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Blood transfusion can have detrimental effects on the pulmonary system, leading to lung injury and respiratory decompensation with subsequent increased morbidity and mortality in surgical and critically ill patients. How much of this effect is carried from a lung donor to transplant recipient is not fully understood, raising questions regarding transplant suitability of lungs from transfused donors.United Network for Organ Sharing data were reviewed. Lung transplants from adult donors and known donor transfusion status were included; multiorgan transplants and retransplants were excluded. Recipient mortality was evaluated based on donor and recipient characteristics using a Kaplan-Meier survival estimate, Cox proportional hazards, and logistic regression models. We further assessed whether recipient mortality risk modified the donor transfusion effect.From March 1996 to June 2017, 20,294 transplants were identified. Outcome analysis based on transfusion status showed nonsignificant difference in 1-year mortality (P = .214). Ninety-day recipient mortality was significantly higher with transfusion of10 units (U) vs 1-10 U or no transfusion (8.5%, 6.1%, and 6.0%, respectively, P = .005). Multivariable analysis showed increased 90-day mortality with transfusion of10 U compared to no transfusion (odds ratio 1.62, P.001), whereas 1-10 U showed no difference (odds ratio 1.07, P = .390). When stratified by recipient transplant risk, transfusion of10 U was associated with increased mortality even with the lowest-risk recipients, while transfusion of 1-10 U showed no mortality increase even in the highest-risk recipients.Donor transfusion of10 U of blood was associated with increased 90-day recipient mortality even in low-risk transplants. This risk should be considered when evaluating donor lungs.

Introduction Advanced breast cancer (aBC) remains incurable and the quest for more effective systemic anticancer agents continues. Promising results have led to the FDA approval of three antibody-drug conjugates (ADCs) and two immune checkpoint inhibitors (ICIs) to date for patients with aBC. Areas covered With the anticipated emergence of newer ADCs and ICIs for patients with several subtypes of breast cancer, and given their potential synergy, their use in combination is of clinical interest. In this article, we review the use of ADCs and ICIs in patients with breast cancer, assess the scientific rationale for their combination, and provide an overview of ongoing trials and some early efficacy and safety results of such dual therapy. Expert opinion Improvement in the medicinal chemistry of next-generation ADCs, their rational combination with ICIs and other agents, and the development of multiparametric immune biomarkers could help to significantly improve the outlook for patients with refractory aBC.

Background Donor lungs with smoking history are perfused in ex vivo lung perfusion (EVLP) to expand donor lung pool. However, the impact of hyperinflation of perfused lungs in EVLP remains unknown. The aim of this study was to investigate the significance of hyperinflation, using an ex vivo measurement delta VT, during EVLP in smoker's lungs. Materials and methods Seventeen rejected donor lungs with smoking history of median 10 pack-years were perfused for 2 h in cellular EVLP. Hyperinflation was evaluated by measuring delta VT = inspiratory − expiratory tidal volume (VT) difference at 1 h. All lungs were divided into two groups; negative delta VT (n = 11, no air-trapping pattern) and positive delta VT (n = 6, air-trapping pattern). Transplant suitability was judged at 2 h. By using lung tissue, linear intercept analysis was performed to evaluate the degree of hyperinflation. Results The positive delta VT group had significantly lower transplant suitability than the negative delta VT group (16 versus 81%, P = 0.035). The positive delta VT group was significantly associated with lower partial pressure of oxygen/fraction of inspired oxygen ratio ratio (278 versus 356 mm Hg, P = 0.049), higher static compliance (119 versus 98 mL/cm H2O, P = 0.050), higher lung weight ratio (1.10 versus 0.96, P = 0.014), and higher linear intercept ratio (1.52 versus 0.93, P = 0.005) than the negative delta VT group. Conclusions Positive delta VT appears as an ex vivo marker of ventilator-associated lung hyperinflation of smoker's lungs during EVLP.

Background Patients with coronavirus disease 2019 (COVID-19) who have underlying malignancy have a higher mortality rate compared with those without cancer, although the magnitude of such excess risk is not clearly defined. We performed a systematic review and pooled analysis to provide precise estimates of the mortality rate among patients with both cancer and COVID-19. Methods A systematic literature search involving peer-reviewed publications, preprints and conference proceedings up to July 16, 2020, was performed. The primary end-point was the case fatality rate (CFR), defined as the rate of death among patients with cancer and COVID-19. The CFR was assessed with a random effects model, which was used to derive a pooled CFR and its 95% confidence interval (CI). Results Fifty-two studies, involving a total of 18,650 patients with both COVID-19 and cancer, were selected for the pooled analysis. A total of 4243 deaths were recorded in this population. The probability of death was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%) in this patient population. Conclusions Patients with cancer who develop COVID-19 have high probability of mortality. Appropriate and aggressive preventive measures must be taken to reduce the risk of COVID-19 in patients with cancer and to optimally manage those who do contract the infection., Highlights • Patients with both cancer and coronavirus disease 2019 (COVID-19) have a higher mortality than reported in the overall COVID-19-positive population. • We aim to provide precise mortality estimates among patients with cancer and COVID-19. • Pooled case mortality rate was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%). • Aggressive measures must be taken to reduce risk of infection in patients with cancer.

Background Although the safety and feasibility of combined coronary artery bypass grafting (CABG) and bone marrow stem cell (BMSC) transplantation have been proven, the efficacy of this approach remains controversial. Therefore, we conducted an updated meta-analysis of randomized controlled trials to evaluate the efficacy of this procedure. Methods Electronic databases were systematically searched for randomized trials comparing 4-month to 6-month follow-up outcomes in patients who underwent isolated CABG (CABG group) and patients who received BMSC transplantation with CABG (BMSC group). A random-effects meta-analysis was conducted across eligible studies. Meta-regression and subgroup analyses were utilized to identify sources of data heterogeneity. Results Thirteen trials were eligible, with a total number of 292 patients in the BMSC group and 247 patients in the CABG group. Compared with the CABG group, the BMSC group showed significant improvement of follow-up left ventricular ejection fraction (n = 539, 4.8%; 95% confidence interval [CI], 2.3%-7.3%; P = .001). The analyzed data showed significant heterogeneity (I2 = 74.2%, P Conclusions The present evidence suggests that combined CABG and BMSC transplantation is associated with improvement of left ventricular ejection fraction. However, the heterogeneity in the data suggests variations in patient response to this therapy. Further studies are required to understand these variations.

