Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial.

BACKGROUND: Sacituzumab govitecan (SG), a novel antibody-drug conjugate (ADC) targeting TROP2, is approved for pre-treated metastatic triple-negative breast cancer (mTNBC). We conducted an investigator-initiated clinical trial evaluating neoadjuvant (NA) SG (NCT04230109), and report primary results. PATIENTS AND METHODS: Participants with early-stage TNBC received NA SG for four cycles. The primary objective was to assess pathological complete response (pCR) rate in breast and lymph nodes (ypT0/isN0) to SG. Secondary objectives included overall response rate (ORR), safety, event-free survival (EFS), and predictive biomarkers. A response-guided approach was utilized, and subsequent systemic therapy decisions were at the discretion of the treating physician. RESULTS: From July 2020 to August 2021, 50 participants were enrolled (median age = 48.5 years; 13 clinical stage I disease, 26 stage II, 11 stage III). Forty-nine (98%) completed four cycles of SG. Overall, the pCR rate with SG alone was 30% [n = 15, 95% confidence interval (CI) 18% to 45%]. The ORR per RECIST V1.1 after SG alone was 64% (n = 32/50, 95% CI 77% to 98%). Higher Ki-67 and tumor-infiltrating lymphocytes (TILs) were predictive of pCR to SG (P = 0.007 for Ki-67 and 0.002 for TILs), while baseline TROP2 expression was not (P = 0.440). Common adverse events were nausea (82%), fatigue (76%), alopecia (76%), neutropenia (44%), and rash (48%). With a median follow-up time of 18.9 months (95% CI 16.3-21.9 months), the 2-year EFS for all participants was 95%. Among participants with a pCR with SG (n = 15), the 2-year EFS was 100%. CONCLUSIONS: In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed.

Periprocedural imaging compared to endometrial biopsy: is biopsy required prior to uterine artery embolisation?

AIM: To compare the detection rate of magnetic resonance imaging (MRI) and ultrasound relative to endometrial biopsy for endometrial abnormalities in both pre- and post-menopausal women. MATERIALS AND METHODS: The present study was an institutional review board-approved, single-institution retrospective analysis of patients who underwent pelvic MRI within 1 year of diagnostic-quality biopsies from 2008-2018 (n=668). There were 303 patients who received uterine artery embolisation (UAE) and 478 patients who received pelvic ultrasound within the study period. Medical records were evaluated for radiological-histopathological correlation, demographics, laboratory studies, and clinical follow-up. RESULTS: In this cohort of 668 patients, there were 37 biopsies positive for malignancy; women with malignancy were older (58 versus 47 years, p<0.0001) and more likely to be post-menopausal (66% versus 12%, p<0.0001). There were 303 patients who underwent UAE and underwent a diagnostic-quality endometrial biopsy during the pre-procedural evaluation, none of whom were post-menopausal and had a mean age of 45 years. In women with abnormal uterine bleeding (AUB) or post-menopausal bleeding (PMB), the sensitivity of MRI for detecting endometrial cancer was 96.2%, with a negative predictive value (NPV) of 99.8%, compared to 68% and 97% for ultrasound, respectively. The receiver operating characteristic (ROC) curve of pre-biopsy MRI in identifying pre-malignant and malignant endometrial pathology demonstrated an AUC of 0.8920 (p<0.0001). CONCLUSION: In women with AUB or PMB, MRI has a 99.8% NPV in ruling out endometrial cancer. Further consideration should be made towards optimising pre-procedural evaluation for UAE.

Use of Palliative Care Consultation Services for Infants With Life-Threatening Conditions in a Metropolitan Hospital.

