Downregulation of praja2 restrains endocytosis and boosts tyrosine kinase receptors in kidney cancer.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and elucidating the mechanisms underlying ccRCC will provide clues to treat this aggressive malignant tumor. Here, we report that the ubiquitin ligase praja2 forms a complex with-and ubiquitylates the AP2 adapter complex, contributing to receptor endocytosis and clearance. In human RCC tissues and cells, downregulation of praja2 by oncogenic miRNAs (oncomiRs) and the proteasome markedly impairs endocytosis and clearance of the epidermal growth factor receptor (EGFR), and amplifies downstream mitogenic and proliferative signaling. Restoring praja2 levels in RCC cells downregulates EGFR, rewires cancer cell metabolism and ultimately inhibits tumor cell growth and metastasis. Accordingly, genetic ablation of praja2 in mice upregulates RTKs (i.e. EGFR and VEGFR) and induces epithelial and vascular alterations in the kidney tissue.In summary, our findings identify a regulatory loop between oncomiRs and the ubiquitin proteasome system that finely controls RTKs endocytosis and clearance, positively impacting mitogenic signaling and kidney cancer growth.

R0 surgical resection of giant dedifferentiated retroperitoneal liposarcomas in the COVID era with and without nephrectomy: A case report.

Retroperitoneal sarcomas (RPSs) are rare findings that can grow into large masses without eliciting severe symptoms. At present, surgical resection is the only radical therapy, whenever it can be performed with the aim to achieve a complete removal of the tumor. The present report describes two consecutive cases of RPSs that resulted in dedifferentiated liposarcomas (DDLPSs) and these patients underwent R0 surgical resection with and without a nephron-sparing procedure. The diagnostic workup, the surgical approach, the impact of late surgical management due to the COVID pandemic and the latest literature on the topic are discussed and analyzed. The patients, who refused to undergo any medical examination during the prior 2 years due to the COVID pandemic, were admitted to Federico II University Hospital (Naples, Italy) complaining about weight loss and general abdominal discomfort. In the first case, a primitive giant abdominal right neoplasm of retroperitoneal origin enveloping and medializing the right kidney was observed. The second patient had a similar primitive retroperitoneal giant left neoplasm, which did not affect the kidney. Given the characteristics of the masses and the absence of distant metastases, after a multidisciplinary discussion, radical surgical removal was carried out for both patients. The lesions appeared well-defined from the surrounding tissues, and markedly compressed all the adjacent organs, without signs of infiltration. In the first patient, the right kidney was surrounded and undetachable from the tumor and it was removed en bloc with the mass. The second patient benefited from a nephron-sparing resection, due to the existence of a clear cleavage plane. The postoperative courses were uneventful. Both the histological examinations were oriented towards a DDLPS and both patients benefited from adjuvant chemotherapy. In conclusion, the treatment of giant RPS is still challenging and requires multidisciplinary treatment as well as, when possible, radical surgical removal. The lack of tissue infiltration and the avoidance of excision or reconstruction of major organs (including the kidney) could lead to an easier postoperative course and an improved prognosis. When possible, surgical management of recurrences or incompletely resected masses must be pursued. Since the COVID pandemic caused limited medicalization of a number of population groups and delayed diagnosis of other oncologic diseases, an increased number of DDLPSs could be expected in the near future.

Multidetector Computed Tomography (MDCT) Findings of Complications of Acute Cholecystitis. A Pictorial Essay.

Acute cholecystitis stands out as one of the most common surgical pathologies that should always be considered in a right-upper abdominal pain emergency. For this, the importance of a correct diagnosis is well described. However, it has been demonstrated that the simple combination of clinical (pain, Murphy's sign) and laboratory (leukocytosis) parameters alone does not provide for ruling in or ruling out the diagnosis of this condition, unless accompanied by a radiological exam. For a long time, and still today, ultrasonography (US) is by far the first-to-proceed radiologic exam to perform, thanks to its rapidity and very high sensibility and specificity for the diagnosis of simple acute cholecystitis. However, acute cholecystitis can undergo some complications that US struggles to find. In addition to that, studies suggest that multidetector computed tomography (MDCT) is superior in showing complicated forms of cholecystitis in relation to sensibility and specificity and for its capability of reformatting multiplanar (MPR) reconstructions that give a more detailed view of complications. They have shown to be useful for a precise evaluation of vascular complications, the anatomy of the biliary tree, and the extension of inflammation to surrounding structures (i.e., colitis). Therefore, based also on our experience, in patients with atypical presentation, or in cases with high suspicion for a complicated form, a MDCT abdomen scan is performed. In this review, the principal findings are listed and described to create a CT classification of acute complications based on anatomical and topographic criteria.