OBJECTIVES Typically, single-lung ex vivo lung perfusion (SL-EVLP) is preferred when there is concern of contamination from the opposite lung. However, a comprehensive assessment of the SL-EVLP has not been completed. The purpose of this study is to compare the physiological parameters of SL-EVLP and double-lung EVLP (DL-EVLP) in the assessment of transplant suitability. METHODS Seven pairs of rejected donor lungs were perfused in cellular EVLP, with a tidal volume of 6 ml/kg ideal body weight and a perfusion flow of 70 ml/kg/min. The transplant suitability of each side was judged in the DL-EVLP. Subsequently, the tidal volume and flow were reduced by half. The right SL-EVLP was maintained for 10 min by clamping the left main pulmonary artery and the bronchus. Similarly, left SL-EVLP was performed. The physiological parameters were compared between SL-EVLP and DL-EVLP. RESULTS PO2/FiO2 ratio was significantly lower in SL-EVLP than in DL-EVLP [182.5 (127.5-309.5) vs 311.5 (257.5-377.0) mmHg, P

BACKGROUND Lung transplantation (LTx) is a definitive treatment for end-stage lung disease. Herein, we reviewed our center experience over 3 decades to examine the evolution of recipient characteristics and contemporary predictors of survival for LTx. METHODS We retrospectively reviewed the data of LTx procedures performed at our institution from January 1990 to January 2019 (n = 1819). The cohort is divided into 3 eras; I: 1990-1998 (n = 152), II: 1999-2008 (n = 521), and III: 2009-2018 (n = 1146). Univariate and multivariate analyses of survival in era III were performed. RESULTS Pulmonary fibrosis has become the leading indication for LTx (13% in era I, 57% in era III). Median recipient age increased (era I: 46 y-era III: 61 y) as well as intraoperative mechanical circulatory support (era I: 0%-era III: 6%). Higher lung allocation score was associated with primary graft dysfunction (P

Aim To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. Patients and methods 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac). Results At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74–1.00) for L+T versus T and 0.93 (95% CI, 0.81–1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70–1.06) for L+T versus T and 0.88 (95% CI, 0.71–1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64–1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69–1.00; 6-yr DFS% = 83% versus79%)] subgroups. Conclusion T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer. Trial Registration clinicaltrials.gov Identifier NCT00490139 .

OBJECTIVES Survival is poor following an orthotopic heart transplant with gender-mismatched donors and recipients. Patients bridged to an orthotopic heart transplant with a ventricular assist device (VAD) frequently become sensitized. We hypothesized that the combination of VAD bridging and gender-mismatch may result in greater rejection and poorer survival. METHODS Data were obtained from the United Network of Organ Sharing database. Patients were divided into 4 groups: (i) VAD recipients who received a heart from a gender-matched donor (VAD-M); (ii) VAD recipients who received a heart from a gender-mismatched donor (VAD-MM); (iii) noVAD recipients who received a heart from a gender-matched donor (noVAD-M); and (iv) noVAD recipients who received a heart from a gender-mismatched donor (noVAD-MM). Rejection episodes within 1-year post-transplant and transplant survival were compared in VAD-M versus VAD-MM and noVAD-M versus noVAD-MM groups, respectively. RESULTS Between January 2000 and June 2017, of 33 401 adult patients who underwent heart transplants, 8648, 2441, 12 761 and 4992 patients were identified as VAD-M, VAD-MM, noVAD-M and noVAD-MM, respectively. Rejection within 1-year post-transplant occurred in 23.3% and 27.3% of the VAD-M and VAD-MM groups, respectively (P CONCLUSIONS Our results indicated that the combination of VAD bridging and gender-mismatch caused greater rejection and worse survival following a transplant. Further study is necessary to prove comparable post-transplant survival of gender-matched or -mismatched recipients without VAD bridging.

Objective To evaluate blue-light flexible cystoscopy (BLFC) with hexaminolevulinate in the office surveillance of patients with non-muscle-invasive bladder cancer with a high risk of recurrence by assessing its impact on pain, anxiety, subjective value of the test and patient willingness to pay. Materials and methods A prospective, multicentre, phase III study was conducted during which the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, Pain and 'Was It Worth It' questionnaires were administered at baseline, after surveillance with BLFC and after resection for those referred to the operating room. Comparisons of scores were performed between groups. Results A total of 304 patients were enrolled, of whom 103 were referred for surgical examination. Of these, 63 were found to have histologically confirmed malignancy. Pain levels were low throughout the study. Anxiety levels decreased after BLFC (∆ = -2.6), with a greater decrease among those with negative pathology results (P = 0.051). No differences in anxiety were noted based on gender, BLFC results, or test performance (true-positive/false-positive). Most patients found BLFC 'worthwhile' (94%), would 'do it again' (94%) and 'would recommend it to others' (91%), with no differences based on BLFC results or test performance. Most patients undergoing BLFC (76%) were willing to pay out of pocket. Conclusions Anxiety decreased after BLFC in patients with negative pathology, including patients with false-positive results. Most of the patients undergoing BLFC were willing to pay out of pocket, found the procedure worthwhile and would recommend it to others, irrespective of whether they had a positive BLFC result or whether this was false-positive after surgery.

Background Limited data exists on the long-term effects of aneurysmal subarachnoid hemorrhage (SAH) on spatial memory. Herein, we used a computerized virtual water maze to evaluate the feasibility of spatial memory testing in pilot cohort of ten patients who survived previous SAH. Methods Ten SAH survivors (5.8 ± 5.1 years after initial hemorrhage) and 7 age-matched controls underwent testing in a virtual water maze computer program. Additional subgroup analyses were performed to evaluate spatial reference memory correlation for ventricular size on admission, placement of an external ventricular drain and placement of a shunt. Results With respect to the spatial memory acquisition phase, there was no significant difference of pathway length traveled to reach the platform between SAH survivors and control subjects. During the probe trial, control subjects spent significantly longer time in target quadrants compared to SAH survivors (F(3, 24) = 10.32, p = 0.0001; Target vs. Right: Mean percent difference 0.16 [0–0.32], p = 0.045; Target vs. Across: Mean percent difference 0.35 [0.19–0.51], p Conclusions Our data demonstrate that SAH survivors have persistent spatial reference memory deficits years after the hemorrhage. Hydrocephalus at presentation and external ventricular drainage were not found to be associated with poor spatial memory outcomes in this pilot cohort. Therefore, other causes such as global cerebral edema or magnitude of initial ICP spike, need to be considered to be examined as root cause as well in subsequent studies. The protocol described in this manuscript is able to demonstrate a spatial reference memory deficit and can be used to study risk factors for spatial memory impairment on a larger scale.