BACKGROUND: Palliative care is becoming an important component for infants with life-limiting or life-threatening conditions and their families. Yet palliative care practices appear to be inconsistent and sporadically used for infants. PURPOSE: The purpose of this study was to describe the use of an established pediatric palliative care team for seriously ill infants in a metropolitan hospital. METHODS: This was a retrospective medical record review. FINDINGS: The population included 64 infants who were admitted to a level IV neonatal intensive care unit (NICU) and then died during hospitalization between January 2015 and December 2016. Most infants died in an ICU (n = 63, 95%), and only 20 infants (31%) received palliative care consultation. Most common reasons for consultation were care coordination, defining goals of care and end-of-life planning, and symptom management. IMPLICATIONS FOR PRACTICE: Palliative care consultation at this institution did not change the course of end-of-life care. Interventions provided by the ICU team to infants surrounding end of life were similar to those in infants receiving palliative care services from the specialists. Our findings may be useful for developing guidelines regarding how to best utilize palliative care services for infants with life-threatening conditions who are admitted to an ICU. IMPLICATIONS FOR RESEARCH: These finding support continued research in neonatal palliative care, more specifically the impact of palliative care guidelines and algorithms.

British Neuropathological Society and International Society of Forensic Radiology and Imaging expert consensus statement for post mortem neurological imaging.

AIMS: To develop an expert consensus statement regarding appropriate clinical and forensic post mortem neurological imaging. METHODS: An expert panel of clinicians were recruited from registered members of the British Neuropathological Society (BNS) and the International Society of Forensic Radiology and Imaging (ISFRI) with post mortem expertise. Following a focus group meeting, 16 core statements were incorporated into an online modified Delphi survey and each panellist was asked to score their level of agreement. Following the first iteration, two statements that failed to reach consensus were modified and re-rated. Consensus was predefined as 75% agreement across responders. RESULTS: Seventeen experts joined the panel and 12 (70.6%) attended the focus group meeting; 14 (82%) completed both iterations of the survey. Consensus was reached for need of adequate clinical history, multidisciplinary discussion, establishment of special interest groups to discuss cases, gathering further evidence to inform imaging choices, establishment of methods for quality assessment in reporting standards and adequate funding for imaging services. The panel agreed that pathologists should be responsible for neuroimaging referrals, collating results of ancillary tests, and producing the final post mortem report. Areas requiring further discussion include the impact of double reporting, indications for neuroimaging and utilities of three-dimensional printing. CONCLUSION: The BNS/ISFRI statement represents current views of an expert panel of health professionals engaged in post-mortem neuroimaging. We hope this provides a working guideline for less experienced operators, stimulates discussion and highlights the most pressing clinical and research questions.

Crystallization Kinetics of Phosphonium Ionic Liquids: Effect of Cation Alkyl Chain Length and Thermal History.

The effects of alkyl chain length on the crystallization kinetics and ion mobility of tetraalkylphosphonium, [P666,n][TFSI], (n = 2, 6, 8, and 12) ionic liquids were studied by differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) over a wide temperature range. The liquid-glass transition temperature (Tg) and ion dynamics examined over a broad T range were almost insensitive to structural modifications of the phosphonium cation. In contrast, the crystallization kinetics were strongly affected by the length of the fourth alkyl chain. Furthermore, the thermal history of the sample (cold vs melt crystallization) significantly impacted the crystallization rate. It has been found that the nature of crystallization phenomena is the same across the homologous series, while the kinetic aspect differs. Finally, electric conductivity in supercooled liquid and crystalline solid phases was measured for all samples, revealing significant ionic conductivity, largely independent of the cation structure.

Managing fistula-in-ano with ligation of the intersphincteric fistula tract procedure: the Western Hospital experience.

