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.

The INTEND 1 randomized controlled trial of duct endoscopy as an indicator of margin excision in breast conservation surgery.

PURPOSE: With early detection, breast conservation surgery with adequate surgical margins is the standard of care. The aim of this study was to evaluate the use of pre-operative duct endoscopy (DE) to target surgical resection, improve adequate margins and reduce re-excision operations. METHODS: Women with DCIS, stage I and II breast cancer suitable for breast conservation were randomized to DE-assisted wide local excision versus standard wide local excision (without DE). The primary endpoint was margin re-excision rates between the two groups. Secondary end points were: (i) volume differences of the surgical specimen; (ii) whether an extensive in situ component (EIC) influenced successful DE-guided resection. RESULTS: 78 women were randomized: 44 patients to no-DE and 34 patients to the DE group. The median age was 59 (49-65) and 56 (48-64) years in the two groups respectively with mean follow-up of 9.1 (4.2-11.1) years. There were 23 positive findings in 17 women in 30 successful DE procedures (17/30 = 56.7%). The surgical specimen volume, no-DE (17 [IQR 10-29] cm3) and DE 20 [IQR 12-28] cm3), did not differ, p = 0.377. The overall re-excision rate was 20/78 (26%), 9 (20%) and 11 (32% in the no-DE and DE groups, respectively, p = 0.233. CONCLUSIONS: This randomized clinical trial was limited by incomplete accrual. DE did not contribute to improved margin excision rates whether a target lesion was visualized or not. The presence of EIC did not improve efficacy of DE.

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.

Evaluation of Copper-64-Labeled αvß6-Targeting Peptides: Addition of an Albumin Binding Moiety to Improve Pharmacokinetics.

The incorporation of non-covalent albumin binding moieties (ABMs) into radiotracers results in increased circulation time, leading to a higher uptake in the target tissues such as the tumor, and, in some cases, reduced kidney retention. We previously developed [18F]AlF NOTA-K(ABM)-αvß6-BP, where αvß6-BP is a peptide with high affinity for the cell surface receptor integrin αvß6 that is overexpressed in several cancers, and the ABM is an iodophenyl-based moiety. [18F]AlF NOTA-K(ABM)-αvß6-BP demonstrated prolonged blood circulation compared to the non-ABM parent peptide, resulting in high, αvß6-targeted uptake with continuously improving detection of αvß6(+) tumors using PET/CT. To further extend the imaging window beyond that of fluorine-18 (t1/2 = 110 min) and to investigate the pharmacokinetics at later time points, we radiolabeled the αvß6-BP with copper-64 (t1/2 = 12.7 h). Two peptides were synthesized without (1) and with (2) the ABM and radiolabeled with copper-64 to yield [64Cu]1 and [64Cu]2, respectively. The affinity of [natCu]1 and [natCu]2 for the integrin αvß6 was assessed by enzyme-linked immunosorbent assay. [64Cu]1 and [64Cu]2 were evaluated in vitro (cell binding and internalization) using DX3puroß6 (αvß6(+)), DX3puro (αvß6(-)), and pancreatic BxPC-3 (αvß6(+)) cells, in an albumin binding assay, and for stability in both mouse and human serum. In vivo (PET/CT imaging) and biodistribution studies were done in mouse models bearing either the paired DX3puroß6/DX3puro or BxPC-3 xenograft tumors. [64Cu]1 and [64Cu]2 were synthesized in ≥97% radiochemical purity. In vitro, [natCu]1 and [natCu]2 maintained low nanomolar affinity for integrin αvß6 (IC50 = 28 ± 3 and 19 ± 5 nM, respectively); [64Cu]1 and [64Cu]2 showed comparable binding to αvß6(+) cells (DX3puroß6: ≥70%, ≥42% internalized; BxPC-3: ≥19%, ≥12% internalized) and ≤3% to the αvß6(-) DX3puro cells. Both radiotracers were ≥98% stable in human serum at 24 h, and [64Cu]2 showed a 6-fold higher binding to human serum protein than [64Cu]1. In vivo, selective uptake in the αvß6(+) tumors was observed with tumor visualization up to 72 h for [64Cu]2. A 3-5-fold higher αvß6(+) tumor uptake of [64Cu]2 vs [64Cu]1 was observed throughout, at least 2.7-fold improved BxPC-3-to-kidney and BxPC-3-to-blood ratios, and 2-fold improved BxPC-3-to-stomach ratios were noted for [64Cu]2 at 48 h. Incorporation of an iodophenyl-based ABM into the αvß6-BP ([64Cu]2) prolonged circulation time and resulted in improved pharmacokinetics, including increased uptake in αvß6(+) tumors that enabled visualization of αvß6(+) tumors up to 72 h by PET/CT imaging.