Purpose Lung weight (LW) gain is a typical characteristic of ischemia reperfusion injury in ex-vivo lung perfusion (EVLP). However, LW gain data is available only at the end of EVLP. Additionally, objective physiological parameters useful in EVLP evaluation are limited. The study purpose was to investigate the usefulness of real-time LW measurement to assess pulmonary edema and to predict clinical outcomes. Methods LW at back table was measured before and after EVLP. During acellular EVLP, real-time LW was continuously measured by a scale attached under the organ chamber. The LW change (weight change per time, g/min) was measured during the non-touching period at multiple time points and the estimated LW gain was calculated by LW change and its duration. Transplant suitability was judged based on the standard criteria including trend of physiological parameters and palpation findings. Results Ten lungs were perfused at our institute and 8 lungs were clinically transplanted. All patients survived and primary graft dysfunction (PGD) grade at 72 hours were Grade 0-1, n = 6; Grade 2, n = 2; Grade 3, n = 0. Estimated LW gain during the entire perfusion period significantly correlated with LW gain at the back table (n = 10, r = 0.95, p Conclusion The data suggest that LW gain calculated by real-time LW measurement might be useful to assess pulmonary edema during EVLP. Initial LW gain at 0-60 min of EVLP might be a predictor of transplant suitability and clinical outcomes.

We present an innovative method for recruiting clinically rejected donor lungs using positive end-expiratory pressure titration during ex vivo lung perfusion. Currently, ex vivo lung perfusion protocols are using a standard positive end-expiratory pressure of 5 cmH2O for all cases. Individualized positive end-expiratory pressure titration combined with recruitment manoeuvres has been found to significantly improve pulmonary functions in mechanically ventilated patients. Applying this concept to ex vivo lung perfusion may be helpful in increasing the conversion rate for transplant suitability.

Purpose Evidence suggests that high grade primary graft dysfunction after lung transplantation (LTx) is a major threat for early and late outcomes. Herein, we aim to examine the risk factors and clinical impact of PGD in a contemporary cohort at a single center. Methods From 1/2008 to 7/2018, 1147 LTx procedures were performed at our institution. Clinical data was prospectively collected and PGD defined according to ISHLT criteria. Median follow up was 3.3 years (interquartile range 1.2 - 7.4). Multi-variable analysis utilizing recipient, donor, and LTx procedure variables was performed to assess risk factors for PGD, acute rejection, chronic lung allograft dysfunction (CLAD), early mortality, and late survival. Results Out of 1147 LTx procedures, 61% were bilateral. The incidence of PGD (grade II & III) was 13% & 15% at 24 hr , 12% & 14% at 48 hr , and 12% & 14% at 72 hr, respectively. Multi-variable analysis identified cardiopulmonary bypass usage/duration, single LTx, recipient pulmonary arterial hypertension, longer ischemic time, earlier year of LTx, older donor, higher Lung Allocation Score, and higher ratio of recipient/donor weight as risk factors for high grade PGD (grade II or III at 48-72 hr). Notably, recipient body mass index, donor smoking history, and diabetes were not significant risk factors for high grade PGD. Further analysis demonstrated that PGD II or III at 48-72 hr were independent significant risk factors for early mortality and higher acute rejection grades, while not significantly associated with CLAD or late survival. PGD grade II or III at 24 hr were not significant risk factors for early mortality, acute rejection, CLAD, or late survival. Conclusion This single-center data analysis of > 1000 contemporary lung transplants identified risk factors for high grade PGD. While high grade PGD at 48-72 hr was associated with higher risk of early mortality and acute rejection, in contrast to previous studies, it was not associated with a higher risk of CLAD or late survival, perhaps due to evolving management strategies.

Purpose Assessment of marginal donor lungs during asanguineous ex vivo lung perfusion (EVLP) can be challenging due to limited objective parameters. We hypothesized that determination of PaO2/FiO2 (P/F) ratio from each lobar vein can provide valuable information regarding lobar function. The aim of this study is to determine lobar vein P/F ratio during EVLP and correlate with standard EVLP assessment parameters as well as post-transplant outcomes. Methods Data from 139 lungs from 75 donors assessed in asanguineous EVLP from Feb 2016 to April 2020 were analyzed for this study. Transplant suitability of lungs was determined based on standard EVLP parameters. pO2 was assessed from each pulmonary vein at the time of standard evaluation. In transplanted EVLP lungs, primary graft dysfunction (PGD) was assessed at 72 hours. Results In the favorable group (defined as PGD grade 0-1), both P/F ratio at left atrium (P/F LA) and P/F ratio at lower lobe pulmonary vein (P/F LPV) were significantly higher than that of the unfavorable group (non-suitable or PGD grade 2-3) (LA, 496±77 vs. 444±74 mmHg, P Conclusion These results suggest that determination of lobar P/F ratio during EVLP can provide additional, valuable information for lung assessment. Deterioration of lobar function might be masked assessment of only LA P/F ratio and potentially lead to a greater incidence of high-grade PGD after lung transplantation.

Purpose Lung assessment of marginal donor lungs on ex vivo lung perfusion (EVLP) can be challenging due to limited objective parameters. Currently, the significance of isolated differential analysis of blood gas (ABG) from each lobar pulmonary vein is not clear. The aim of this study is to identify the impact of differential ABG (D-ABG) on EVLP evaluation, and compare the D-ABG with the post-transplant outcomes. Methods From Feb 2016 to August 2019, 110 EVLP lungs from 57 donors were analyzed for this study. Donor lungs were perfused with an acellular EVLP protocol, and transplant suitability of lungs was evaluated based on standard EVLP parameters. D-ABGs were taken from each pulmonary vein at the same time of standard evaluation. In transplanted EVLP lungs, primary graft dysfunction (PGD) was assessed at 72 hours. Results In the favorable group (defined as PGD grade 0-1), both PaO2/FiO2 (P/F) ratio at left atrium (P/F LA) and P/F ratio at lower lobe pulmonary vein (P/F LPV) were significantly higher than that of the unfavorable group (non-suitable or PGD grade 2-3) [LA, 526 (466-574) vs. 437 (386-499) mmHg, P Conclusion These results suggest that D-ABG on EVLP could provide additional, valuable information for evaluation. The deterioration of lobe oxygenation might be masked throughout whole lung ABG; however, low D-ABG of the lower lobe may predict a greater incidence of high-grade PGD after lung transplantation.

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease.

