum levels was achieved in each patient. Aparathyroidism was never observed; in case of severe postoperative hypocalcemia, hypocalcemic seizures were never reported and the long-term recurrence rate was 8%. Only one patient received a kidney transplantation. Postoperative cardiovascular events (hypertension, peripheral artery disease, arrhythmia, coronary or cerebrovascular disease) were observed in 32% of cases and mortality rate was 16%. CONCLUSIONS: Considering its low long-term relapse rate and the absence of postoperative aparathyroidism, TP may still be considered the treatment of choice in patients with aggressive forms of 2HPT or of advanced dialytic vintage, with no access to renal transplantation. In case of postoperative hypoparathyroidism, hypocalcaemia can be effectively managed by medical treatment.

Surgical treatment of papillary thyroid carcinoma without lymph nodal involvement.

BACKGROUND: In the treatment of differentiated thyroid cancer (DTC), in absence of enlarged lymph nodes, the role of routine central lymph node dissection (RCLD) remains controversial. The aim of this study is to analyze data resulting from total thyroidectomy (TT) not combined with RCLD in the treatment of DTC. METHODS: We retrospectively evaluated the clinical records of 80 patients treated between January 1996 and December 2003 with TT without RCLND, in absence of suspected enlarged lymph nodes at preoperative ultrasonography and intraoperatively during neck exploration. In this series, 75 patients (93.7%) underwent radioiodine (RAI) ablation, followed by Thyroid Stimulating Hormone (TSH) suppression therapy. In case of locoregional lymph nodal recurrence, a central (VI) and ipsilateral (III-IV) selective lymph node dissection was performed. RESULTS: Incidence of permanent hypoparathyroidism (iPTH < 10 pg/ml) and unilateral temporary vocal fold paralysis were respectively 2.55% and 2.55%. Locoregional recurrence, with positive cervical lymph nodes, after a 10.3 ± 4.7 years mean follow-up was observed in 3 patients (3.75%). They were submitted to a central (VI) and ipsilateral (III-IV) selective neck dissection without significant complications. CONCLUSIONS: In our series, TT not combined with RCLD was associated to a low locoregional recurrence rate, even if the lack of a control group treated with RCLD does not allow any generalized assumption. RCLD may be indicated in high risk patients, in whom lymph nodal recurrence is more frequent. More prospective randomized studies are needed to better define the role of RCLD and postoperative radioiodine ablation.

Molecular and clinical analysis of predictive biomarkers in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-specific death in the USA and Europe. Over the last two decades, the pathogenetic mechanisms and the molecular alterations of NSCLC have been investigated more intensively, a number of potential therapeutic targets have been identified and new agents against specific molecular targets have been introduced in the treatment of NSCLC. Acquired abnormalities in the genes encoding RAS, p53, KRAS, EGFR and ALK, are particularly important in this field. Whenever targetable mutations are not found, the research of other genetic abnormalities can be useful to personalize chemotherapy. The attention has been focused, in particular, on the endonuclease excision repair cross-complementing1 and BRCA1 status. The use of antimetabolite drugs and the level of expression of their cellular targets seem to be correlated and influence the clinical efficacy of those agents. This review will focus on the role of predictive biomarkers for the treatment of non-small cell lung cancer.

Evaluation of the 'putative' role of intraoperative intact parathyroid hormone assay during parathyroidectomy for secondary hyperparathyroidism. A retrospective study on 35 consecutive patients: intraoperative iPTH assay during parathyroidectomy.

In the surgical treatment of secondary hyperparathyroidism (2HPT) of chronic kidney disease (CKD), a parathyroidectomy (PTx) of 4 glands can only be presumed as 'total', and indications for autoimplantation are complex. Intraoperative rapid parathyroid hormone assay could be useful to predict a radical resection. We evaluated iPTH levels 20 min and 24 h after a 4-gland PTx in 35 patients to determine the predictive value of intraoperative iPTH assay. We analysed retrospectively 35 patients affected by 2HPT of CKD, 13 undergoing total parathyroidectomy (TP) and 22 TP + autoimplantation (TPai), after removing 4 glands in 33 cases and 5 glands in 2. Intact PTH assays were acquired after 40 min before induction of anaesthesia, after removing both ipselateral glands, at 20 min after surgery and on postoperative day 1. 20 min after 4-gland PTx, a decrease of iPTH levels >80 % of the preoperative value was observed in 27 of 35 cases (77.1 %) and <80 % in 8 of 35 cases (22.8 %). In 6 of these 8 patients, iPTH levels were within the normal range 24 h after surgery. Although the intraoperative iPTH assays are of interest in the treatment of 2HPT, the predictive value of this method is not entirely satisfactory. In fact, a 4-gland PTx ensures euparathyroidism in most cases, even when intraoperative iPTH assays are not trustworthy; however, intraoperative iPTH assay, although not a perfect 'tool', is a proved aid for the surgeon in making his decision.