Are vancomycin dosing guidelines followed? A mixed methods study of vancomycin prescribing practices.

AIMS: Despite the availability of international consensus guidelines, vancomycin dosing and therapeutic drug monitoring (TDM) remain suboptimal. This study aimed to assess concordance of vancomycin dosing and TDM with institutional guidelines and to identify factors taken into consideration by clinicians when prescribing vancomycin. METHODS: A retrospective audit of 163 patients receiving vancomycin therapy (≥48 hours) was undertaken. Data collected included patient characteristics, dosing history and plasma vancomycin and creatinine concentrations. Concordance of dosing and TDM with institutional guidelines was evaluated. Semi-structured interviews, including simulated prescribing scenarios, were undertaken with prescribers (n = 17) and transcripts analysed. RESULTS: Plasma vancomycin concentrations (n = 1043) were collected during 179 courses of therapy. Only 24% of courses commenced with a loading dose with 72% lower than recommended. The initial maintenance dose was concordant in 42% of courses with 34% lower than recommended. Only 14% of TDM samples were trough vancomycin concentrations. Dose was not adjusted for 60% (21/35) of subtherapeutic and 43% (18/42) of supratherapeutic trough vancomycin concentrations, respectively. Interview participants reported that patient characteristics (including renal function), vancomycin concentrations, guidelines and expert advice influenced vancomycin prescribing decisions. Despite referring to guidelines when completing simulated prescribing scenarios, only 37% of prescribing decisions aligned with guideline recommendations. CONCLUSION: Poor compliance with institutional vancomycin guidelines was observed, despite prescriber awareness of available guidelines. Multifaceted strategies to support prescriber decision-making are required to improve vancomycin dosing and monitoring.

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.

Prostate cancer: performance characteristics of combined T2W and DW-MRI scoring in the setting of template transperineal re-biopsy using MR-TRUS fusion.

OBJECTIVES: To measure the performance characteristics of combined T2-weighted (T2W) and diffusion-weighted (DW) magnetic resonance imaging (MRI) suspicion scoring prior to MR-transrectal ultrasound (TRUS) fusion template transperineal (TTP) re-biopsy. METHODS: Thirty-nine patients referred for prostate re-biopsy, with prior MRI examinations, were retrospectively included. The MR images, including T2W and DW-MRI, had been independently evaluated prospectively by two radiologists using a structured scoring system. An MR-TRUS fusion TTP re-biopsy was used for MR target and non-targeted biopsy cores. Targeting performance and correlation with disease status were evaluated on a per-patient and per-region basis. RESULTS: The cancer yield was 41% (16/39 patients). MR targeting accurately detected the disease in 12/16 (75%) cancerous patients and missed the disease in 4/16 (25%) patients, all with Gleason 3 + 3 disease. There was a significant relationship (P < 0.01) between MR suspicion score and the significance of cancer. Reader 1 had significantly higher sensitivity in the transition zone (TZ; 0.84) compared with the peripheral zone (PZ; 0.32) (P = 0.04). Inter-reader agreement was moderate for the PZ and substantial for the TZ. CONCLUSIONS: MRI targeting is beneficial in the setting of TTP MR-TRUS fusion re-biopsy and MR suspicion score relates to prostate cancer clinical significance. A T2W and DW-MRI structured scoring system results in good inter-reader agreement in this setting. KEY POINTS: • Pre-biopsy MRI aids the detection of high significance cancer during prostate re-biopsy. • MRI suspicion level correlates with the clinical significance of prostate cancer detected. • T2W and DW-MRI structured scoring of pre-biopsy MRI permits good inter-reader agreement.

Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics.

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger receptor MARCO in mice, non-human primates and humans. Therapeutic blockade of MARCO is shown to decrease the phagocytic uptake of nanoparticles and improve the antitumour effect of clinically approved cancer nanotherapeutics in young but not aged mice. Together, these results reveal an age-associated disparity in the phagocytic clearance of nanotherapeutics that affects their antitumour response, thus providing a strong rationale for an age-appropriate approach to cancer nanomedicine.

The clinical impact of anti-hypertensive treatment drug-gene pairs in the asian population: a systematic review of publications in the past decade.