To summarize the current knowledge about the clinical role of novel urinary markers in bladder cancer (BCa) management, from diagnosis to follow-up, from prognosis of oncological outcomes to response to intravesical therapy.Urinary markers have been developed to overcome the limitations of the current available tools for the diagnosis and surveillance of BCa patients. However, to date, because of their limited performances, urinary markers are not generally used in clinical practice. For a marker to be of clinical benefit, it needs to be better, easier, faster and cheaper. The differential requirements for a marker's diagnostic performances depend on goals for clinical utility. Their most promising role seems to be in settings such as in case of equivocal cystoscopy/cytology during follow-up of nonmuscle invasive tumors. Newer markers are available or in development using panels of markers of RNA expression or methylation.To date, there are multiple urine markers that have improved sensitivity over cytology but there is lack of validation of clinical utility. Some of the recently developed markers aim to change the paradigm of BCa follow-up by replacing or reducing the need of invasive investigations. Further prospective validations are needed to confirm these findings.

Objective Prone positioning has been shown to improve oxygenation in patients with lung injury. We hypothesized that prone positioning of lungs during ex vivo lung perfusion (EVLP) can not only improve oxygenation but also diminish ischemia–reperfusion injury (IRI). The aim of our study was to evaluate the potential benefits of prone positioning of lungs during EVLP compared with the standard supine position. Methods Ten pigs were kept in the supine position at room temperature for 2 hours after circulatory death after which lungs were procured and subjected to 5 hours of cold storage. Lungs then underwent 2 hours of cellular EVLP with either supine positioning (Control group, n = 5) or prone positioning (Prone group, n = 5). Lung function was evaluated by assessment of physiological parameters and tissue histology and cytokines. Results IRI in the Prone group was significantly less than in the Control group. Lungs in the Prone group were significantly associated with greater partial pressure of oxygen/fraction of inspired oxygen ratio median (minimum-maximum) (301 mm Hg [272-414 mm Hg] vs 166 mm Hg [109-295] mm Hg, P = .03), better static compliance (38.9 mL/cmH2O [31.1-44.3 mL/cmH2O] vs 21.5 mL/cmH2O [12.2-33.3 mL/cmH2O], P = .03), lower lung weight ratio (1.26 [1.24-1.41] vs 1.48 [1.36-2.34], P = .02), and lower interleukin-1β levels (1.6 ng/mL [0.9-5.3 ng/mL] vs 7.5 ng/mL [5.0-16.1 ng/mL], P = .04) compared with lungs in the Control group. Conclusions These data suggest that prone positioning of lungs during EVLP may diminish IRI during EVLP and improve lung function.

Objective of the study: There is enough evidence for the carcinogenicity of HPV16 type in the head and neck cancers. This study aimed to address key information gaps of the prevalence of HPV infection in laryngeal squamous cell carcinoma in Azerbaijan population. Materials and methods: 50 LSCC pretreatment FFPE biopsy tumor materials, 10 cervical cancer FFPE samples and 38 fresh pretreatment LSCC tumor materials were analyzed using RT-PCR technology and Anyplex II HPV28 genotyping assay. The FFPE tumor material with HPV positive history from cervical cancer was as control in this study. Results: DNA extraction from FFPE and fresh samples was successful for all 98 tumor materials. The results of HPV genotyping of cervical cancer patients (n=10) with Anyplex II HPV28 assay detected 8 HPV16-positive cancers, 1 samples with HPV18-positive and 1 cancer material with HPV16+HPV18+HPV58. The results were predictable, because in these patients, HPV positivity was validated by Pap smear method. Based on this, we expect to get true information about HPV-related LSCC. Anyplex IIHPV28 genotyping assay was detected only one HPV positive sample of 61 LSCC: it was low-risk cancer-related HPV54 subtype in 47 age’s patient with 20 years tobacco and alcohol consumption history. High-risk cancer related HPV16 and HPV18 subtypes have no detected in analysis patients. Conclusion: Thus, we suggested that PCR techniques and Anyplex II HPV28 genotyping assay were available to detect HPVs from fresh LSCC material. Our results support us to believe that Azerbaijan belongs to HPV low-incidence geographic region of laryngeal squamous cell carcinoma patients, but large-scale population-based studies are needed to confirm our findings.

Purpose We previously reported that prone positioning (PP) of porcine lungs during cellular ex vivo lung perfusion (EVLP) diminished inflammatory injury and improved oxygenation and other pulmonary parameters during cellular EVLP. We hypothesized that prone positioning of human lungs during cellular EVLP may diminish injury and improve function, as well. The aim of this study is to validate the previous results with porcine lungs and evaluate the potential benefits of PP EVLP with human rejected donor lungs. Methods Eleven human rejected donor lungs were flushed and stored for 15-16 hours with Perfadex. Lungs were then subjected to 2 hours of cellular EVLP with either maintenance of prone positioning (prone group, n = 6) or supine positioning (control group, n = 5). Lung function was evaluated using blood gas analysis, airway and vascular parameters, visual findings, wet/dry (W/D) ratio and lung weight at 2 hours of EVLP. Results Lung weight (LW) ratio (LW at 2 hours of EVLP/ LW prior to EVLP) was lower in Prone group than in Control group [median (interquartile range)] [1.09 (0.82-1.32) vs. 1.22 (1.01-1.50), p = 0.5] (not statistical significant). The PaO2/FiO2 (P/F) ratio of left atrial blood was significantly higher in Prone group than in Control [335.5 (297.2-392.5) vs. 198.0 (190.5-271.0) mmHg, p Conclusion These results demonstrate that PP during 2 hours of cellular EVLP result in less lung weight gain, and better P/F ratio, especially in the lower lobes. These results were consistent with our previous animal study, and suggest that prone positioning EVLP of rejected human donor lungs also may diminish IRI during EVLP.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.

