A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer.

We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.

Disseminated Saksenaea infection in an immunocompromised host associated with a good clinical outcome: a case report and review of the literature.

BACKGROUND: Saksenaea species (spp.) are uncommon causes of mucormycosis but are emerging pathogens mostly associated with trauma and soil contamination often in immunocompetent hosts. Due to lack of sporulation in the laboratory, diagnosis and susceptibility testing is difficult so optimal treatment regimens are unknown. CASE PRESENTATION: A 67 year-old man from the Northern Territory in Australia, with a history of eosinophilic granulomatosis with polyangiitis, developed disseminated Saksenaea infection after initially presenting with symptoms consistent with bacterial pyelonephritis. Despite a delay in diagnosis; with aggressive surgical management and dual therapy with amphotericin B and posaconazole, he survived. CONCLUSIONS: We describe an unusual case of disseminated infection with a favourable outcome to date.

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.

Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.

BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.

Evaluation of aortopexy in the management of severe tracheomalacia after esophageal atresia repair.

Severe tracheomalacia (TM) is a difficult problem in esophageal atresia (EA) patients. We reviewed our experience with aortopexy and other interventions for severe TM in this population. With review ethics board approval, a retrospective review of TM in postoperative EA patients was conducted (1989-2010). Demographics, perinatal, and surgical information regarding EA repair was collected. TM infants were analyzed for symptomatology, clinical severity, investigations, interventions, and outcomes. Data are presented as proportions or median(range). One hundred and thirty-two EA patients were reviewed. Most had type C atresia (87.3%), and 18 patients (13.6%) died. Twenty-five patients (18.9%) had TM of whom five (20%) died. Median symptom onset was 18 days (0-729) after EA repair, with stridor (64%) or retractions/distress (44%) being most frequent. Four and two patients had airway obstruction or cardiorespiratory arrest, respectively. Median time from symptom onset to investigations was 11 days; these were most commonly rigid bronchoscopy (56%) and fluoroscopy (36%). Ten patients (40%) had severe TM on bronchoscopy. Six underwent aortopexy, one fundoplication, and three were treated medically. Length of hospital stay (LOS) post-aortopexy was 13 days (5-60), and ventilation time was 2 days (0-9). LOS was 60.5 (1-69) days postdiagnosis in non-aortopexy patients. Readmission rates for respiratory issues were significantly less in the aortopexy (median 0 vs. 5; P = 0.048) group over 2-year follow up after discharge. Complications of aortopexy included transfusion (1) and temporary diaphragmatic paresis (1), and one mortality secondary to severe congenital cardiac anomalies. Our experience suggests that aortopexy is safe and effective for the treatment of severe TM. It is associated with reduced LOS compared with other treatment strategies and few complications or long-term sequelae.

Human T-lymphotropic virus-1 serology in the Northern Territory: 2008-2011.

A retrospective observational study of human T-lymphotropic virus-1 (HTLV-1) serology requests made to the Northern Territory Government Pathology Service (NTGPS) between 2008 and 2011, was undertaken to review aspects of HTLV-1 sero-epidemiology and performance of the assays. A total of 5686 HTLV-1 serology requests, representing 3555 individual patients, were received during the study period; 368 HTLV-1 confirmed positive serology results were identified from the 3555 individual patients included in the sample. There was a distinct difference in the performance of the two antibody assays in use during this period, with the Serodia particle agglutination having a 5.7% indeterminate positivity rate compared to 18.1% indeterminate positivity rate of the Abbott HTLV 1/2 assay. We believe this is partially a serological anomaly related to current Australian western blot positive interpretative criteria, rather than false positive screening assay results.The majority (99.7%) of positive results occurred in Indigenous patients. The HTLV-1 positive rate varied geographically from a regional high of 51.7%, and falling inversely with distance from Central Australia. Patients with positive serology had a mean age of 49.9 (±13.9) years, with positivity occurring equally in males and females.

Human T-cell lymphotropic virus type 1 exposures following blood-borne virus incidents in central Australia, 2002-2012.

