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.

Divining responder populations from survival data.

BACKGROUND: Biomarkers that predict treatment response are the foundation of precision medicine in clinical decision-making and have the potential to significantly improve the efficiency of clinical trials. Such biomarkers may be identified before clinical testing but many trials enroll unselected populations. We hypothesized that time-varying treatment effects in unselected trials may result from identifiable responder subpopulations that may have associated biomarkers. MATERIALS AND METHODS: We first simulated scenarios of clinical trials with biomarker populations of varying prevalence and prognostic and predictive associations to illustrate the impact of subgroup-specific effects on overall population estimates. To show a real-world example of time-dependent treatment effects resulting from a prognostic and predictive biomarker, we re-analyzed data from a published clinical trial (RTOG, Radiation Therapy Oncology Group, 9402). We then demonstrated a quantitative framework to fit survival data from clinical trials using statistical models incorporating known estimates of biomarker prevalence and prognostic value to prioritize predictive biomarker hypotheses. RESULTS: Our simulation studies demonstrate how biomarker subgroups that are both predictive and prognostic can manifest as time-dependent treatment effects in overall populations. RTOG 9402 provides a representative example where 1p/19q co-deletion and IDH mutation biomarker-specific effects led to time-varying treatment effects and a considerable deviation from proportional hazards in the overall trial population. Finally, using biomarker data from The Cancer Genome Atlas, we were able to generate statistical models that correctly identified and prioritized a commonly used biomarker through retrospective analysis of published clinical trial data. CONCLUSIONS: Biomarkers that are both predictive and prognostic can result in characteristic changes in survival results. Retrospectively analyzing survival data from clinical trials may highlight potential indications for which an underlying predictive biomarker may be found.

Radial artery bypass graft is a feasible and durable conduit for challenging infrainguinal revascularization: 17 years of Melbourne experience.

OBJECTIVES: The superiority of autogenous venous conduits in infrainguinal bypass surgery is well established. In the absence of suitable leg or arm veins the radial artery can be utilized as an alternative autogenous conduit. In contrast to cardiac surgery, experience with the radial artery as a conduit for infrainguinal bypass surgery is limited. The purpose of this study was to review the outcomes of our radial artery bypasses over the last 17 years. METHODS: All radial artery bypasses performed between 1995 and 2012 were identified from a prospective database. Patency, limb salvage, and survival were calculated using the Kaplan-Meier survival estimate method. RESULTS: Twenty-nine radial artery bypasses were performed in 28 patients. Median follow-up was 55 months (range 1-170). Twelve-month primary, assisted primary, and secondary patency rates were 49%, 62%, and 73% respectively; Both 3-year and 5-year primary, assisted primary, and secondary patency rates were 49%, 56% and 67% respectively. Limb salvage rate was 75% at 1- and 5-year follow-up. Patient survival at 1, 3, and 5 years was 96%, 88%, and 76%. CONCLUSIONS: For patients with need of challenging infrainguinal revascularization without suitable autogenous venous conduit, a radial artery bypass can be performed safely with favorable long-term patency and limb salvage rates.

Importance of sustainable local government funding in tackling health inequalities in the UK.

This article looks at how there is evidence that policies that alter our environment are more effective than those that work to change individual behaviour. In order to create change, a more nuanced methodology to allocate local government funding is needed.

Description of measles D4-Hamburg outbreak in Hamburg, Germany, December 2008 to June 2009, which disproportionally affected a local Roma community.

From December 2008 to June 2009 a measles outbreak occurred in the Federal State of Hamburg, Germany. The outbreak affected 216 persons and was caused by a new measles strain termed D4-Hamburg which led to consecutive outbreaks between 2009 and 2011 in at least 12 European countries. Here, we describe epidemiological characteristics of the outbreak and evaluate the control measures taken in Hamburg. In one of the seven boroughs of Hamburg a local Roma community comprised more than 50% of the notified cases.We compared in a stratified analysis the age distribution of these cases with cases of fellow citizens who did not belong to the Roma community. The age group of infants (0-11 months) comprised 33% among the non-Roma measles cases, while in the Roma community only 4% belonged to this stratum. In the stratum of 5-17 year-olds only 8% were affected among the non-Roma cases, whereas in the Roma community 50% belonged to this age group. We discuss the influencing factors that might have led to this difference in age distribution between the two groups.