INTRODUCTION Diffuse idiopathic skeletal hyperostosis (DISH) is a musculoskeletal disorder in which ligaments and entheses slowly become ossified, leading to decreased mobility and pain. The prevalence is variably reported as between 3% and 25% of the population over 50. In Australasia, the prevalence and severity of DISH has long been thought by radiologists to be high in certain populations, particularly among Pacific Islanders. The purpose of this study is to investigate the prevalence and severity of DISH in a Pacific Islander community. METHODS Chest radiographs in 459 individuals were retrospectively reviewed to assess for the presence of features consistent with DISH, as per the Resnick Criteria. Each radiograph was also assessed for the number of vertebral bodies involved. The clinical records of these patients were accessed to obtain the patient's ethnicity. RESULTS The prevalence of DISH in our group overall was 138/459 (30%) with a prevalence of 42/96 (44%) in the Pacific Islanders. The difference compared to the Europeans in the group is highly significant (P

Introduction: Certain genotypes of human papillomavirus (HPV) are linked to cervical abnormalities. HPV DNA and genotype prevalence among women residing in Riyadh, Saudi Arabia is investigated in this hospital-based study. Methodology: Cervical specimens were taken from 519 subjects along with consent and demographic data. DNA was extracted and PCR was performed on all specimens using general primers. Low- and high-risk HPV genotypes were determined by reverse blot hybridization assay using specific probes. SPSS version 17 was used for the data analysis. Results: Of 519 cervical specimens, 164 (31.6%) were positive for HPV DNA. There was a significant association between HPV positivity and abnormal cytology (p < 0.00001). Even though the HPV positivity was relatively high, the squamous intraepithelial lesions were minimal, with one low grade and one high grade case among those HPV DNA-positive specimens. Regardless of single or multiple infections per specimen, HPV-16 was found in 87.8%, followed by HPV-18 in 86%, and HPV-11 in 78.3%. Conclusions: Amplification technology showed that HPV is common among women in Riyadh, Saudi Arabia, with a strong association between HPV infection and cytological changes. HPV-16 was the most frequent genotype but had a low prevalence of cervical cancer.

Purpose Normothermic cellular ex-vivo lung perfusion (EVLP) can provide a platform for studying ischemia-reperfusion injury (IRI), with the donor lungs being the only source of cytokine appearance in the perfusate. The inflammatory effects of cellular EVLP on lungs are inadequately explored. Herein, we aimed to examine the reperfusion inflammatory state during cellular EVLP in relation to donor factors and impact on lung function. Methods For research purposes, 42 clinically rejected donor lungs underwent normothermic cellular EVLP with open left atrium and flow equivalent to 100% of cardiac output for 2 hours. Reasons for rejection were donor old age, smoking history, low PO2/FiO2 (P/F) ratio, or unavailability of a matched recipient. Perfusate samples were collected at the beginning of EVLP (0 hours), then at 1 and 2 hours of EVLP. Lung weight was measured at the end of EVLP as an indicator for the degree of edema. Data were presented as median (interquartile range). Results Interleukin (IL)-6, IL-8, IL-10, IL-1β, and tumor necrosis factor (TNF)-α were significantly up-regulated in the EVLP perfusate at 1 and 2 hours compared to baseline 0 hours (p Conclusion Cytokine array has shown that cellular EVLP is associated with reperfusion inflammatory state in human lungs. IL-1β and IL-10 were mostly affected by donor factors, while IL-6, IL-8, and TNF-α had the most effect on lung function during EVLP. These results suggest that cellular EVLP can be utilized to study human lung IRI and develop therapeutic targets.

Purpose Antibody-mediated rejection (AMR) affects survival and incidence of chronic lung allograft dysfunction (CLAD) after lung transplantation, however, the impact has not been adequately assessed. The aim of this study was to investigate the survival of AMR patients based on new criteria established by International Society of Heart and Lung Transplantation (ISHLT) committee and to assess the risk ratio for CLAD including bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Methods We performed a retrospective, single center cohort study and identified cases who developed AMR based on the new ISHLT-criteria. Risk factors including AMR as a time varying covariate for death and incidence of CLAD were assessed with multivariate analysis. Results Between Jan 2012 and Dec 2016, 489 adult lung transplants were performed. Follow up was completed through Jun 2018. The mean ± SD of age was 58 ± 13 yo, and there were 140 (29%) females. Mean overall follow-up time was 3.5 ± 1.5 years. There were 328 cases with AMR (clinical definite, 4; clinical probable, 29; clinical possible, 26; subclinical definite, 3; subclinical probable, 47; subclinical possible 219). Class II donor specific antibodies (DSA) (hazard ratio; 3.64 ± 0.29, p Conclusion Our study demonstrated that subclinical, definite, probable or possible AMR did not significantly associated with death or CLAD after lung transplantation, although clinical AMR independently affected transplant survival and incidence of CLAD. Further study is necessary to investigate the reliability of the criteria.

Background: About one third of hormone-receptor (HR)-positive, HER2-normal breast cancer (BC) patients with residual disease after neoadjuvant chemotherapy (NACT) have a substantial risk of relapse. Those patients can be identified using validated clinical-pathologic stage–estrogen/grade (CPS-EG) scoring system. Palbociclib is an oral, highly selective inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by inhibiting cell cycle progression. Luminal tumors have been shown to be sensitive to palbociclib. In a phase 2 study, palbocilcib extended PFS in combination with letrozole as first-line hormonal treatment for advanced BC. In addition, it has shown single agent activity in patients with multiply relapsed hormone positive ABC. Methods: PENELOPE (NCT01864746) is a prospective, international, multicenter, randomized, double-blind, placebo-controlled, phase 3 study aiming to demonstrate that 1 year of adjuvant treatment with palbociclib, in addition to standard anti-hormonal therapy, provides a superior invasive disease-free survival (iDFS) and acceptable safety profile compared to placebo in women with HR-positive/HER2-normal early BC who did not obtain a pathological complete response (pCR) after taxane-containing NACT and are at high risk of relapse (CPS-EG score ≥3). After completion of NACT and adequate surgery and radiotherapy, 800 patients will receive standard adjuvant endocrine treatment (5years) and will be randomized (1:1) to 13 cycles of palbociclib 125mg daily or matching placebo on d1-21 in a 28d cycle. Randomization will be dynamic and patients will be stratified by histological lymph node status at surgery (ypN 0-1 vs ypN2-3), age at first diagnosis (< = 50 vs >50 yrs), Ki-67 (>15% vs < = 15%), pRB and cyclin D immunoreactive scores in residual tumor after NACT (< = 2 vs >2 points), global region of participating site (Eur vs N.America vs RoW). Patients will be followed until any invasive local, regional or distant recurrence, diagnosis of secondary malignancy, unacceptable toxicity, withdrawal of consent or study termination. Primary objective is to compare iDFS for palbociclib vs placebo. Secondary objectives are iDFS excluding second non-breast cancers, overall, distant disease-free and locoregional recurrence-free survival, iDFS per treatment arm in luminal-B tumors, compliance and safety, patient reported outcomes, health economics, correlations between drug exposure and efficacy/safety findings. Further objectives are translational and aim to identify scores/markers for their prognostic value and predictive information on efficacy/safety of palbociclib in this specific setting. Results: Recruitment is planned to start in Oct 2013 at 200-250 sites in 11 countries and continue for 3years. Conclusion: PENELOPE will study whether palbociclib is an effective treatment with a sufficiently favorable safety profile for patients with high risk of recurrence and high CPS-EG score after NACT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-11.