AIM: To review the preliminary results of the ligation of the intersphincteric fistula tract (LIFT) technique in treating complex anal fistulas at our hospital. METHOD: Between March and November 2010, patients with cryptoglandular anal fistulas were recruited prospectively from the colorectal clinic and treated using the LIFT procedure. A database was set up to collect information on demographics, past surgical treatments, fistula characteristics, MRI scan results, operative data and follow-up findings. The primary end-point measured was cure of the disease. The secondary end-point was the degree of postoperative continence. Preoperative and postoperative incontinence rates were recorded using Wexner's Incontinence Scale. RESULTS: Twenty-five patients (eight women and 17 men; median age, 40 years) underwent the LIFT procedure. Ten patients had recurrent fistulas and previous fistula surgery. The median operating time was 39 min. No intraoperative complications were documented. The median follow-up duration was 22 (3-43) weeks. Primary healing was observed in 17 (68.0%) patients and the median healing time was 6 weeks; one wound remained incompletely healed. Seven patients (28.0%) had disease recurrence presenting between 7 and 20 weeks postoperatively. No patients reported any incontinence postoperatively. CONCLUSION: The LIFT procedure has favourable healing rates with little or no risk of incontinence. This operation is safe and easy to learn. The early results from this pilot study show promise and affirm some of the findings of other researchers. These results will suggest opportunities to conduct further controlled studies comparing the LIFT procedure with standard therapies.

The importance of informed consent in patients with wet age-related macular degeneration considering intravitreal anti-vascular endothelial growth factor treatments.

Retinal pigment epithelial (RPE) tears are now a documented potential complication following the intravitreal injection of anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration. Patients are often not well consented regarding this risk and thus we retrospectively analyzed the data from all of our patients undergoing this treatment over a six month period. Our findings highlighted the fact that the three patients (out of thirty) who had developed this RPE tear complication were initially all diagnosed with a pigment epithelial detachment (which is a type of macular degeneration in question). Therefore, we have adjusted our informed consent procedure such that all patients with "wet" macular degeneration and especially those with pigment epithelial detachments are now fully consented regarding the risks of the intravitreal treatment, which could potentially damage their vision further.

An open study of maintenance antibiotic therapy for chronic antibiotic-dependent pouchitis: efficacy, complications and outcome.

AIM: About 5% of restorative proctocolectomy (RPC) patients develop chronic antibiotic-dependent pouchitis. These require antibiotic maintenance therapy. We report our experience in managing this patient group. METHOD: Patients with RPC that was treated with antibiotic maintenance therapy were identified from the hospital pouch database. Data including faecal antibiotic sensitivity, functional outcome, side effects and Cleveland Global Quality of Life (CGQOL) score were recorded. RESULTS: Twenty-five patients were identified. The median length of treatment was 15.8 (range 3-62) months. Ten (40%) patients had pouchitis with co-existing prepouch ileitis. The median frequency of defecation was 7 (range 4-11)/24 h, the median clinical Pouch Disease Activity Index (PDAI) was 0 (range 0-1) and the CQGOL score was 0.7 (range 0.5-1.0). Of those who relapsed, three (50%) patients had achieved mucosal healing following the induction of remission. Failure of mucosal healing did not predict a reduced time to relapse (P = 0.18). Prepouch ileitis was associated with an increased risk of developing antibiotic resistance (P = 0.023). Treatment of this with alternating antibiotic combination therapy was successful in all cases. CONCLUSION: Antibiotic maintenance therapy appears safe, well-tolerated and effective for the treatment of chronic antibiotic-dependent pouchitis. It results in an improved quality of life and function. Prepouch ileitis, but not failure of mucosal healing, is associated with an increased risk of developing antibiotic resistance.

Predictors of clinic non-attendance: opportunities to improve patient outcomes in colorectal cancer.

AIM: Colorectal cancer is one of the few tumour types, where routine patient follow up has been demonstrated to impact significantly on survival. Patients who fail to attend regular clinic reviews may compromise their outcome, but the frequency at which this occurs is unknown. Identifying the extent of this problem, and the factors that predict non-attendance, may provide opportunities to improve patient outcomes. METHODS: Utilizing the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) colorectal database at Royal Melbourne and Western Hospitals and the Hospital Patient Management System (HOMER) we collected attendance data for colorectal surgical and oncology outpatient clinic appointments. RESULTS: A total of 619 patients (368 men and 251 women) with curatively treated Australian ClinicoPathological Staging System (ACPS) Stage A, B and C colorectal cancer was identified from the two sites over 1988-2008. Twenty-one per cent (n= 130) of patients failed to attend one or more appointments. Patients who failed to attend were more likely to require the services of an interpreter (25% vs 18%; P= 0.007), to have a smoking history and to have not received adjuvant therapy. Tumour site, patient age, sex and comorbidities were not associated with non-attendance. CONCLUSION: A significant percentage of patients fail to attend routine clinic visits to colorectal speciality clinics. Patients at risk of non-attendance can be identified. More research is needed to identify barriers as to why patients do not attend appointments and to develop measures that may improve patient attendance.