Multidisciplinary approach to carotid stenting.

BACKGROUND: Stroke neurologists, vascular surgeons, interventional neuroradiologists and interventional cardiologists have embraced carotid angioplasty and stenting (CAS) because of potential advantages over carotid endarterectomy (CEA). At Austin Health, a multidisciplinary neuro-interventional group was formed to standardise indications and facilitate training. The aims of this study were to describe our organisational model and to determine whether 30-day complications and early outcomes were similar to those of major trials. METHODS: A clinical protocol was developed to ensure optimal management. CAS was performed on patients with high medical risk for CEA, with technically difficult anatomy for CEA, or who were randomised to CAS in a trial. RESULTS: From October 2003 to May 2008, 47 patients (34 male, mean age 71.5) underwent CAS of 50 carotid arteries. Forty-three cases had ipsilateral carotid territory symptoms within the previous 12 months. The main indications for CAS were high risk for CEA (n= 17) and randomised to CAS (n= 21). Interventionists were proctored in 27 cases. The procedural success rate was 94% with two cases abandoned because of anatomical problems and one because of on-table angina. Hypotension requiring vasopressor therapy occurred in 12 cases (24%). The duration of follow up was one to 44 months (mean 6.8 months). The 30-day rate of peri-procedural stroke or death was 6% and the one-year rate of peri-procedural stroke or death or subsequent ipsilateral stroke was 10.6%. Restenosis occurred in 13% (all asymptomatic). CONCLUSION: A multidisciplinary approach is a useful strategy for initiating and sustaining a CAS programme.

Increasing case numbers of adenovirus conjunctivitis in Germany, 2010.

In 2010 (as of 13 October 2010), the number of adenovirus conjunctivitis cases reported to the Robert Koch Institute in Berlin, Germany, has increased by more than 250% compared with same period in the previous two years. An investigation was initiated to identify spatial or temporal clusters, possible sources of infection and potential connections to cases abroad. The analysis did not show a disproportionately affected sex or age group, but many infections were preceded by exposure to ophthalmological facilities, communal facilities or public places.

[Teleconferences for national surveillance of infectious diseases and public health events in Germany. Evaluation after three quarters in 2009]. / Die telefonische infektionsepidemiologische Bund-Länder-Lagekonferenz in Deutschland. Eine Zwischenbilanz nach drei Quartalen 2009.

Public health threats are increasingly triggered by events which span across international, national and state level jurisdictions. Innovative surveillance methods are needed to ensure adequate and timely response to such threats. In January 2009 the Department of Infectious Disease Epidemiology at the Robert Koch Institute (RKI) established a system of weekly telephone conferences with all competent authorities of the German federal states to identify, discuss and respond to infectious disease events in real-time. A regular and structured platform was developed for use between participants from state level public health authorities, the military and the RKI. During the first three quarters, 46 infectious diseases were covered, including mandatory reports of measles and meningococcal meningitis and outbreaks of cowpox, which does not have to be notified in Germany. Results of a targeted evaluation and a consistently high attendance rate both indicate that the teleconference has met additional needs for supplemental information exchange among participants. The telephone conference has proven to be a useful resource for rapid and direct communication, coordination and evaluation of signals for public health events in Germany.

Nickel metabolism in humans investigated with an oral stable isotope.

