A Phase II study assessing Long-Term Response to Ibrutinib Monotherapy in recurrent or refractory CNS Lymphoma.

BACKGROUND: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK). We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 PCNSLs, 15 SCNSLs). Patients received ibrutinib at 560mg or 840mg daily in the dose-escalation and 840mg daily in the expansion cohort. Median follow up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid (CSF) collected before and during ibrutinib therapy. RESULTS: Tumor responses were observed in 23/31 (74%) PCNSLs and 9/15 (60%) SCNSLs, including 12 complete responses in PCNSL and 7 in SCNSL. Median progression-free survival (PFS) for PCNSL was 4.5 months (95%CI: 2.8-9.2) with 1y-PFS at 23.7% (95%CI: 12.4%-45.1%). Median duration of response (DOR) in the 23 PCNSL responders was 5.5 months. Median PFS in SCNSL was 5.3 months (95%CI: 1.3-14.5) with a median DOR 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (p=0.0075). Clearance of circulating tumor DNA from CSF was associated with complete and long-term ibrutinib response. CONCLUSIONS: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow up. CLINICAL TRIAL INFORMATION: NCT02315326.

Locally invasive recurrence or metastasis of pheochromocytoma into the liver?-clinicopathological challenges.

Pheochromocytomas (PCC) are rare and functional neuroendocrine tumors developing from adrenal chromaffin cells. Predicting malignant behavior especially in the absence of metastasis can be quite challenging even in the era of improved understanding of the molecular mechanisms involved in PCCs. Currently, two histopathological grading systems Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) score are used in clinical practice, but these are subject to significant interobserver variability. Some of the most useful clinical factors associated with malignancy are large size ([4-5 cm), and genetic features such as presence of SDHB germline mutations. Local invasion is uncommon in PCC and metastasis seen in 10 to 17% but higher in germline mutations and when this occurs management can be challenging. Here, we report on a case with challenges faced by the pathologist and clinicians alike in diagnosis and management of PCC recurrence.

Incidence of a subsequent carbapenem-resistant Enterobacteriaceae infection after previous colonisation or infection: a prospective cohort study.

OBJECTIVES: In patients with a history of carbapenemase-producing, carbapenem-resistant Enterobacteriaceae (CP-CRE), the need for CP-CRE targeted treatment in subsequent sepsis episodes is unclear. This study aimed to characterise the incidence of subsequent CP-CRE infective episodes in individuals with prior CP-CRE colonisation and/or infection, and identify predictors for these subsequent CP-CRE infections. METHODS: All adult inpatients with CP-CRE detected from any site between June 2012 and May 2014 at a tertiary-care hospital were prospectively followed for two years to assess for any subsequent CP-CRE infections. Potential factors to which patients were exposed during the follow-up period were collected from medical records and analysed. RESULTS: A total of 171 patients were enrolled. Of 151 patients who entered the follow-up period, 16 (10.6%) developed a subsequent CP-CRE infection. The median time to a subsequent infective episode was 24.5 days (12-105 days). The type of carbapenemase was highly conserved within index and subsequent paired episodes (16 of 17 pairs). Patients with first CP-CRE isolated from intra-abdominal or respiratory sources were ≥7 times more likely to develop a subsequent infection, while most rectal carriers remain colonised. For carriers (n = 133), Klebsiella spp. (OR 4.7) and OXA carbapenemase (OR 9.4) were significant predictors of subsequent infection. In patients with initial infection (n = 18), end-stage renal failure requiring dialysis (OR 22.0) was the only predisposing factor. CONCLUSION: The incidence of subsequent infections in patients with prior colonisation was low. Consideration for CP-CRE targeted therapy is recommended in patients on dialysis and previous CP-CRE infections involving the bloodstream and/or respiratory tract.

Systematic Review and Meta-Analysis of Prophylactic Transarterial Embolization for High-Risk Bleeding Peptic Ulcer Disease.