We retrospectively audited hospital occupational exposure events over a 10-year period, in a human T-cell lymphotropic virus type 1 (HTLV-1)-endemic area of Central Australia, and report on 53 individuals exposed to HTLV-1 with no transmissions documented (95% confidence interval, 0%-1.5%). This has important implications for the management of exposures including the role of postexposure prophylaxis.

The role of surgery in patients with advanced gynaecological cancers participating in phase I clinical trials.

OBJECTIVE: While gynaecological cancer patients who participate in Phase I clinical trials are not routinely considered for elective surgery because of a short life expectancy, this should not be overlooked in carefully selected responding patients. METHODS/RESULTS: We describe two cases of patients with different gynaecological cancers, who received treatment within separate phase I trials, and who then proceeded to surgical resection of their cancers, resulting in complete remission. CONCLUSION: Surgery, when feasible, should be taken into consideration as a potential management option, even when patients are receiving treatment within a phase I trial.

Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction.

BACKGROUND: Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities. METHODS: Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m(-2) per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m(-2) per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change. RESULTS: Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19%; P=0.80), stomatitis (0% vs 1%; P=0.50) or grades 2-4 hand foot syndrome (16% vs 11%; P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5%; P=0.03) and all grades hyperbilirubinaemia (60% vs 40%; P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11%; P=0.53). CONCLUSIONS: No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.

The effect of acute normovolaemic haemodilution on the inflammatory response and clinical outcome in abdominal aortic aneurysm repair--results of a pilot trial.

OBJECTIVES: To determine the effect of acute normovolaemic haemodilution (ANH) on the inflammatory response and clinical outcome in elective open abdominal aortic aneurysm (AAA) repair. DESIGN: Randomised controlled clinical trial. METHODS: Thirty-six patients were randomised to undergo ANH or act as controls. Cell salvage was permitted in both groups. Heterologous blood was transfused according to pre-determined triggers. Outcome measures were markers of the systemic inflammatory response in serum and urine observed at multiple time points, and clinical recovery. RESULTS: Median 890 (range 670-1620) ml of blood was removed at ANH in 16 patients. There were no differences in peri-operative changes in neutrophil count ( P = 0.13), serum C-reactive protein ( P = 0.38), interleukin-6 ( P = 0.50), total antioxidant capacity ( P = 0.73), urinary secretion of albumin ( P = 0.97) or retinol binding protein ( P = 0.41). There were no differences in the mortality and morbidity rates, systemic inflammatory response syndrome, ITU or hospital stay. CONCLUSIONS: ANH, when used in combination with cell salvage, made no impact on systemic inflammatory response and clinical outcome when compared to cell salvage alone after AAA repair. ANH cannot be recommended for routine use in patients undergoing abdominal aortic aneurysm surgery when cell salvage is available.

Management of Mason type-III radial head fractures with a titanium prosthesis, ligament repair, and early mobilization. Surgical technique.

BACKGROUND: Radial head fractures often occur in association with other elbow fractures and soft-tissue injuries. Radial head replacement is indicated for irreparable radial head fractures associated with elbow instability. The purpose of this study was to analyze the results after treatment of such injuries with a titanium radial head prosthesis, repair of torn collateral ligaments, and early mobilization of the elbow. MATERIALS: Sixteen patients with sixteen Mason type-III radial head fractures and collateral ligament injury were treated with use of a titanium radial head prosthesis over a five-year period at the Royal Adelaide Hospital and Modbury Public Hospital in South Australia. The surgery was performed acutely in ten patients and was delayed an average of thirty-seven days (range, fifteen to seventy-nine days) in six. All patients were followed clinically and radiographically for a mean of 2.8 years (range, 1.2 to 4.3 years). RESULTS: Eight patients had an excellent result; five, a good result; and three, a fair result, according to the Mayo Elbow Performance Score. The three fair results occurred in patients with delayed surgery. The mean flexion contracture was 15 degrees (range, 0 degrees to 42 degrees ), with an average loss of 10 degrees (range, 0 degrees to 25 degrees ) of full flexion compared with that of the contralateral elbow. Both pronation and supination decreased an average of 12 degrees (range, 0 degrees to 45 degrees ) compared with that of the contralateral forearm. CONCLUSIONS: The results of treatment of Mason type-III radial head fractures with a monoblock titanium radial head prosthesis and soft-tissue reconstruction are satisfactory. Early mobilization of the elbow is important for the restoration of elbow range of motion and function.