Physical activity in elderly kidney transplant patients with multiple renal arteries.

BACKGROUND: Kidney transplantation (KT) is the gold standard for treatment of patients with end-stage-renal disease. To expand the donor reserve, it is necessary to use marginal/suboptimal kidneys. METHODS: We retrospectively evaluated the short/long-term outcome of 34 KT elderly patients who received allografts with vascular abnormalities (MRA group), in comparison with 34 KT patients who received a kidney with a single renal artery (SRA group) pair-matched by age, length of time on dialysis, comorbidity and donor age. RESULTS: All participants completed the International Physical Activity Questionnaire at KT, and then 4, 8, and 12 weeks after transplantation. Our data indicate that kidney with vascular anatomical variants may be successfully transplanted, since the overall rate of surgical complications was 20.6% in the SRA group and 17.6% in the MRA group and that the 5-year survival rate after KT was 100% in both groups. CONCLUSIONS: The data also underlined that individualized physical activity programs induced similar excellent results in both groups, improving physical capacities, arterial pressure, lipid metabolism, insulin sensitivity, quality of life and physical and mental status.

One-stage resection of primary colorectal cancer and hepatic metastases using the Habib Device: analysis of 40 consecutive cases treated in a Unit of general surgery.

BACKGROUND: More than 50% of patients with colorectal cancer (CRC) present or develop hepatic metastases (HM). The intraoperative use of the Habib 4X® radio frequency probe device is safe in resetting HM and allows a one-stage resection of both CRC and HM with a similar mortality rate than a two-stage surgical treatment. METHODS: After an exhaustive residential training at the reference center for hepato-biliary surgery of the Imperial College of London, we treated at our unit of general surgery 40 consecutive patients with CRC and HM with the one-stage resection, using the Habib 4X® intraoperative radiofrequency probe device to reset HM. RESULTS: None of the 40 patients died during the intra-operatory and post-operatory periods, none presented liver failures during the postoperative course nor complication related to the Habib's resection procedure (e.g. bleeding, abscess, bile leak). The amount of intra-operative liver bleeding was minimal. New HM arose in 10 (25%) cases, with a mean disease-free interval of 13 months, but the hepatic tissue close to previous resections remained cancer-free. The 69.7% of patients were disease-free at month 24 of the post-operative follow-up and 5-year rate was about 70%. CONCLUSIONS: The data suggest that surgeons well trained at a reference center for hepato-biliary surgery may perform with excellent results the one-stage CRC and HM resection with the Habib 4X® device even in a Unit of general surgery.

Renal involvement in COVID-19: focus on kidney transplant sector.

INTRODUCTION: Kidney transplant recipients and patients on the waiting list for kidney transplant who acquire SARS-CoV-2 infection are at serious risk of developing severe COVID-19, with an increased risk of mortality for the their immunosuppressive state; other risk factors for mortality have been identified in some comorbidities such as obesity, diabetes, asthma and chronic lung disease. MATERIALS AND METHODS: The COVID-19 pandemic has led to a sharp reduction in kidney transplants in most countries, mainly due to the concern of patients on the waiting list for their potential increased susceptibility to acquire SARS-CoV-2 infection in healthcare facilities and for the difficulties of transplant centers to ensure full activity as hospitals have had to focus most of their attention on COVID-19 patients. Indeed, while the infection curve continued its exponential rise, there was a vertical decline in kidney donation/transplant activity. CONCLUSION: This review article focuses on the damage induced by SARS-CoV-2 infection on kidney and on the adverse effect of this pandemic on the entire kidney transplant sector.

Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update.