Pharmacogenetics play an important role in determining the anti-hypertensive effects of blood pressure-lowering medications and have the potential to improve future patient care. Current literature on the topic, however, has a heavy focus on Caucasians and may not be generalisable to the Asian populations. Therefore, we have conducted this systematic review to summarise and evaluate the literature of the past decade. PubMed, Embase, and the Cochrane Register of Controlled Trials were searched for relevant studies from 1 January 2011 to 23 July 2021. The outcome of interest was the response to anti-hypertensive treatment in Asians according to each genetic polymorphism. A total of 26 studies with a total of 8837 patients were included in our review, covering five classes of anti-hypertensive agents-namely, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta-blockers (BB), calcium channel blockers (CCB), and thiazide-like diuretics. Response to ACEI therapy was most susceptible to genotypic variations, while the efficacy of ARB and CCB were affected by pharmacogenetic differences to varying extent. For BB, only variations in the ADRB1 genotype significantly affects therapeutic response, while the therapeutic efficacy of thiazide-like diuretics was correlated with genotypic variations in the REN and ACE. This systematic review evaluated the impact of pharmacogenetic variations on the therapeutic efficacy of anti-hypertensive treatment in Asians and has described numerous drug-gene pairs that are potentially clinically important. Future prospective studies with larger sample sizes and longer follow-up periods are needed to better elucidate the impact of these drug-gene pairs.

Preclinical Evaluation of 68Ga- and 177Lu-Labeled Integrin αvß6-Targeting Radiotheranostic Peptides.

The integrin αvß6, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel αvß6-targeting peptide, DOTA-5G (1) radiolabeled with 68Ga, for PET/CT imaging and 177Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G (2). Methods: Peptides 1 and 2 were synthesized on solid phase, and their affinity for αvß6 was assessed by enzyme-linked immunosorbent assay. The peptides were radiolabeled with 68Ga and 177Lu. In vitro cell binding, internalization, and efflux of 68Ga-1 and 177Lu-2 were evaluated in αvß6-positive BxPC-3 human pancreatic cancer cells. PET/CT imaging of 68Ga-1 and 68Ga-2 was performed on female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for 68Ga-1 (1 and 2 h after injection), 68Ga-2 (2 and 4 h after injection), and 177Lu-1 and 177Lu-2 (1, 24, 48, and 72 h after injection). The 177Lu-2 biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of 177Lu-2 was evaluated in mice bearing BxPC-3 tumors. Results: Peptides 1 and 2 demonstrated high affinity (<55 nM) for αvß6 by enzyme-linked immunosorbent assay. 68Ga-1, 68Ga-2, 177Lu-1, and 177Lu-2 were synthesized in high radiochemical purity. Rapid in vitro binding and internalization of 68Ga-1 and 177Lu-2 were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the albumin-binding moiety in 177Lu-2 resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data, the dose-limiting organ for 177Lu-2 is the kidney. Treatment with 177Lu-2 prolonged median survival by 1.5- to 2-fold versus controls. Conclusion: 68Ga-1 and 177Lu-2 demonstrated high affinity for the integrin αvß6 both in vitro and in vivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in preclinical studies, with predominantly renal excretion and good tumor-to-normal-tissue ratios. Favorable human dosimetry data suggest the potential of 177Lu-2 as a treatment for pancreatic ductal adenocarcinoma.

Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer.

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications.

Analysis of Short-Term versus Long-Term Readmission-Free Survival After Metastatic Spine Tumor Surgery.

BACKGROUND: Readmission-free survival (ReAFS) is a novel clinical and quality metric after metastatic spine tumor surgery (MSTS). We believe that factors influencing ReAFS after index MSTS vary based on time. We considered 2 time frames and defined short-term ReAFS as survival without an unplanned hospital readmission up to 90 days and long-term ReAFS as survival without unplanned hospital readmission up to 1 year after MSTS. METHODS: We retrospectively analyzed 266 patients who underwent MSTS between 2005 and 2016. All relevant oncologic, surgical and follow-up data were collected. Multivariate logistic regression analysis was used to analyze prognostic factors associated with higher probability of short-term ReAFS and long-term ReAFS. RESULTS: Multivariate analysis showed that Eastern Cooperative Oncology Group score ≤2 (P = 0.011), preoperative hemoglobin (Hb) level >12 g/dL (P = 0.008), ≤3 comorbidities (P = 0.052), shorter index length of stay ≤10 days (P = 0.007), and absence of neurologic/hematologic complications during index stay (P = 0.015) significantly increased the probability of short-term ReAFS, whereas preoperative Hb level >12 g/dL (P = 0.003) or tumor primaries with advanced treatment modalities such as breast (P = 0.012), hematologic (P = 0.006), prostate (P = 0.004), and renal/thyroid (P = 0.038) as opposed to aggressive lung tumor primaries were associated with significantly higher probability of long-term ReAFS. CONCLUSIONS: Patient and treatment factors predominantly influence ReAFS up to 90 days, whereas primary tumor-related factors alongside general health influence ReAFS beyond 90 days after index MSTS. Awareness of these factors may help oncologists and surgeons optimize treatment planning. The clinical significance of this study will continue to evolve, because we have been witnessing over the past decade that patients are becoming more involved in both their general health and understanding the natural history of the diseases that affect them.