Drug resistance reversal--are we getting closer?

Clinical drug resistance is a major barrier to overcome before chemotherapy can become curative for most patients presenting with metastatic cancer. Rational attempts to tackle clinical drug resistance need to be based on an understanding of the mechanisms involved; these are likely to be complex and multifactorial, and may be due to inadequate drug exposure or alterations in the cancer cell itself. This article reviews a number of strategies used to tackle drug resistance, focussing on work in our institution related to the treatment of ovarian cancer and resistance to platinum and taxane-based chemotherapy. Further progress towards drug resistance reversal will require a three-pronged approach, namely: the development of novel cytotoxics which exploit selectively expressed targets; modulation of resistance to conventional agents and, most importantly, a serious attempt to understand resistance mechanisms in tumour samples taken both pre- and post-chemotherapy.

Haemodilutional effect of standard fluid management limits the effectiveness of acute normovolaemic haemodilution in AAA surgery--results of a pilot trial.

OBJECTIVE: To evaluate the impact of standard fluid management on the effectiveness of ANH as a blood conservation method in elective open AAA repair. DESIGN: Prospective randomised controlled study. METHODS: Thirty-four patients undergoing elective AAA repair were randomised to have ANH (16) or act as controls (18). Intra-operative cell salvage was permitted in both groups. Haemoglobin (Hb) concentrations were determined at variable intervals peri-operatively. Blood loss and the use of heterologous blood were recorded. RESULTS: The pre- and post-operative Hb concentrations, surgical blood loss and the use of cell salvage were similar in both groups. Hb concentration (median, range) decreased significantly from pre-operative to aortic clamping (with blood loss <100 ml) in ANH patients from 8.8 (7.5-10.2) to 5.7 (4.2-6.6)mmol/l following ANH but also in controls from 8.6 (7.5-9.7) to 7.0 (4.5-9.0)mmol/l due to fluid infusion (P<0.01 for every comparison). Bank blood requirements were similar: median 2 units in ANH and 2.5 units in control patients (P=0.68). CONCLUSIONS: Large volumes of fluids infused during AAA repair already conserve blood by the mechanism of hypervolaemic haemodilution. When cell salvage is used with standard fluid management during AAA repair, additional ANH is ineffective in saving blood.

Reoperation for neurological complications following carotid endarterectomy.

BACKGROUND: There remains a dilemma whether or not to re-explore the carotid artery when a neurological complication occurs after carotid endarterectomy. This study reviewed the indications for, findings and clinical outcomes following re-exploration. METHODS: Patients who experienced transient or permanent neurological events following carotid endarterectomy were identified from a prospectively compiled computerized database. Case notes were retrieved to determine time to onset of symptoms, use of carotid artery imaging and details about patients who had surgical re-exploration, and outcomes. RESULTS: Some 780 consecutive carotid endarterectomies were performed over 16 years, with an incidence of major stroke or death of 2.3 per cent (18 patients). Fifty-one patients experienced transient or permanent neurological events following surgery, 25 of whom underwent re-exploration. The findings included carotid thrombosis (ten patients), flap or other technical cause (three), haematoma (two) and no abnormality (ten). The neurological outcome after 30 days was similar, whether or not the carotid artery was re-explored. CONCLUSION: Carotid artery re-exploration was undertaken in approximately half of the patients who developed neurological complications following carotid endarterectomy. Although the cause was identified and a secondary procedure was undertaken in 14 of 25 patients, there was no improvement in clinical outcome at 30 days compared with that of patients managed non-operatively.