The lack of a precise stratification algorithm for predicting patients at high risk of graft rejection challenges the current solid organ transplantation (SOT) clinical setting. In fact, the established biomarkers for transplantation outcomes are unable to accurately predict the onset time and severity of graft rejection (acute or chronic) as well as the individual response to immunosuppressive drugs. Thus, identifying novel molecular pathways underlying early immunological responses which can damage transplant integrity is needed to reach precision medicine and personalized therapy of SOT. Direct epigenetic-sensitive mechanisms, mainly DNA methylation and histone modifications, may play a relevant role for immune activation and long-term effects (e.g., activation of fibrotic processes) which may be translated in new non-invasive biomarkers and drug targets. In particular, the measure of DNA methylation by using the blood-based "epigenetic clock" system may be an added value to the donor eligibility criteria providing an estimation of the heart biological age as well as a predictive biomarkers. Besides, monitoring of DNA methylation changes may aid to predict acute vs chronic graft damage in kidney transplantation (KT) patients. For example, hypermethylation of genes belonging to the Notch and Wnt pathways showed a higher predictive value for chronic injury occurring at 12 months post-KT with respect to established clinical parameters. Detecting higher circulating cell-free DNA (cfDNA) fragments carrying hepatocyte-specific unmethylated loci in the inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), insulin like growth factor 2 receptor (IGF2R), and vitronectin (VTN) genes may be useful to predict acute graft injury after liver transplantation (LT) in serum samples. Furthermore, hypomethylation in the forkhead box P3 (FOXP3) gene may serve as a marker of infiltrating natural Treg percentage in the graft providing the ability to predict acute rejection events after heart transplantation (HTx). We aim to update on the possible clinical relevance of DNA methylation changes regulating immune-related pathways underlying acute or chronic graft rejection in KT, LT, and HTx which might be useful to prevent, monitor, and treat solid organ rejection at personalized level.

The Role of Immunosuppressive Therapy in Aneurysmal Degeneration of Hemodialysis Fistulas in Renal Transplant Patients.

BACKGROUND: Venous aneurysms are long-term complications of arteriovenous fistula (AVF) for hemodialysis with an estimated incidence rate of around 5-6%. The purpose of our study is to investigate the role of immunosuppressive therapy in the development of AVF aneurysms in renal transplant patients, and to determine whether AVF closure following transplantation is necessary. METHODS: Forty-six patients with symptomatic venous AVF aneurysms underwent ligation and resection of their fistulas between January 2013 and January 2020. Immunohistochemical expression of CD3, CD4, and CD8 was assessed on the surgical specimens to characterize lymphocytic infiltrate in the aneurysm wall. Patients were subdivided into "Group A"-kidney transplant patients undergoing immunosuppressive therapy which was comprised of 39 patients and "Group B"-patients who had not undergone kidney transplant which was comprised of 7 patients. The 2 groups did not significantly differ in age, sex nor risk factors for aneurysms. RESULTS: Group A showed a significantly higher aneurysm diameter (P < 0.0001), mean flow (P < 0.0001) and required a longer duration of surgery (P = 0.0007). A CD3+ lymphocytic infiltrate was significantly more common in Group A than in the Group B (90% vs 29%; P < 0.001). No significant differences in localization (adventitia, media or intima) and type (CD4+ vs CD8+) of lymphocytes were found between the 2 groups. CONCLUSION: AVF venous aneurysms were significantly larger and with a more intense T-lymphocytic infiltrate in patients undergoing immunosuppressive therapy. This finding suggests that immunosuppressive therapy plays a role in aneurysm formation, supporting the need for AVF closure in patients with an estimated low risk of rejection.

Outcomes of Renal Stone Surgery Performed Either as Predonation or Ex Vivo Bench Procedure in Renal Grafts from Living Donors: A Systematic Review.

AIMS: We aimed to summarize available evidence about intraoperative and postoperative donors' and recipients' outcomes following stone surgery in renal grafts from living donors performed either before donation or as ex vivo bench surgery at the time of living-donor nephrectomy. METHODS: A systematic review of PubMed, ISI Web of Knowledge, and Scopus databases was performed in September 2020. We included full papers that met the following criteria: original research, English language, human studies, and describing the results of stone surgery in renal grafts from living donors performed either before transplantation or as ex vivo bench surgery. RESULTS: We identified 11 studies involving 106 patients aged between 22 and 72 years. Predonation and bench stone surgery was performed in 9 (8.5%) and 96 (90.6%) patients, respectively. Predonation stone surgery involved extracorporeal shock wave lithotripsy, retrograde intrarenal surgery, and percutaneous nephrolithotomy in 8, 1, and 1 patient, respectively. The overall success rate of predonation stone surgery was 78%, and the complication rate was 0%. Bench stone surgery involved ureteroscopy, pyelolithotomy, or a combination of both in 79 (82.3%), 10 (10.4%), and 7 (7.3%) cases, respectively, with an overall success rate of 95.8% and an overall complication rate of 9.37%. CONCLUSIONS: Predonation and bench stone surgery in grafts from living donors represents efficacious and safe procedures. Further studies on wider series with a longer follow-up are required.