The present systematic review determined the role of transarterial embolization (TAE) as a prophylactic treatment in bleeding peptic ulcers after initial successful endoscopic hemostasis. PubMed and Ovid Medline databases were searched from inception until July 2019 for studies that included patients deemed high-risk based on Forrest Classification, Rockall score ≥ 5, or endoscopic evaluation in addition to those who underwent prophylactic TAE after initial successful endoscopic hemostasis. Meta-analysis was performed to compare patients who underwent endoscopic therapy (ET) and TAE with those who underwent ET alone. The primary outcomes measured included rates of rebleeding, reintervention, and 30-day mortality. Secondary outcome measures evaluated length of hospitalization, technical success rates, and complications associated with TAE. Of 916 publications, 5 were eligible for inclusion; 310 patients with high-risk peptic ulcer bleeding underwent prophylactic TAE, and 255 were compared against a control group of 580 patients that underwent standard treatment with ET alone. Patients who underwent ET with TAE had lower 30-day rebleeding rates (odds ratio [OR], 0.35; 95% confidence interval [CI] 0.15-0.85; P = .02; I2 = 50%). The ET with TAE group had a lower 30-day mortality rate (OR, 0.28; 95% CI, 0.10-0.83; P = .02; I2 = 58%). There was no difference in pooled reintervention rates (OR, 0.68; 95% CI, 0.43-1.08; P = .10; I2 = 0%) and length of hospitalization (mean difference, -0.32; 95% CI, -1.88 to 1.24; P = .69; I2 = 0%). Technical success rate of prophylactic TAE was 90.5% (95% CI, 83.09-97.98; I2 = 75.9%). Pooled proportion of overall complication rate was 0.18% (95% CI, 0.00-1.28; I2 = 0%). Prophylactic TAE has lower rebleeding and mortality with a good success rate and low complications. Prophylactic TAE after primary ET may be recommended for selected patients with high-risk bleeding ulcers; however, further studies should be performed to establish this as a routine tool in patients with bleeding peptic ulcer disease.

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.

A multidisciplinary antimicrobial stewardship programme safely decreases the duration of broad-spectrum antibiotic prescription in Singaporean adult renal patients.

Patients with chronic kidney disease have increased risk of infections. Thus, physicians may favour prolonged broad-spectrum antibiotic use. Studies focused on antimicrobial stewardship programmes (ASPs) in renal patients are currently lacking. Here we describe the role of a multidisciplinary ASP and the impact of ASP interventions in renal patients. A multidisciplinary ASP was initiated at a tertiary hospital in Singapore. Patients prescribed broad-spectrum parenteral antibiotics were identified daily and were subjected to prospective review with immediate concurrent feedback. ASP data from January 2010 to December 2011 were analysed for all renal patients. Outcome measures included the duration and appropriateness of antibiotics, intervention acceptance rates, cost savings and safety outcomes. A total of 2084 antibiotic courses were reviewed, of which 24% were inappropriate, with meropenem most commonly prescribed inappropriately (31.0%). The commonest reasons for inappropriate use were wrong choice (51.0%) and wrong duration (21.4%). In total, 634 recommendations were made, with high acceptance rates (73.3%). Recommendations to discontinue antibiotics (33.4%) and to optimise doses (17.2%) comprised the bulk of ASP work. A mean reduction of -1.28 days of antibiotic use was observed among patients with interventions accepted versus those rejected (P<0.001), with direct cost savings of SGD$90,045. No difference in 30-day mortality (P=0.91) was observed between the accepted and rejected intervention groups. In conclusion, a multidisciplinary ASP resulted in a shorter duration of antibiotic use without compromising safety in renal patients. Continued effort is needed to produce a long-term impact on antibiotic prescription and resistance.

MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma.

The PI3K/AKT/mTOR axis promotes survival and is a frequently mutated pathway in cancer. Yet, inhibitors targeting this pathway are insufficient to induce cancer cell death as single agents in some contexts, including diffuse large B cell lymphoma (DLBCL). In these situations, combinations with inhibitors targeting BCL-2 survival proteins (ABT-199 and ABT-263) may hold potential. Indeed, studies have demonstrated marked synergy in contexts where PI3K/mTOR inhibitors suppress expression of the pro-survival protein, MCL-1. In this study, we use BH3 profiling to confirm that BCL-2 and BCL-XL support survival following PI3K pathway inhibition, and that the dual PI3K/mTOR inhibitor BEZ235 strongly synergizes with BCL-2 antagonists in DLBCL. However, we identify an alternative mechanism of synergy between PI3K/mTOR and BCL-2 inhibitors, independent of MCL-1 down-regulation. Instead, we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro-apoptotic BAD and BIM, and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism. Thus, our work identifies an additional mechanism of synergy between PI3K pathway inhibitors and BCL-2 antagonists that strengthens the rationale for testing this combination in DLBCL.

mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells.

High activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis in pre-B-cell acute lymphoblastic leukemia (B-ALL), suggesting that inhibiting mTOR might be clinically useful. However, emerging data indicate that mTOR inhibitors are most effective when combined with other target agents. One strategy is to combine with histone deacetylase (HDAC) inhibitors, since B-ALL is often characterized by epigenetic changes that silence the expression of pro-apoptotic factors. Here we tested combinations of mTOR and pan-HDAC inhibitors on B-ALL cells, including both Philadelphia chromosome-positive (Ph+) and non-Ph cell lines. We found that mTOR kinase inhibitors (TOR-KIs) synergize with HDAC inhibitors to cause apoptosis in B-ALL cells and the effect is greater when compared to rapamycin plus HDAC inhibitors. The combination of TOR-KIs with the clinically approved HDAC inhibitor vorinostat increased apoptosis in primary pediatric B-ALL cells in vitro. Mechanistically, TOR-KI and HDAC inhibitor combinations increased expression of pro-death genes, including targets of the Forkhead Box O (FOXO) transcription factors, and increased sensitivity to apoptotic triggers at the mitochondria. These findings suggest that targeting epigenetic factors can unmask the cytotoxic potential of TOR-KIs towards B-ALL cells.

Mechanisms of ß-lactam antimicrobial resistance and epidemiology of major community- and healthcare-associated multidrug-resistant bacteria.

Alexander Fleming's discovery of penicillin heralded an age of antibiotic development and healthcare advances that are premised on the ability to prevent and treat bacterial infections both safely and effectively. The resultant evolution of antimicrobial resistant mechanisms and spread of bacteria bearing these genetic determinants of resistance are acknowledged to be one of the major public health challenges globally, and threatens to unravel the gains of the past decades. We describe the major mechanisms of resistance to ß-lactam antibiotics - the most widely used and effective antibiotics currently - in both Gram-positive and Gram-negative bacteria, and also briefly detail the existing and emergent pharmacological strategies to overcome such resistance. The global epidemiology of the four major types of bacteria that are responsible for the bulk of antimicrobial-resistant infections in the healthcare setting - methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Enterobactericeae, and Acinetobacter baumannii - are also briefly described.

Biomarkers in the diagnosis of primary and recurrent breast cancer.

Despite the widespread use of mammography for breast cancer screening, breast cancer remains the most common cause of cancer-related mortality among women worldwide. The identification of biomarkers that identify cancers when they are small, localized and most treatable is an important aim of current breast cancer research. Biomarkers need to be sensitive, specific, reproducible and easily collected from patients from readily accessible tissue or body fluids. While conventional biomarker research has focused on soluble proteins, cell markers, proteomics and DNA methylation, much progress has also been made in the field of immunobiomarkers and multiparameter gene arrays. Currently, no one biomarker has demonstrated sufficient sensitivity and reproducibility for independent clinical and commercial use. This review summarizes the current state of breast cancer biomarker research and anticipated future directions.

A review of the oncologic and surgical management of breast cancer in the augmented breast: diagnostic, surgical and surveillance challenges.

BACKGROUND: The challenges of managing breast cancer in women with augmented breasts include screening, diagnosis, oncologic and revisional surgery, and surveillance. In addition, women with augmented breasts frequently have greater expectations of cosmetic outcomes. More breast clinicians will be affected by these challenges as augmentation grows in popularity and women with implants reach the age range in which they are at higher risk of developing breast cancer. In the United States, more than 2 million women have undergone augmentation, making this the second most commonly performed cosmetic procedure. With a lifetime risk of developing breast cancer of 1 in 8, it is projected that more than 50,000 women who undergo augmentation each year in the United States will develop breast cancer at some point in their lives. METHODS: This is a review of current practice based on an exhaustive literature search of PubMed, Google Scholar, and conference proceedings. A series of case studies is presented to illustrate mammographic changes and cosmetic outcomes in augmented breasts that have required treatment for breast cancer. RESULTS: An evidence-based summary of recommendations has been produced to guide breast surgeons in managing this particular group of patients. CONCLUSIONS: Management of breast cancer in previously augmented breasts presents a unique range of challenges. Patients can be reassured that the presence of an implant does not increase the risk of breast cancer developing or affect the prognosis if breast cancer does develop. Clinical judgement is made balancing surgical and oncologic principles to provide the best cosmetic outcome.

Mammary ductoscopy in the current management of breast disease.