Total parathyroidectomy without autotransplantation in the surgical treatment of secondary hyperparathyroidism of chronic kidney disease.

BACKGROUND: Subtotal parathyroidectomy (SP) and total parathyroidectomy (TP) with autotransplantation (TPai) are the most commonly adopted operations for the treatment of secondary hyperparathyroidism (2HPT). TP without autotransplantation had previously been confined to patients with advanced dialytic vintage, not eligible for kidney transplantation. Over the years, the procedure has gained more widespread use, but there is no precise knowledge on the immediate and long-term effects. METHODS: The authors analyzed the immediate and long-term results of TP without autotransplantation, that is after the systematic removal of at least four glands in 20 patients operated for 2HPT, which were compared with results from TPai in an equal number of cases. RESULTS: An improvement of the typical clinical symptoms was found in every patient undergoing surgery, and a significant reduction in intact PTH (iPTH) serum levels was achieved. Immediate normalization of iPTH level was observed in 11/20 TP cases, hypoparathyroidism in 4/20 and persistent HPT in 5/20 cases. One year of follow-up showed a slight increase in hypoparathyroidism, with 1/20 (5%) recurrence of the disease. One-year TPai results showed a similar percentage of euparathyroidism, as well as a higher longterm recurrence rate (4/20, 20%), although values do not reach statistical significance. CONCLUSIONS: TP may still be considered the operation of choice in patients with aggressive forms of 2HPT or of advanced dialytic vintage, with no access to renal transplantation, because of its low recurrence rate (5%). Post-operative aparathyroidism is rare, while hypoparathyroidism and hypocalcemia can be well controled by medical treatment.

Integrated treatment of secondary hepatolithiasis. Case report.

Hepatolithiasis is defined as the occurrence of stones proximal to the biliary confluence and represents a prevalent disease in South East Asia being uncommon in Western countries. Biliary sepsis, hepatic abscesses and cholangiocarcinoma are considered potential complications. The Authors describe a case of a 68 years male patient affected by a left massive intrahepatic lithiasis secondary to common duct stones and associated to acute pancreatitis. The patient refused surgery and was submitted to a conservative transhepatic percutaneous treatment. After a complete removal of intrahepatic stones and a positioning of external internal biliary drainage (14F), a laparoscopic cholecistectomy was performed. The MRI control showed a complete resolution of the intrahepatic lithiasis. Conservative transhepatic percutaneous approach to hepatolithiasis represents a safe and effective treatment allowing good medium-long term results. Surgery is recommended in case of severe hepatic fibrosis or atrophy, suspected cholangiocarcinoma or multiple strictures with biliary distorsion. Integrated therapeutical protocols in referral multidisciplinary centers-offers the best long term results.

[Surgical treatment of secondary hyperparathyroidism. Results from 47 consecutive patients]. / Trattamento chirurgico dell'iperparatiroidismo secondario. Esperienza clinica in 47 pazienti.

To date surgical treatment of secondary hyperparathyroidism (HPTs) is still controversial. Subtotal parathyroidectomy with sparing of a part of not-nodular gland and total parathyroidectomy with autotransplantation (subcutaneous or muscular) represent the most common procedures with the aim to warrant a condition of euparathyroidism. Total parathyroidectomy (or so presumed) represent an unusual therapeutic option as the risks arising from aparathyroidism and from the need of a substitutive therapy are largely known. The authors evaluate the surgical results collected from 47 consecutive patients affected by HPTs and Chronic Renal Failure (CRF) and operated on between January 1999 and January 2006. Probably, a proper indication to the type of surgical procedure could be based on the severity of the disease, on the age of the patient and on the expectation of transplant. The significant incidence of recurrence and persistent disease is due to autoimplantation or residual gland hypertrophy after subtotal parathyroidectomy, to the presence of supernumerary or ectopic glands, to cervico-mediastinic hypertrophy of cellular foci. The identification and removal of supernumerary glands, which may cause persisting hyperparathyroidism, is mandatory.

Great saphenous varicose vein surgery without saphenofemoral junction disconnection.