Gastroenterological complications in kidney transplant patients.

Kidney transplantation is the surgical operation by which one of the two original kidneys is replaced with another healthy one donated by a compatible individual. In most cases, donors are recently deceased. There is the possibility of withdrawing a kidney from a consenting living subject. Usually, living donors are direct family members, but they could be volunteers completely unrelated to the recipient. A much-feared complication in case of kidney transplantation is the appearance of infections. These tend to arise due to immune-suppressor drugs administered as anti-rejection therapy. In this review, we describe the gastrointestinal complications that can occur in subjects undergoing renal transplantation associated with secondary pathogenic microorganisms or due to mechanical injury during surgery or to metabolic or organic toxicity correlated to anti-rejection therapy. Some of these complications may compromise the quality of life or pose a significant risk of mortality; fortunately, many of them can be prevented and treated without the stopping the immunosuppression, thus avoiding the patient being exposed to the risk of rejection episodes.

COVID-19 and Living Donor Kidney Transplantation in Naples during the Pandemic.

INTRODUCTION: SARS-CoV-2 is a virus that causes a potentially deadly syndrome that affects especially the respiratory tract. Kidney-transplanted patients are immunosuppressed and more susceptible to viral infections. We have examined our transplantation activity to explore the future role of kidney transplantation from deceased and living donors in COVID-19 era. Patients and Methods. The activity of our transplant center of Naples (one of the two transplant centers in Campania, South Italy) continued during the COVID-19 pandemic. We have analysed the kidney transplants carried out between March 9 and June 9, 2020, comparing these data with the numbers of procedures performed in the two previous years. Moreover, we have considered the possibility of performing living donor transplants during a worldwide pandemic. RESULTS: From March 9, 2020, when the Italian lockdown begun, till June 9, 2020, five kidney transplants have been performed at our transplant center in Naples, all from deceased donors. The donors and the recipients have been screened for COVID-19 infection, and the patients, all asymptomatic, followed strict preventive measures and were fully informed about the risks of surgery and immunosuppression during a pandemic. All the transplanted patients remained COVID negative during the follow-up. The number of transplants performed has been constant compared to the same months of 2018 and 2019. In agreement with the patients, we decided to postpone living donor transplants to a period of greater control of the SARS-CoV-2 spread in Italy. CONCLUSION: Deceased donor kidney transplantation should continue, especially in a region with moderate risk, like Campania, with a more careful selection of donors and recipients, preferring standard donors and recipients without severe comorbidities. Living donor transplantation program, instead, should be postponed to a period of greater control of the SARS-CoV-2 spread, as it is an elective surgery and its delay does not determine additional risks for patients.

Relation Between Wound Complication and Lymphocele After Kidney Transplantation: A Monocentric Study.

INTRODUCTION: Wound complication frequently arises after kidney transplantation and its risk factors are well known. In a previous paper we analyzed these factors, and in this new retrospective study we evaluate the influence of lymphocele in the development of wound complications. PATIENTS AND METHODS: From January 2000 to December 2018, 731 consecutive kidney transplants have been performed in our center. We have analyzed the incidence of wound complication and lymphocele and their risk factors. RESULTS: Out of 731 kidney transplants, we have observed wound complications in 115 patients (15.7%) and lymphocele in 158 patients (21.7%). Of these, 70 patients developed both complications (9.5%), but 6 patients have been excluded because they were in therapy with mammalian target of rapamycin inhibitors. Twenty-nine patients (45.3%) presented a first level and 35 patients (54.7%) showed second level wound complications. Lymphocele was the only present factor in just 3 cases (4.6%). The other patients showed diabetes in 28 cases (43.7%), overweight/obesity in 38 (59.3%), delayed graft function in 17 (26.5%), and 60 years or more in 38 (57.8%). The association has been found in 30 out 64 patients treated with tacrolimus (46.8%) and in 34 with cyclosporine (53.1%); 40 patients did not receive muscular layer's reconstruction (62.5%). CONCLUSION: Our experience shows that lymphocele alone is not a predisposing factor for wound dehiscence after kidney transplantation, and they often coexist because they share the same risk factors, the most important being obesity, diabetes and delayed graft function, older age, and surgical techniques. No relation has been observed with calcineurin inhibitor therapy.

Does Physical Activity Regulate Prostate Carcinogenesis and Prostate Cancer Outcomes? A Narrative Review.