Leucocytoclastic and renal vasculitis in a patient with autoimmune pancreatitis: new associations.

Autoimmune pancreatitis (AIP) is an uncommon condition which comprises diffuse or discrete pancreatic enlargement and irregular pancreatic duct strictures of autoimmune origin leading to pain or obstructive jaundice associated with extra-pancreatic manifestations. It is characterized by an elevated IgG, especially IgG4, level. We illustrate the first described case of a patient with AIP in association with leucocytoclastic and renal vasculitis.

Relative humidity: important modifier of pollutant uptake by plants.

Laboratory measurements of foliar uptake of sulfur dioxide and ozone by red kidney beans demonstrated a strong effect of relative humidity on internal pollutant dose. Foliar uptake was enhanced two- to threefold for sulfur dioxide and three- to fourfold for ozone by an increase in relative humidity from 35 to 75 percent. For the same exposure concentration, vegetation growing in humid areas (such as the eastern United States) may experience a significantly greater internal flux of pollutants than that in more arid regions.

Trace elements in tree rings: evidence of recent and historical air pollution.

Annual growth rings from short-leaf pine trees in the Great Smoky Mountains National Park show suppressed growth and increased iron content between 1863 and 1912, a period of smelting activity and large sulfur dioxide releases at Copperhill, Tennessee, 88 kilometers upwind. Similar growth suppression and increases of iron and other metals were found in rings formed in the past 20 to 25 years, a period when regional fossil fuel combustion emissions increased about 200 percent. Metals concentrations in phloem and cambium are high, but whether they exceed toxic thresholds for these tissues is not known.

The dielectric constant of phospholipid bilayers and the permeability of membranes to ions.

The Born charging equation predicts that the permeability of a phospholipid bilayer membrane to ions should depend markedly on the dielectric constant of the membrane. Increasing the dielectric constant of an artificial bilayer increases its permeability to perchlorate or thiocyanate by a factor of 1000, to a value comparable to that of mitochondrial membranes.

A blinded pilot comparison of capsule endoscopy and small bowel histology in unresponsive celiac disease.

This study compares video capsule endoscopy (VCE) with histological specimens of proximal small bowel in patients with celiac disease who have failed to respond to a gluten-free diet. Patients with nonresponsive celiac disease underwent capsule endoscopy, and concordance between endoscopy and histology was then calculated using the kappa statistic. In 19 patients, endoscopy videos were reported as normal in ten (53%) case, as having mild changes in three (16%) cases, and as having moderate-severe changes in six (31%) cases. Two (11%) had acute ulcers. No small bowel tumors were seen. Endoscopy demonstrated concordance with histological changes in 14 of the 18 patients with histology available (78% concordance). The kappa statistic suggested a substantial degree of concordance between histology and endoscopic findings. Endoscopy with distal duodenal biopsies is superior to VCE in detecting proximal, nonresponsive celiac disease, but more distal lesions may be missed such that the strength of VCE lies in its ability to visualize the entire small bowel.

The myristoyl-electrostatic switch: a modulator of reversible protein-membrane interactions.

Hydrophobic insertion of the acyl chain into the bilayer is necessary but not sufficient for the membrane binding of a myristoylated protein. The myristoylated alanine-rich C kinase substrate (MARCKS), Src, ADP-ribosylation factor and human immunodeficiency virus-1 matrix proteins also contain a cluster of basic residues that bind to acidic phospholipids; the hydrophobic and electrostatic interactions act together to anchor the protein to a membrane. For MARCKS, and perhaps other proteins, phosphorylation of serines within its basic cluster reduces the electrostatic attraction, producing translocation of the protein from the membrane to the cytosol by a simple 'electrostatic switch' mechanism.