Background: The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is important for the oncogenic function of HER2. Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in patients (pts) with advanced BC as a single agent, and in combination with paclitaxel (Dirix et al. ESMO 2012) or trastuzumab (Pistilli et al. ESMO 2012). Study design: NeoPHOEBE (NCT01816594) is a Phase II, randomized, double-blind, parallel-cohort study of neoadjuvant buparlisib or matched placebo plus trastuzumab and weekly paclitaxel. Upfront stratification of pts into 2 independent cohorts according to PIK3CA mutation status will determine whether pts with PIK3CA-mutant tumors may benefit more from this treatment combination. Adult women with newly diagnosed, HER2-positive, primary non-inflammatory BC who have not previously received systemic therapy for invasive disease are eligible. Other eligibility criteria: tumor size >2 cm; unilateral disease; available tumor tissue for central review of estrogen receptor (ER) and HER2 status, and PIK3CA genotype; known PIK3CA mutation status; and ECOG PS ≤1. Pts in each cohort (PIK3CA mutant or wild-type [wt]) are randomized (1:1) to receive continuous daily buparlisib (100 mg) or placebo and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg) for 6 weeks, followed by continuous daily buparlisib (80 mg) or placebo with weekly trastuzumab (2 mg/kg) and weekly paclitaxel (80 mg/m2) for 12 weeks. Study treatment is followed by surgery within 4 weeks of last paclitaxel dose. Stratification at randomization is based on PIK3CA (mutant vs wt) and ER (positive vs negative) status. Endpoints: All endpoints will be measured in both PIK3CA-mutant and wt cohorts. The primary endpoint is rate of pathologic complete response (pCR; ypT0) at time of surgery. The key secondary endpoint is objective response rate (ORR) at the end of week 6. Other secondary endpoints include pCR by other definitions, ORR prior to surgery, pCR and objective response by ER status, percent of pts with node-negative disease at surgery, rate of breast conserving surgery, and safety. Exploratory objectives include change in standardized uptake value (SUV) at Day 15 by FDG-PET; and ORR and pCR by PTEN expression, Ki67 level, apoptosis rates, percentage of tumor infiltrating lymphocytes (TIL), and by phenotype of 50% TIL at baseline. Statistical methods: The sample size is based on a minimax 2-stage randomized Phase II design with a prospective control. This design allows for early stopping if the desired efficacy is not observed after stage 1. Both cohorts are powered (80%) to detect a clinically meaningful increase in pCR of 18% at a one-sided significance level (α = 0.15). Target accrual: Planned enrollment for NeoPHOEBE is up to 220 pts at 65 sites in 12 countries across South America, Europe, and Asia-Pacific. Contact: For further study information, contact BIG@bordet.be. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-08.

Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus.

Urothelial tumors represent a spectrum of diseases with a range of prognosis. After a diagnosis is established at any point within the urothelial tract, the patient remains at risk for developing a new lesion at a different or the same location and at a similar or more advanced stage. Continued monitoring for recurrence is an essential part of management, because most recurrences are superficial and can be managed endoscopically. Within each category of disease, more refined methods to determine prognosis and guide management, based on molecular staging, are under development with the goal of optimizing the individual patient's likelihood of cure and chance for organ preservation. For patients with more extensive disease, newer treatments typically involve combined-modality approaches, using recently developed surgical procedures, or three-dimensional treatment planning for more precise delivery of radiation therapy. Although these are not appropriate in all cases, they do offer the promise of an improved quality of life and prolonged survival. Finally, within the category of metastatic disease, a number of new agents have been identified that appear to be superior to those currently considered to be standard therapies. Experts believe, therefore, that the treatment of urothelial tumors will evolve rapidly over the next few years, with improved outcomes for patients at all stages of disease.

We report a case of gastro-pleural fistula following a thoraco-abdominal penetrating trauma that was diagnosed early with very simple noninvasive modalities. Such type of penetrating injuries should be monitored closely and investigated adequately to exclude this type of complication. In spite of being a rare complication for penetrating chest trauma, gastro pleural fistula is a severe and sometimes fatal complication that requires early diagnosis and prompt surgical intervention.

In the recent past, there has been an impressive growth in the number of clinical trials launched worldwide, including India. Participation in well-designed oncology clinical trials is of advantage to Indian healthcare system in general, and cancer patients in particular. However, the number of clinical trials being run in India is not commensurate with the cancer burden prevailing in the country. In this article, the authors investigate the reasons for this discrepancy, highlight critical bottlenecks, and propose ways to ameliorate the situation.

A range of studies have analyzed prognostic factors in bladder cancer. However, prior cohorts have included heterogeneous pT classification at biopsy and others were derived from large, multi-institutional clinical trials over the span of many years. Our objective was to analyze prognostic factors in a recent radical cystectomy (RC) cohort at a single institution and evaluate outcomes based on current practice patterns. A retrospective analysis of overall survival (OS) was conducted on 180 RC patients with biopsy proven pT2 disease between 2007-2010. Increasing pT classification was a negative predictor of survival. pT was grouped into three categories with pT0/a/is/1/2a surviving longer than pT2b/3a/3b, and pT4 having the worst prognosis. Subclassifying pT2 and pT3 showed no statistically significant difference in survival. Lymphovascular invasion (LVI) and node positivity correlated with decreased OS. Patients treated with neoadjuvant chemotherapy (NAC) had a higher incidence of pT0, yet pN1+ was more common and NAC was not associated with improved OS. This investigation provides reference OS values for patients with pathologically diagnosed muscle-invasive bladder cancer based on current medical guidelines outside the context of a clinical trial. pT4 was the strongest negative predictor of survival, followed by pN1+, the group pT2b/3a/3b, and presence of LVI. NAC patients were noted to have a higher frequency of low pT classification, yet more frequent node positivity, suggesting that pT classification in NAC patients may not accurately reflect remaining tumor burden.