Background: Prostate cancer (PCa) represents a common disease in men aged >65 years. The role of physical activity (PA) in patients at risk or diagnosed with PCa represents an evolving issue. We aimed to summarize available evidences about the impact of PA on the pathophysiology and clinical outcomes of PCa. Methods: We performed a narrative review. Evidences about the role of PA in elderly patients in terms of PCa biology, epidemiology, oncological and functional outcomes, as well as in terms of impact on the outcomes of androgen deprivation therapy (ADT) were summarized. Results: Potential pathophysiological pathways hypothesized to explain the benefits of PA in terms of prostate carcinogenesis include circulating levels of Insulin-like growth factor-1 (IGF-1), oxidative stress, systemic inflammation, sex hormones, and myokines. Clinically, emerging evidences support the hypothesis that PA is associated with decreased PCa risk, improved PCa-related survival, improved functional outcomes, and reduced ADT-related adverse events.

Lymphomatoid papulosis.

Lymphomatoid papulosis (LyP) is a non-aggressive skin disorder characterized by papulonodular injuries, sometimes necrotic, often scattered, relapsing, which frequently regress spontaneously. LyP represents about 12% of cutaneous lymphomas. The etiology of LyP is unknown. Based on its histopathology, in 2018, the World Health Organization (WHO) classified LyP into six types with similar prognosis (A,B,C,D,E and DUSP22). Once the diagnosis of LyP has been made, having an excellent prognosis, this pathology must be managed mainly with a "watch and wait" strategy. Treatment should be given only in the presence of diffuse, symptomatic lesions with disfiguring evolution, with the aim of reducing time of resolution and preventing recurrences or the formation of new lesions.

Familial Polyposis Coli: The Management of Desmoid Tumor Bleeding.

Background: There is currently no standard treatment for desmoid tumors (DTs) associated with familial polyposis coli (FAP). Familial adenomatous polyposis in DT patients is sometimes a life-threatening condition. Methods: We enrolled all consecutive patients with FAP treated at Unit of General Surgery and Transplant, University of Naples Federico II and evaluated the incidence of DTs on FAP between 1996 and 2016. Results: We observed 45 consecutive patients with FAP; of these 5 were DT-FAP-associated. All 5 cases with FAP were young women, age 25 to 65 years, previously treated by colectomy. Of these, 4 patients presented a parietal localization and had been treated with a wide surgical exeresis; one patient had an intra-abdominal, mesenteric tumor that was unresectable at laparotomy. We performed CT-guided drainage, ureteral stenting, medical therapy (sulindac+tamoxifene), and chemotherapy (dacarba-zine+doxorubicine).All patients were alive and underwent follow-ups for 5 years post-surgery; only 1 patient with parietal localization showed a local relapse after 2 years. Conclusions: We propose a modulated approach to the single patient with FAP, with surgery as treatment of choice for parietal localization disease and integrating different kinds of therapies (surgery alone or associated with RT, CT) for the intra-abdominal tumor.

[Organ donation and transplantation: the "friendly access initiative" in the Federico II Hospital (Naples), between nudging and narrative medicine]. / Donazione e trapianto d'organi: l'esperienza dello "sportello amico" dell'AOU Federico II (Napoli), tra nudging e medicina narrativa.

In Italy, to show the willingness to donate one's organs, there is the principle of the explicit consensus (or disagreement) (Law n. 91 of the 01.04.1999, Art. 23; Decree of the Italian Health Ministry of the 08.04.2000). According to data of the Italian Association for the donation of organs, tissues and cells (AIDO), in 2017 in Campania Region (Southern Italy) an average of 12.5 people x1,000,000 donated their organs vs. a national average of 23.7. This negative discrepancy between national and regional data highlights that it is imperative to promote awareness-raising measures to address to the population of Campania Region in order to improve the following of a practice which is still object of preconceptions and scarce knowledge. This paper describes a pilot project started in 2017 by the "Sportello amico trapianti" (friendly access to transplantation) to promote the donation of organs within the university-hospital "Federico II" (Naples, Campania Region). The first phase of this project was based on the nudge theory, that is the "little push" to direct decisional processes of groups and individuals. This phase took place during the "Atelier della salute" (a health workshop), organized by the Medicine and Surgery school of the university-hospital "Federico II": here, a questionnaire was administered to 60 people. The questionnaire consisted in 12 questions, answered by volunteers, which aim was to test the general knowledge about organ donation and transplantation. Analysing the answers, a panel of 7 experts (2 epidemiologists, 1 social worker, 2 experts in public and institutional communication, 1 biologist expert in donation of haematopoietic progenitor cell, 1 transplant surgeon), responsible for the coordination and monitoring of the activities, identified the critical elements to bring attention to in order to raise awareness in the population. The second phase consisted in a literary workshop which aim was to identify nudge cases. The text used was Never let me go by Kazuo Ishiguro, a novel focused on organ donation in a dystopic context where the protagonists are clones created to facilitate the donation of organs. Six students participated in this workshop: all six considered the dystopic scenario as a potential nudge to humanize the approach to organ donation and transplant. In conclusion, we believe that the nudge methodology may be used in order to improve awareness and adherence to donation of organs.