Mechanistic studies on Hsp90 inhibition by ansamycin derivatives.

Heat shock protein 90 (Hsp90) is a molecular chaperone that is required for the maturation and activation of a number of client proteins, many of which are involved in cancer development. The ansamycin family of natural products and their derivatives, such as geldanamycin (GA), are well-known inhibitors of the essential ATPase activity of Hsp90. Despite structural studies on the complexes of ansamycin derivatives with the ATPase domain of Hsp90, certain aspects of their inhibitory mechanism remain unresolved. For example, it is known that GA in solution exists in an extended conformation with a trans amide bond; however, it binds to Hsp90 in a significantly more compact conformation with a cis amide bond. GA and its derivatives have been shown to bind to Hsp90 with low micromolar affinity in vitro, in contrast to the low nanomolar anti-proliferative activity that these drugs exhibit in vivo. In addition, they show selectivity towards tumour cells. We have studied both the equilibrium binding, and the association and dissociation kinetics of GA derivative, 17-DMAG, and the fluorescently labelled analogue BDGA to both wild-type and mutant Hsp90. The mutants were made in order to test the hypothesis that conserved residues near the ATP-binding site may catalyse the trans-cis isomerisation of GA. Our results show that Hsp90 does not catalyse the trans-cis isomerisation of GA, and suggests that there is no isomerisation step before binding to Hsp90. Experiments with BDGA measured over a wide range of conditions, in the absence and in the presence of reducing agents, confirm recent studies that have suggested that the reduced dihydroquinone form of the drug binds to Hsp90 considerably more tightly than the non-reduced quinone species.

Single-institution experience of adjuvant 5-fluorouracil-based chemotherapy for stage III colon cancer.

BACKGROUND: Adjuvant 5-flourouracil-based chemotherapy is standard care for patients with stage III colon cancer. Limited data are available regarding use of adjuvant treatment in routine clinical practice, where patients are often frail and/or elderly. METHODS: A review of patients with stage III colon cancer over a 7-year period at Western Hospital using a prospective, comprehensive colorectal database was carried out. Results were compared to recent clinical trial data. RESULTS: We identified 554 patients with colon cancer, including 165 patients (30%) with stage III disease. Median patient age was 69 years, with a median follow up of 38 months. There were nine early postoperative deaths. Thirty other patients (19%) were not offered adjuvant chemotherapy, mainly because of advanced patient age and/or comorbidity. Of 124 patients offered adjuvant therapy 12 (10%) elected not to pursue treatment. Thirty-four of the 112 patients that commenced treatment had a dose reduction, with 30 not completing treatment because of toxicity (14) or other reasons (16). The 5-year progression-free survival was 50% and 5-year overall survival 59%. CONCLUSION: In routine practice many patients with stage III colon cancer do not receive adjuvant chemotherapy. For those receiving treatment the experience is not significantly different from that reported in the carefully selected clinical trial group.

New frontiers for health information systems using Epi Info in developing countries: structured application framework for Epi Info (SAFE).

BACKGROUND: For more than two decades, Epi Info software has been used to meet the data management, analysis, and mapping needs of public health professionals in more than 181 countries and 13 languages. Until now, most Epi Info systems have been relatively simple, mainly because of a lack of detailed and structured guidance for developing complex systems. OBJECTIVE AND RESULTS: We created the structured application framework for Epi Info (SAFE), which is a set of guidelines that allows developers to create both simple and complex information systems using accepted good programming practices. This has resulted in application code blocks that are re-useable and easy to maintain, modify, and enhance. The flexibility of SAFE allows various aggregate and case-based application modules to be rapidly created, combined, and updated to create health information systems or sub-systems enabling continuous, incremental enhancement as national and local capacity increases. CONCLUSIONS: SAFE and Epi Info are both cost-free and have low system requirements--characteristics that render this framework and software beneficial for developing countries.