Therapeutic drug monitoring of meropenem and piperacillin-tazobactam in the Singapore critically ill population - A prospective, multi-center, observational study (BLAST 1).

PURPOSE: To determine percentage of patients with sub-therapeutic beta-lactam exposure in our intensive care units (ICU) and to correlate target attainment with clinical outcomes. MATERIALS AND METHODS: Multi-centre, prospective, observational study was conducted in ICUs from three hospitals in Singapore from July 2016 to May 2018. Adult patients (≥21 years) receiving meropenem or piperacillin-tazobactam were included. Four blood samples were obtained during a dosing interval to measure and determine attainment of therapeutic targets: unbound beta-lactam concentration above (i) minimum inhibitory concentration (MIC) at 40% (meropenem) or 50% (piperacillin) of dosing interval (40-50%fT > MIC) and (ii) 5 × MIC at 100% of dosing interval (100%fT > 5 × MIC). Correlation to clinical outcomes was evaluated using Cox regression. RESULTS: Beta-lactam levels were highly variable among 61 patients, with trough meropenem and piperacillin levels at 21.5 ± 16.8 mg/L and 101.6 ± 81.1 mg/L respectively. Among 85 sets of blood samples, current dosing practices were able to achieve 94% success for 40-50%fT > MIC and 44% for 100%fT > 5 × MIC. Failure to achieve 40-50%fT > MIC within 48 h was significantly associated with all-cause mortality (HR: 9.0, 95% CI: 1.8-45.0), after adjustment for APACHE II score. Achievement of 100%fT > 5 × MIC within 48 h was significantly associated with shorter length of hospital stay. CONCLUSION: Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.

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.

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.

Correction to: Evaluation of Two Optical Probes for Imaging the Integrin αvß6- In Vitro and In Vivo in Tumor-Bearing Mice.

This article was updated to correct the axes in Figures 4e and 5d.

Evaluation of Two Optical Probes for Imaging the Integrin αvß6- In Vitro and In Vivo in Tumor-Bearing Mice.

PURPOSE: The purpose of this study was to develop and evaluate two αvß6-targeted fluorescent imaging agents. The integrin subtype αvß6 is significantly upregulated in a wide range of epithelial derived cancers, plays a key role in invasion and metastasis, and expression is often located at the invasive edge of tumors. αvß6-targeted fluorescent imaging agents have the potential to guide surgical resection leading to improved patient outcomes. Both imaging agents were based on the bi-PEGylated peptide NH2-PEG28-A20FMDV2-K16R-PEG28 (1), a peptide that has high affinity and selectivity for the integrin αvß6: (a) 5-FAM-X-PEG28-A20FMDV2-K16R-PEG28 (2), and (b) IRDye800-PEG28-A20FMDV2-K16R-PEG28 (3). PROCEDURES: Peptides were synthesized using solid-phase peptide synthesis and standard Fmoc chemistry. Affinity for αvß6 was evaluated by ELISA. In vitro binding, internalization, and localization of 2 was monitored using confocal microscopy in DX3puroß6 (αvß6+) and DX3puro (αvß6-) cells. The in vivo imaging and ex vivo biodistribution of 3 was evaluated in three preclinical mouse models, DX3puroß6/DX3puro and BxPC-3 (αvß6+) tumor xenografts and a BxPC-3 orthotopic pancreatic tumor model. RESULTS: Peptides were obtained in > 99% purity. IC50 values were 28 nM (2) and 39 nM (3). Rapid αvß6-selective binding and internalization of 2 was observed. Fluorescent intensity (FLI) measurements extracted from the in vivo images and ex vivo biodistribution confirmed uptake and retention of 3 in the αvß6 positive subcutaneous and orthotopic tumors, with negligible uptake in the αvß6-negative tumor. Blocking studies with a known αvß6-targeting peptide demonstrated αvß6-specific binding of 3. CONCLUSION: Two fluorescence imaging agents were developed. The αvß6-specific uptake, internalization, and endosomal localization of the fluorescence agent 2 demonstrates potential for targeted therapy. The selective uptake and retention of 3 in the αvß6-positive tumors enabled clear delineation of the tumors and surgical resection indicating 3 has the potential to be utilized during image-guided surgery.