An evaluation of the benefit-versus-risk of bevacizumab in the treatment of advanced breast cancer is timely and relevant. Recently, the US FDA has withdrawn the approval of bevacizumab as a therapeutic option for the treatment of advanced breast cancer, generating controversy in the scientific community. Although the pivotal study (Eastern Cooperative Oncology Group 2100 trial [E2100]) had shown doubling of the progression-free survival when bevacizumab was added to chemotherapy, this magnitude of benefit could not be replicated in subsequent studies. Furthermore, individual studies and meta-analyses failed to demonstrate an overall survival benefit with the addition of bevacizumab to different chemotherapy regimens. In addition, this agent is associated with an increased incidence of serious adverse events such as hypertension, congestive heart failure and thromboembolism, and its cost is likely to be a consideration in its use for many patients worldwide. Retrospective biomarker-based studies aiming to identify the subpopulation of patients most likely to benefit from the addition of bevacizumab to standard chemotherapy in breast cancer should be a research priority.

HER2-positive tumors comprise 15% to 20% of all breast cancers (BC) and are associated with worse clinical outcomes [Slamon et al. Science 1987;235:177-82]. Trastuzumab is a humanized monoclonal antibody designed to target the extracellular domain of the HER2 receptor, and is the foundation of care of women with early and advanced HER2-positive BC. However, a significant proportion of patients with this type of BC display either primary or secondary resistance to trastuzumab. Therefore, in an effort to overcome such resistance and further improve the outcome of patients with HER2-positive disease, several new anti-HER2 agents are currently being developed. These include small molecules that inhibit the HER2 tyrosine kinase activity (lapatinib, neratinib), monoclonal antibodies directed at other epitopes of the HER2 extracellular domain (pertuzumab), antibody-drug conjugates (trastuzumab-DMl), and heat shock protein 90 inhibitors (tanespimycin). A great deal of interest has been generated by recent data from the randomized neo-adjuvant studies NeoALTTO and NeoSphere, which have shown that dual blockade of the HER2 receptor with anti-HER2 agents is significantly superior to using one agent alone. If these results are validated in larger ongoing and planned phase III studies in early BC, they could lead to a paradigm shift in treatment strategy. Therefore, to avoid unnecessary toxicities and costs, it is critical to intensify the research for biomarkers that can identify those patients most likely to benefit from specific targeted therapies., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Takotsubo cardiomyopathy (TTC) is characterized by clinical and electrocardiographic features that mimic acute myocardial infarction, normal or mildly elevated cardiac enzymes, distinctive left ventricular wall motion abnormalities, and absence of significant obstructive coronary artery disease. Often there is a history of emotional stress and usually encountered in postmenopausal women. Excessive catecholamine stimulation plays an important role in the pathogenesis of TTC. Usually, this condition is reversible within several weeks to months. Only two cases of TTC were described in patients on hemodialysis. To our knowledge, we report the first case of TTC in peritoneal dialysis and the first case associated with peritonitis.

In 1997, the anti-CD20 monoclonal antibody (MAb) rituximab became the first MAb approved for clinical use in oncology, and ushered in a new era of rationally designed targeted agents in cancer therapeutics. It is currently approved for use in non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and rheumatoid arthritis (RA). Rituximab is non-mutagenic, associated with low treatment-related toxicity, and few, if any, long term adverse events, making it an attractive agent to be tried in off-label settings like Hodgkin lymphoma (HL). HL consists of two distinct subtypes - classic HL (cHL) and lymphocyte predominant HL (LPHL). CD20 is present in virtually all patients with LPHL, and in a significant minority of patients with cHL. In this CD20 positive sub-population, the use of rituximab is a rational intervention strategy. Rituximab has been used in patients with cHL as well as LPHL with good efficacy. In this article, we provide a clinically-oriented overview of the use of rituximab in the different sub-types of HL, and report updated results of our series of 8 LPHL patients treated with rituximab. A systematic review of the literature is also presented. © 2010 Elsevier Ltd.

Background: Maternal, fetal, and neonatal outcomes in parturients with intrahepatic cholestasis of pregnancy (ICP) have been retrospectively documented. We aimed to present pregnancy outcomes of parturients with ICP who underwent delivery. The study was conducted during a 1-year period in a tertiary care centre.Methods: Data from 1 January to 31 December 2017 were collected to identify parturients with ICP.Results: Almost 3/4th of births came to a vaginal delivery (76.74%) and only 10 parturients had cesarean delivery. 4 of 10 parturients underwent nonelective cesarean section, while 6 had elective cesarean delivery. 15.15 % vaginal deliveries were instrumental. The most common indications for emergency LSCS and instrumental deliveries was fetal distress followed by failure to progress of labour. Most births occurred at or after 37 weeks of gestation (65%). Regarding neonatal outcomes in terms of birth weight and Apgar scores at 1 and 5 min, they were positive, as well. None of the babies had Apgar score < 7 at 5 minutes. No case of perinatal death was observed.Conclusions: Although the results were generally positive, larger studies need to be conducted to evaluate the maternal and fetal outcomes in ICP and correlation with serum bile acid levels.

Celiac disease (CD) is an autoimmune disorder that causes varying degrees of villous atrophy and chronic malabsorption in genetically predisposed persons. Once considered a rare disease affecting children, younger adults, and persons of European ancestry, CD is increasingly recognized in all demographic groups with a prevalence rate in the United States of almost 1%. We offer an overview of the evaluation and management of CD vis-à-vis the case of a 41-year-old man who was hospitalized after presenting with the classic symptoms of chronic abdominal complaints, diarrhea, iron-deficiency anemia, and weight loss. Celiac disease remains an underdiagnosed condition in the United States, which is unfortunate given the potential treatment with a gluten-free diet.

In traditional medicine, Panax ginseng has been used to treat various behavioral effects of psychostimulants (e.g., cocaine) and other drugs of abuse and to ameliorate withdrawal symptoms. The neurochemical bases for this efficacy, however, remain to be elucidated. We previously used the real-time fast-scan cyclic voltammetry in rat nucleus accumbens slices to demonstrate that cocaine not only enhances DA release evoked by single-pulse electrical stimulation and inhibits DA uptake during application but also further increases the release upon washout (termed a “rebound” release enhancement). In the present study, we determined whether co-application and washout of ginseng total saponin (GTS), the active ingredient of Panax ginseng, with cocaine attenuate cocaine-induced enhancement of evoked DA release, DA uptake inhibition and/or withdrawal-associated rebound enhancement. Cocaine rapidly potentiated the DA release within the first 10 min of application, and acute cocaine withdrawal caused a rebound increase. Co-application of GTS with cocaine inhibited the release enhancement and subsequently prevented the rebound increase during acute withdrawal. The effect of GTS was concentration-dependent. In contrast, GTS had no significant effects on the cocaine-mediated DA uptake inhibition. These results suggest that the attenuation of the cocaine-induced enhancement of impulse-dependent DA release, rather than uptake inhibition, might be one of the pharmacological bases for attenuation of behavioral effects of cocaine and amelioration of acute withdrawal symptoms by ginseng.