BACKGROUND: The aim of this case-control study was to determine whether preoperative duplex imaging could predict the outcome of varicose vein surgery without saphenofemoral junction (SFJ) disconnection. The duplex protocol included a reflux elimination test (RET) and assessment of the competence of the terminal valve of the femoral vein. METHODS: One hundred patients with chronic venous disease who had a positive RET result and an incompetent terminal valve were compared with 100 patients matched for age, sex, clinical class (Clinical Etiologic Anatomic Pathophysiologic (CEAP) class C2-C6) and disease duration, but who had a positive RET result and a competent terminal valve. All patients underwent ligation and proximal avulsion of the incompetent tributaries from the great saphenous vein trunk without SFJ disconnection. Clinical and duplex follow-up lasted for 3 years, and included Hobbs' clinical score. RESULTS: Of legs with a competent terminal valve, 100 per cent were rated as cured (Hobbs' class A or B) and 14.0 per cent developed recurrent varices. Patients with an incompetent terminal valve had significantly worse results: 29.0 per cent had Hobbs' class A or B and 82.0 per cent developed recurrence (P < 0.001). CONCLUSION: Preoperative duplex assessment of the terminal valve could be used to identify patients suitable for varicose vein surgery without the need for SFJ disconnection.

Past, present and future of targeted therapy in solid tumors.

Targeted therapies affecting specific molecular target, expressed preferentially by neoplastic cells, block cancer growth. Current targets are represented by cell-surface trans-membrane proteins, intracellular proteins, and by growth factors. Today a targeted therapy exists for most commonly diagnosed types of human cancer often combined with chemotherapy or sometimes as monotherapy option. The epidermal growth factor receptors (EGFR) and vascular endothelial growth factors (VEGF) are known as the two main control key intracellular pathways, governing fundamental processes in cancer cells. The concept of using anti-EGFR and anti-VEGF strategies, as cancer treatment, has been recently developed and exploited extensively. We review targeted drugs currently available for routine treatment of lung, breast, colorectal and renal cell cancers, summarizing the history of identification and molecular characterization of targets or signaling pathways responsible for abnormal cell growth. We also focus on new targeted strategies, still under investigation, able to affect simultaneously tightly interconnected biological pathways or directed against new molecular targets.

Videolaparo-assisted subtotal colectomy with cecorectal anastomosis in the treatment of chronic slow transit constipation.

Mechanical cecorectal anastomosis after subtotal colectomy, in the treatment of slow transit constipation, probably represents the most attractive surgical alternative to total colectomy and ileorectal anastomosis. In fact the operation allows better results in terms of postoperative diarrhoea, fecal incontinence and postoperative adherential syndrome. Literature data have demonstrated the feasibility of the laparoscopic approach with tipically advantages of less invasive surgery respect of parietal integrity,less postoperative pain and ileus, fewer postoperative adhesions, a reduced hospitalitation and finally, a better cosmesis. The Authors report a case of mechanical end to end cecorectal anastomosis after laparo-assisted subtotal colectomy (by four trocars) preserving superior rectal and ilecolic vessels, for the treatment of slow transit constipation in a 20 years old male patient .The reported operative approach which links tipical laparoscopic advantages to a more "safety" and "accurate" extracorporeal mechanical anastomosis.

Hints of theta13>0 from global neutrino data analysis.

Nailing down the unknown neutrino mixing angle theta{13} is one of the most important goals in current lepton physics. In this context, we perform a global analysis of neutrino oscillation data, focusing on theta{13}, and including recent results [ (unpublished)]. We discuss two converging hints of theta{13}>0, each at the level of approximately 1sigma: an older one coming from atmospheric neutrino data, and a newer one coming from the combination of solar and long-baseline reactor neutrino data. Their combination provides the global estimate sin{2}theta{13}=0.016+/-0.010(1sigma), implying a preference for theta{13}>0 with non-negligible statistical significance ( approximately 90% C.L.). We discuss possible refinements of the experimental data analyses, which might sharpen such intriguing indications.

Regression rate of clinical HPV infection of the lower genital tract during pregnancy after laser CO2 surgery.

The objective of the study was to evaluate the effects of laser CO2 surgery during pregnancy to prevent clinical HPV infection recurrence after delivery and vertical infection. A case-control study was performed on 280 pregnant women affected by clinical HPV infection treated during pregnancy with 256 women treated three months after delivery. Follow-up was performed for a minimum of three colposcopic examinations for two years. Recurrence rates were calculated considering the number of positive findings for at least one colposcopic examination confirmed by biopsy after a negative control in a year. Statistical comparison of rates was performed by chi-squared and Fisher's exact test. Recurrence rates were higher in the women treated in postpartum (p < .01) than in the group treated during gestation (p < .005). Clinical HPV infections treated during the second trimester of pregnancy showed a sensitive decrease in recurrence-rate of infection. Rarity of respiratory papillomatosis makes conclusions inconsistent for the prevention of vertical infection.