We report the results of the first complete study of nickel metabolism in human subjects using a stable nickel isotope (62Ni) as tracer. Four healthy adult subjects (two women and two men) fasted overnight before ingesting 10 microg 62Ni/kg body wt. Blood samples were drawn after fixed intervals of time and the total daily output of urine and feces was collected for the first 5 d after dose ingestion. 62Ni in plasma, urine, and feces was determined by isotope-dilution inductively coupled plasma-mass spectrometry with 61Ni. The direct measurement of the fecal excretion of the tracer allowed a reliable assessment of nickel absorption from the gastrointestinal tract and we found no evidence of the excretion of absorbed nickel via the gut. The percentage absorption calculated from the amount of 62Ni excreted in the feces ranged from 29% to 40%. Urinary excretion over 5 d ranged from 51% to 82% of the absorbed dose. Plasma 62Ni peaked between 1.5 and 2.5 h after ingestion and decreased by a factor of > 10 over the next few days. We observed low between-subject variability of nickel absorption and excretion. Confounding factors such as contamination and dietary intake of nickel, which hampered earlier measurements in subjects dosed with naturally abundant nickel, were eliminated by using the tracer isotope 62Ni.

Effect of inflammation on measures of antioxidant status in patients with non-small cell lung cancer.

This study examined the effect of an inflammatory response on measures of antioxidant status in patients with non-small cell lung cancer (NSCLC). In healthy, control subjects (n = 13) and NSCLC patients (n = 22) fasting concentrations of albumin, C-reactive protein, cholesterol, and the antioxidants alpha-tocopherol, retinol, lutein, lycopene, and alpha- and beta-carotene were measured. The two groups were similar in terms of age, sex, and body mass index. However, the cancer group had an inflammatory response as evidenced by significantly increased C-reactive protein concentrations. Concentrations of all the measured antioxidants of the NSCLC group were significantly lower than those of the control group (P < 0.01). The lowest concentrations were those of the carotenoids lycopene and alpha- and beta-carotene. In the cancer group there were significant negative correlations between concentrations of C-reactive protein and retinol (r = -0.682, P < 0.01), alpha-tocopherol (r = -0.464, P < 0.05), and lutein (r = -0.599, P < 0.01). The results of this study have implications for the interpretation of circulating antioxidant concentrations in patients with NSCLC.

Histopathology of early effects of oral cadmium in the rat kidney.

Adult male Wistar rats were given 50 ppm Cd in drinking water over a period of 1-24 weeks. The rats were killed and the cadmium concentration of whole blood, blood plasma red cells, liver and kidneys estimated. The plasma metallothionein concentration was measured by radioimmunoassay. Kidney samples were taken for light, transmission and scanning electron microscopic examination. The accumulation of cadmium in the tissues was shown by a linear increase with time, after exposure for 12 weeks. Plasma Cd concentrations showed a clear increase after 3 weeks and preliminary investigation suggests that most is present as Cd-thionein. Early pathological changes in the rat kidney were seen around the 4-6 week period which coincided with the distinct rise in plasma Cd. At 12 weeks, signs of tubular necrosis, interstitial fibrosis and glomerular epithelial cell hypertrophy were present in small areas of the cortex. By 24 weeks, the renal cortex showed clear evidence of tubulo-interstitial nephritis at a Cd concentration of 60 micrograms Cd/g wet weight.

Carotid arterial disease in patients undergoing coronary artery bypass operations.

The occurrence of stroke associated with coronary artery bypass operations is approximately 2%. In an attempt to reduce this incidence some centers have proposed carotid thromboendarterectomy for symptomatic and asymptomatic carotid arterial disease in patients undergoing a coronary artery bypass operation. To obtain a better understanding of the incidence of carotid occlusive disease in candidates for the coronary bypass operation and to evaluate the practical use of a noninvasive method to screen patients preoperatively, we evaluated 102 patients preoperatively with an ultrasonic Duplex scanner; 24 studies were requested on the basis of either previous neurologic problems or the presence of a bruit and 78 patients were evaluated as part of a study protocol. In the unrequested group 6% (5/78) of the patients had a stenosis of 50% diameter reduction or more. In the requested group 54% (13/24) had a stenosis of 50% diameter reduction or more. In the postoperative phase one stroke and one transient ischemic attack were noted among the unrequested group and none in those suspected of having carotid disease on clinical grounds. Neither affected patient had a high-grade stenosis. There is little evidence to support the contention that noninvasive screening of patients free of symptoms or signs of carotid disease prior to coronary artery bypass operation is a valuable method of screening for patients who will sustain a focal neurologic event.