Testicular cancer is the most common malignancy in men aged 20-35 years and accounts for approximately 1% of all male malignancies. Testicular cancer has a propensity to spread via the lymphatic system to the retroperitoneal lymph nodes, and retroperitoneal lymph node dissection remains an essential component in the cure of these patients. This review summarizes the basic principles of surgical management of germ cell tumors.

The evolving field of HER2-targeted therapy has significantly improved the outcome of women diagnosed with HER2-positive invasive breast cancer. In this review, we sought to summarise the efficacy of trastuzumab-based regimens in the adjuvant and neoadjuvant setting with a special emphasis on relevant clinical questions: treatment duration, sequence of trastuzumab administration, toxicity, the role of anthracycline-based regimens, and optimal management of small HER2+ tumours. Controversial topics are discussed taking into consideration the development of modern anti-HER2 agents., SCOPUS: re.j, info:eu-repo/semantics/published

Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) histotype, after invasive ductal carcinoma (IDC), representing ∼10-15% of the global BC population. The vast majority of ILC are estrogen receptor (ER)-positive. PIK3CA has been reported to be the most frequently mutated gene in ER-positive BC. However, until now PIK3CA mutations have mainly been described in IDC. In this study, we sought to characterize the type, prevalence, intra-patient (pt) mutational heterogeneity, and the association with transcriptomic phenotype and clinical outcome of PIK3CA mutations in ILC. Methods: Gene expression data (HG-U133 Plus2.0) was generated from frozen samples of 116 ILC (primary tumors). For the same series, PIK3CA mutation profiling (Sequenom) was performed on at least 2 formalin-fixed paraffin embedded (FFPE) tissue blocks of the primary tumor for 102 cases, and on the only available block for the remaining 14 cases. Matched local recurrence (LR) and multiple metastatic (M) samples were also characterized for 3 and 8 pts respectively. For the transcriptomic and survival analyses, we evaluated the association between PIK3CA mutation status and gene signatures recapitulating important biological processes, and invasive disease-free & overall survival, respectively. Results: PIK3CA mutations were detected in the primary tumor of 40/116 (35%) ILC pts: 14 (35%) mutations in the helical domain and 25 (62.5%) in the kinase domain. PIK3CA analysis in different blocks from the same primary tumors revealed a mutational heterogeneity in 7/102 (7%) cases. There was a discordance between primary and LR samples in 1/3 patients with LR, with a mutation reported in the primary but in not the LR. In 3/8 pts for which M samples were available, we observed intra-pt heterogeneity. In the first pt, a mutation in the kinase domain was reported only in 1/2 investigated blocks from the primary tumor, and in only 1/2 liver Ms. In the second pt, a mutation in the helical domain was found in the primary tumor and in the LR but not in the pleura M. In the third pt, although no mutation was observed in the primary tumor, a mutation in the helical domain was found in the M of the epiploon, but not in the Ms from the diaphragm or the ovary. Transcriptomic analyses revealed that primary tumors with a PIK3CA mutation in the helical domain were associated with increased levels of 2 stroma signatures (Bonferroni p-val: PLAU sign -Desmedt 2008–0.042 and DCN sign- Farmer 2009 – 0.048) compared to tumors without mutation. The survival analyses did not reveal any significant difference in survival between pts with and without a PIK3CA mutation. Conclusions: This study represents the largest series described so far which investigated PIK3CA mutations in ILC. The incidence of PIK3CA mutations reported here is similar to the one reported for IDC. The investigation of multiple tumor samples per pt revealed intra-tumor as well as primary/recurrence heterogeneity. To get a definitive answer on the prognostic role of PIK3CA mutation in ILC, we are currently performing a PIK3CA mutation profiling study (Sequenom) on a series of ∼1000 consecutive ILC with long-term follow up (Iorfida et al. 2012); results will be available by SABCS2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-03.

Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients., SCOPUS: re.j, info:eu-repo/semantics/published

The association of neurofibromatosis type I with invasive male breast cancer is a rare clinical entity with only one case in literature reported in 1953. Women with NF1 are at risk of developing breast cancer and men also may be at risk but there is scarce data on the risk and association of NF1 with male breast cancer due to its rarity. Established clinical trials in male breast cancer patients are lacking and the results are extrapolated from female breast cancer patients. The treatment of male breast cancer is followed as per the guidelines of premenopausal female breast cancer and tamoxifen is the hormone treatment in them. Mendes et al suggests that silencing of NF1 gene confers resistance to tamoxifen. Our conclusions are that since NF1 is mutated or deleted in one third of sporadic breast cancers, its role as a molecular driver for treatment has to be further explored. © 2014 Lakshmaiah et al. licensee BioMed Central Ltd., SCOPUS: ar.j, info:eu-repo/semantics/published

Evaluation of left ventricular function in the presence of valvular regurgitation is still a clinical problem because ejection phase indices including ejection fraction are heavily dependent on preload and afterload and cannot be regarded as reliable indices of contrac tility in diseases associated with altered loading conditions. The authors attempted to evaluate the usefulness of the new index-corrected ejection fraction in the evaluation of left ventricular (LV) function in patients with chronic mitral (MR) or aortic regurgitation (AR). The study included 21 patients with chronic severe MR (11 patients) and AR (10 patients) with a mean age of 18 years. All patients underwent valve replacement or repair. Echo Doppler study was performed preoperatively and postoperatively and included measurement of the following LV parameters: end-diastolic dimension (EDD), end-diastolic volume (EDV), end-systolic dimension (ESD), end-systolic volume (ESV), ejection fraction (EF), systolic blood pressure/end-systolic dimension (SBP/ESD); also mitral and aortic stroke volume were calculated cross-sectional area (CSA) x time velocity integral TVI. Corrected ejection fraction (EFc) was derived from the following equation: ( continued on next page) The mean preoperative EFc did not change significantly after surgical correction of mitral or aortic regurgitation. Preoperative EFc did not show significant difference compared with postoperative EF in the two groups. Preoperative EFc correlated significantly with other preoperative and postoperative indices of LV function. Postoperative EFc showed very close correlation with other postoperative parameters. Thus, using the new index-corrected ejection fraction in the assessment of LV function in patients with mitral or aortic regurgitation has several advantages: Noninvasive, inde pendent of loading changes, helpful in predicting the immediate postoperative clinical course, and a reliable index for evaluation of LV systolic function preoperatively and postoperatively.