HLA-G and anti-HCV in patients on the waiting list for kidney transplantation.

PURPOSE: Human leukocyte antigen (HLA)-G is a non-classic major histocompatibility complex HLA class I molecule. HLA-G may have tolerogenic properties which are linked to epigenetic-sensitive pathways. There is a correlation of sHLA-G levels and graft acceptance in transplantation studies. There are previous data on correlation of sHLA-G with graft rejection as well as with viral infections such as hepatitis C virus (HCV) in kidney transplanted patients. Here, we report the sHLA-G expression in patients on the waiting list for kidney transplantation, with and without anti-HCV compared to a control group. METHODS: Serum of 67 patients on the waiting list for kidney transplantation (n = 43 with anti-HCV and n = 24 without anti-HCV) was analyzed. Among these patients, n = 39 were on the waiting list for the first transplantation, while n = 28 were patients who returned in the list. The control group included n = 23 blood donors with anti-HCV (n = 13) and without anti-HCV (n = 10). RESULTS: The expression of sHLA-G was significantly lower in the control group (39.6 ±â€¯34.1 U/ml) compared to both - patients on the waiting list for the first transplantation (62.5 ±â€¯42.4 U/ml, p=0.031) and patients who returned in the list (76.7 ±â€¯53.9 U/ml, p=0.006). No significant differences were observed in all anti-HCV positive groups. A positive linear correlation between sHLA-G and TNF-α, and patient age was observed. CONCLUSIONS: Serum sHLA-G values were significantly increased in both - patients on the waiting list for the first transplantation and patients who returned in the list, as compared to control group. Our findings confirm the key tolerogenic role of sHLA-G levels as epigenetic-related marker for measuring the state of kidney allograft acceptance.

Impact of neoadjuvant chemotherapy and pathological complete response on eligibility for breast-conserving surgery in patients with early breast cancer: A meta-analysis.

PURPOSE: We conducted a meta-analysis of randomised trials evaluating pathological complete response (pCR) and surgical outcomes after neoadjuvant systemic therapy (NST) in patients with early breast cancer (EBC). PATIENTS AND METHODS: The primary outcome was breast-conserving surgery (BCT) rate. Secondary outcomes were pCR rate and association to BCT. Meta-analyses were performed using random effects models that use inverse-variance weighting for each treatment arm based on evaluable patients. Point estimates are reported with 95% confidence interval (CI), and p < 0.05 was considered statistically significant. RESULTS: Thirty-six studies were identified (N = 12,311 patients). We selected for the analysis 16 of 36 studies reporting both pCR and BCT for at least one treatment arm. Arms per study ranged from one to six; 42 independent units were available to evaluate the association between pCR and BCT. BCT rate ranged 5-76% across arms with an average BCT of 57% (95% CI 52-62%). Significant heterogeneity was observed among the trials (Cochrane Q = 787, p < 0.001, I2 = 97%). In the meta-regression model, BCT rates were not significantly associated with year of first patient-in (p = 0.89), grade (p = 0.93) and hormone-receptor status (p = 0.39). Clinical N-stage (p = 0.01) and human epidermal growth factor receptor (HER2) status (p = 0.03) were significantly associated with BCT. pCR rate ranged 3-60% across studies. The average pCR across all study arms was 24% (95% CI 19-29%). No association was observed between pCR rate in a study arm and the resulting BCT rate in a univariate model (p = 0.34) nor after adjusting for HER2 and clinical nodal status (p = 0.82). In the subset of 14 multi-arm studies, no significant association was seen between the differences in pCR and BCT between treatment arms (p = 0.27). CONCLUSIONS: pCR does not increase BCT in patients receiving NST for EBC.