BACKGROUND: The majority of benign and malignant lesions of the breast are thought to arise from the epithelium of the terminal duct-lobular unit (TDLU). Although modern mammography, ultrasound, and MRI have improved diagnosis, a final pathological diagnosis currently relies on percutaneous methods of sampling breast lesions. The advantage of mammary ductoscopy (MD) is that it is possible to gain direct access to the ductal system via the nipple. Direct visualization of the duct epithelium allows the operator to precisely locate intraductal lesions, enabling accurate tissue sampling and providing guidance to the surgeon during excision. The intraductal approach may also have a role in screening individuals who are at high risk of breast cancer. Finally, in spontaneous nipple discharge (SND), as biopsy instruments improve and intraductal therapeutics, such as intraductal excision and laser ablation, become a possibility, normal or benign ductoscopic findings may help minimize surgery in selected patients. As MD technology is rapidly advancing, a comprehensive review of current practice will be a valuable guide for clinicians involved in the management of breast disease. METHODS: This is a review of current ductoscopic practice based on an exhaustive literature search of Pubmed, Google Scholar, and conference proceedings. The search terms "ductoscopy", "duct endoscopy", "mammary", "breast," and "intraductal" were used. RESULTS/CONCLUSIONS: Duct endoscopes have become smaller in diameter with working channels and improved optical definition. Currently, the role of MD is best defined in the management of SND facilitating targeted surgical excision, potentially avoiding unnecessary surgery, and limiting the extent of surgical resection for benign disease. The role of MD in breast-cancer screening and breast conservation surgery has yet to be fully defined. Few prospective randomized trials exist in the literature, and these would be crucial to validate current opinion, not only in the benign setting but also in breast oncologic surgery.

The mortality from acute respiratory distress syndrome after pulmonary resection is reducing: a 10-year single institutional experience.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is a major cause of death following lung resection. At this institution we reported an incidence of 3.2% and a mortality of 72.2% in a review of patients who underwent pulmonary resection from 1991 to 1997 [Kutlu C, Williams E, Evans E, Pastorino U, Goldstraw P. Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Ann Thorac Surg 2000;69:376-80]. The current study compares our recent experience with this historical data to assess if improved recognition of ARDS and treatment strategies has had an impact on the incidence and mortality. METHODS: We identified and studied all patients who developed ARDS following a lung resection of any magnitude between 2000 and 2005 using the 1994 consensus definition: characteristic chest X-ray or CT, PaO2/FiO2 < 200 mmHg, pulmonary capillary wedge pressure < 18 mmHg and clinical acute onset. Overall incidence and mortality were recorded. Univariate analyses (t-test or chi(2), as appropriate) were carried out to identify correlations between pre-, peri- and postoperative variables and outcomes. RESULTS: We performed 1376 lung resections during the study period. Of these 705 (51.2%) were for lung cancer and 671 (48.8%) for other diseases. Twenty-two patients fulfilled the criteria for ARDS with 10 deaths in this group. The incidence and mortality from ARDS had fallen significantly over the two study periods (incidence from 3.2% to 1.6%, p=0.01; mortality from 72% to 45%, p=0.05). Although no significant correlations with incidence and mortality were identified, we found a number of significant trends. In keeping with the ARDS network study recommendations, postoperative tidal volumes were maintained at a lower level when a higher number of pulmonary segments were excised (p=0.001). Furthermore, consistent with findings in previous studies, the highest incidence and death from ARDS were in pneumonectomy patients (incidence 11.4%; mortality 50%). Although the incidence and mortality from ARDS following pneumonectomy were not significantly different between the two study periods (p=0.08, p=0.35), we found that fewer pneumonectomies were performed in the later period (pneumonectomy rate of 6.4% vs 17.4%). CONCLUSIONS: The incidence and mortality of ARDS have decreased in our institution. We postulate that this is due to more aggressive strategies to avoid pneumonectomy, greater attention to protective ventilation strategies during surgery and to the improved ICU management of ARDS.

Successful double bioprosthetic valve replacement in a 64-year-old man with carcinoid syndrome and bipolar disorder: case report.

The case is described of a 64-year-old man with bipolar disorder and severe carcinoid heart disease who required a double valve replacement. Multidisciplinary team involvement and extensive preoperative investigations resulted in a successful regimen which prevented reactivation of carcinoid syndrome and avoided the serious side effects of lantreotide and lithium therapy. In addition, two bioprosthetic valves were used, thereby avoiding the potential complications of anticoagulation in a patient with known hepatic metastases.