Risk factor documentation in elective and emergency vascular surgical admissions.

OBJECTIVES: this study investigates current practice of risk factor documentation in a vascular unit and compares variations in risk factor assessment between elective and emergency admissions. METHODS: one hundred and forty-four patients who underwent vascular surgical intervention for atherosclerotic disease during the year 2000 were retrospectively identified from computerised database. Case note review collated demographic details, data on risk factor assessment and the nature of surgery. Data were analysed using SPSS statistical software. RESULTS: the male to female ratio was 2.3:1 with a median (range) age of 73 (31-95) years. For 55 (38%) emergency admissions the following risk factors were not documented; ischaemic heart disease (8), diabetes mellitus (10), hypertension (10), smoking habit (13) and antiplatelet therapy (18). For 89 (62%) elective admissions the following risk factors were not documented; ischaemic heart disease (11), diabetes mellitus (9), hypertension (4), smoking habit (5) and antiplatelet therapy (19). Sixty-six (72.5%) routine admissions and 11 (20.8%) emergency admissions had estimations of serum cholesterol documented (chi(2) p < 0.001). There were no statistically significant differences in the documentation of other risk factors between the 2 groups. CONCLUSION: risk factors are not documented consistently for emergency vascular surgical admissions. Staff education should aim to improve risk factor assessment for elective and emergency admissions to reduce cardiovascular events and possibly improve surgical outcome in patients with atherosclerotic disease.

Pre-operative hand-held Doppler run-off score can be used to stratify risk prior to infra-inguinal bypass surgery.

OBJECTIVES: to investigate the relationship between calf vessel run-off assessed by hand-held Doppler, graft patency and patient survival following infra-inguinal graft surgery. DESIGN: prospective cohort study of 258 consecutive patients undergoing infra-inguinal bypass grafts in one centre between 1995-99. MATERIALS AND METHODS: ankle Doppler auditory waveform characteristics were documented for patients considered for infra-inguinal bypass grafting. Doppler signals from the anterior tibial, posterior tibial and dorsalis pedis arteries were scored triphasic/biphasic (2), monophasic (1) or absent (0). A total Doppler run off score (0-6) was calculated. Following surgery graft surveillance was undertaken using duplex ultrasound at 6, 12, 26 and 52 weeks. Graft and patient survival were analysed using Cox regression analysis. RESULTS: overall primary assisted graft patency at one year was 80%. With an increasing Doppler score from 0 to 6, primary assisted graft patency steadily rose from 50% to 100% (p = 0.0002), accompanied by a steady fall in patient mortality from 50% to 5% (p = 0.0003).

A randomised, double blind, placebo-controlled study to determine the efficacy of immune modulation therapy in the treatment of patients suffering from peripheral arterial occlusive disease with intermittent claudication.

OBJECTIVES: this study examined the effect of immune modulation therapy (IMT) on claudication distances. MATERIALS AND METHODS: a double-blind placebo controlled trial was performed on patients with disabling intermittent claudication with randomisation stratified for short and long distance IC. For IMT, following exposure to UV light, oxidisation and 42.5 degrees C, 10 ml of citrated autologous blood was administered by intra-muscular injection. One course consisted of 6 injections in 3-weeks followed by 3-weeks rest. Patients received 2, 3 or 4 courses depending on response. The primary end-point was the number of responders (>50% increase in initial claudication distance (ICD)) in each group. Secondary end-points included percentage changes in ICD and change in quality of life. RESULTS: at week 24, there were more responders in the IMT group (20/31, 65%) compared to placebo (16/39, 41%) (p=0.06). In the subgroup of short distance claudicants this difference reached significance (IMT 17/26, 65%) (Placebo 12/33, 36%) (p=0.04). The median increase in ICD was significantly greater in the IMT group (81%) compared to placebo (44%, p=0.04). These results were supported by quality of life measurements. CONCLUSIONS; IMT is a safe and apparently effective treatment for patients with short distance claudication.