The Effects of an Albumin Binding Moiety on the Targeting and Pharmacokinetics of an Integrin αvß6-Selective Peptide Labeled with Aluminum [18F]Fluoride.

PURPOSE: The αvß6-BP peptide selectively targets the integrin αvß6, a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[18F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [18F]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life. PROCEDURES: The peptides NOTA-αvß6-BP (1) and NOTA-K(ABM)-αvß6-BP (2) were synthesized on solid phase, radiolabeled with aluminum [18F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroß6 [αvß6(+)]/DX3puro [αvß6(-)], and for [18F]AlF 2, BxPC-3 [αvß6(+)] cell xenografts (PET imaging, biodistribution). RESULTS: The peptides were radiolabeled in 23.0 ± 5.7 % and 22.1 ± 4.4 % decay-corrected radiochemical yield, respectively, for [18F]AlF 1 and [18F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin αvß6 by ELISA (IC50(αvß6) = 3-7 nM vs IC50(αvß3) > 10 µM) and in cell binding studies (51.0 ± 0.7 % and 47.2 ± 0.7 % of total radioactivity bound to DX3puroß6 cells at 1 h, respectively, vs. ≤ 1.2 % to DX3puro for both compounds). The radiotracer [18F]AlF 1 bound to human serum at 16.3 ± 1.9 %, compared to 67.5 ± 1.0 % for the ABM-containing [18F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1 % ID/g remaining in blood for [18F]AlF 1 as soon as 1 h p.i. vs. > 2 % ID/g for [18F]AlF 2 at 6 h p.i.) and higher αvß6(+) tumor uptake (4 h: DX3puroß6; [18F]AlF 1: 3.0 ± 0.7 % ID/g, [18F]AlF 2: 7.2 ± 0.7 % ID/g; BxPC-3; [18F]AlF 2: 10.2 ± 0.1 % ID/g). CONCLUSION: Both compounds were prepared using standard chemistries; affinity and selectivity for integrin αvß6 in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher αvß6-targeted uptake.

Construction of the secondary care administrative records frailty (SCARF) index and validation on older women with operable invasive breast cancer in England and Wales: a cohort study.

OBJECTIVES: Studies that use national datasets to evaluate the management of older women with breast cancer are often constrained by a lack of information on patient fitness. This study constructed a frailty index for use with secondary care administrative records and evaluated its ability to improve models of treatment patterns and overall survival in women with breast cancer. DESIGN: Retrospective cohort study. PARTICIPANTS: Women aged ≥50 years with oestrogen receptor (ER) positive early invasive breast cancer diagnosed between 2014 and 2017 in England. METHODS: The secondary care administrative records frailty (SCARF) index was based on the cumulative deficit model of frailty, using International Statistical Classification of Diseases, Injuries and Causes of Death, 10th revision codes to define a set of deficits. The index was applied to administrative records that were linked to national cancer registry datasets. The ability of the SCARF index to improve the performance of regression models to explain observed variation in the rate of surgery and overall survival was evaluated using Harrell's c-statistic and decision curve analysis. External validation was performed on a dataset of similar women diagnosed in Wales. RESULTS: The SCARF index captured 32 deficits that cover functional impairment, geriatric syndromes, problems with nutrition, cognition and mood, and medical comorbidities. In the English dataset (n=67 925), the prevalence of frailty in women aged 50-69, 70-79 and ≥80 years was 15%, 28% and 47%, respectively. Adding a frailty measure to regression models containing age, tumour characteristics and comorbidity improved their ability to: (1) discriminate between whether a woman was likely to have surgery and (2) predict overall survival. Similar results were obtained when the models were applied to the Welsh cohort (n=4 230). CONCLUSION: The SCARF index provides a simple and consistent method to identify frailty in population level data and could help describe differences in breast cancer treatments and outcomes.