Neutron activation analysis ofr copper in biological material applied to Wilson's disease.

A method for the neutron activation analysis of copper in biological material is described and applied to the diagnosis and management of four cases of Wilson's disease. Results obtained for serum and urine are in agreement with values obtained by established colorimetric techniques. The method described can estimate 10(-9) g. copper to within 10% and this sensitivity has allowed the determination of copper from biopsy material such as liver, spleen, hair, and nail.

ACP Best Practice No 163. Wilson's disease: acute and presymptomatic laboratory diagnosis and monitoring.

Wilson's disease, the most common inherited disorder of copper metabolism, is a recessive genetic condition. The clinical presentation of Wilson's disease is very variable. It is characterised by low serum copper and caeruloplasmin concentrations coupled with the pathological accumulation of copper in the tissues. However, there are diagnostic difficulties and these are discussed. The current value of DNA diagnosis, both in gene tracking in families or as applied to de novo cases, is examined. Wilson's disease can be treated successfully but treatment must be life long. Patients are best treated by specialist centres with experience and expertise in the condition.

Evaluation of carotid bifurcation disease: the role of common carotid artery velocity patterns.

We evaluated duplex ultrasonographic velocity patterns from the common carotid artery in 156 patients with arteriographically verified internal carotid artery disease. Flow to zero during diastole in the common carotid was found in three groups of patients: (1) those with flow to zero in both common carotids not related to disease of the carotid bulb; (2) those with a tight (90% to 99%) stenosis in the internal carotid; and (3) those with total occlusion of the internal carotid. Although such flow to zero is commonly observed with total occlusion of the internal carotid artery, it may also be seen with high-grade stenosis. Thus, when found, it is essential to ascertain if flow is indeed present in the internal carotid artery; understanding changes in velocity patterns of the common carotid has improved our overall accuracy in detecting extracranial carotid artery disease.

Hypercalciuria related to cadmium exposure.

A work force has been investigated for possible cadmium intoxication. One group who are coppersmiths have an 18.5 per cent prevalence of upper urinary tract stone disease associated with a statistically highly significant hypercalciuria and reduced serum inorganic phosphate. Proof of exposure to cadmium has been confirmed in all workers. The trace element cadmium should be kept in mind when investigating stone formers who exhibit an unexplained hypercalciuria.

Determination of copper in urine by graphite furnace atomic absorption spectrometry.

Two methods are described for the determination of copper in urine by graphite furnace atomic absorption spectrometry. The first, suitable for spectrometers capable of making good background correction at 325 nm, involves a direct determination against simple aqueous standards after 2 X dilution of the sample. The second requires no background correction and can be used when background correction is not available or is inadequate. The copper is extracted from the urine with ammonium tetramethylenedithiocarbamate into methylisobutylketone and the extract is analysed for copper. No significant matrix effect was observed for either method. Analysis of random urine samples from 16 normal subjects gave a mean concentration of 0.42 mumol/l with a range of 0.06--1.04 mumol/l.

Observations on serum iron, zinc, copper and magnesium in intravenously fed patients with chronic sepsis.

In a retrospective study of 176 people who received intravenous nutrition, eight developed a septic episode of at least 12 days duration. We investigated the metabolism of four essential elements (iron, zinc, copper and magnesium) in this group. Plasma concentrations of iron, copper and magnesium followed expected trends; unexpectedly the plasma concentration of zinc was maintained. The implications of these findings in relation to the septic patient are discussed.

Selenium depletion and its correction in a child with homocystinuria.

A child of 10 months with proven homocystinuria was found to be selenium depleted and we report the serial monitoring of replacement therapy. Selenium, as an enriched yeast preparation, equivalent to 50 mug on alternate days was required for maintenance. Indices of selenium status returned to normal in varying times. The child initially demonstrated an abnormality of an in vitro challenge by hydrogen peroxide to her erythrocytes, that returned to within normal limits with selenium therapy alone, the serum vitamin E concentration being normal.