Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Use of bevacizumab in a patient with Whipple's disease: managing diagnostic uncertainty.

A man in his 30s with intellectual disability presented with 1 month of diarrhoea, weight loss and dyspnoea. Investigations were hampered due to significant anxiety. Laboratory tests detected microcytic anaemia and hypoalbuminaemia. CT demonstrated a fat-containing infiltrate in the mediastinum, mesentery and axillae, and pulmonary ground-glass infiltrates. Biopsy of the axilla showed cystic lymphatic malformations involving adipose tissue and lymph nodes, leading to a provisional diagnosis of generalised lymphatic anomaly. Over the subsequent 4 months, the patient's respiratory status deteriorated, leading to type 1 respiratory failure necessitating intubation. After multidisciplinary discussion, a decision was made to trial bevacizumab, an anti-VEGF agent, with subsequent improvement in respiratory status. While intubated, gastroscopy was performed; duodenal biopsies revealed pathognomonic changes of Whipple's disease, confirmed on PCR of duodenal and axillae biopsies. This was deemed the most likely unifying diagnosis; antibiotic treatment was commenced, bevacizumab was ceased, and the patient has remained well after 18 months.

Amyloid-ß (Aß)-Related Cerebral Amyloid Angiopathy Causing Lobar Hemorrhage Decades After Childhood Neurosurgery.

BACKGROUND: Recent reports raise the possibility of cerebral amyloid angiopathy (CAA) leading to intracerebral hemorrhage in young adults following childhood neurosurgery, suggesting transmission of amyloid-ß (Aß) through neurosurgical procedures including dura mater grafting. Parenchymal Aß deposition, and to a lesser extent tau aggregation, similar to that seen in Alzheimer disease, have also been described. METHODS: We conducted a database review of 634 consecutive intracerebral hemorrhage patients aged <65 years at a tertiary stroke center over 20 years to identify such patients. RESULTS: We identified 3 patients aged in their thirties who presented with spontaneous lobar intracerebral hemorrhage, with imaging or neuropathology consistent with CAA, and a history of childhood neurosurgery. Two of these patients had undergone a dural repair using cadaveric dura mater (Lyodura). In addition to CAA, both patients had neuropathologically confirmed parenchymal Aß and tau deposits, characteristic of Alzheimer disease. CONCLUSIONS: Our findings support the concept of neurosurgical Aß transmission but suggest that such cases are rare in standard clinical practice.

Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma.

The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2-Positive Metastatic Breast Cancer.

Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated "on-target" lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. SIGNIFICANCE: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors.See related commentary by Drago et al., p. 323.This article is highlighted in the In This Issue feature, p. 305.

Histological and Extended Clinical Outcomes After ABO-Incompatible Renal Transplantation Without Splenectomy or Rituximab.

BACKGROUND: Excellent short-term results have been reported in ABO-incompatible (ABOi) renal transplant recipients managed solely with antibody removal and conventional immunosuppression. However, long-term clinical outcomes with this regimen and predictive information from protocol biopsies are lacking. METHODS: We compared outcome data in ABOi and ABO-compatible (ABOc) recipients receiving this regimen approximately 4 years posttransplant, and histology from biopsies approximately 12 months posttransplant. RESULTS: Patient and graft survivals among 54 ABOi recipients were 98.1% and 90.7%, respectively, at 4 years. Graft function was similar between ABOi (creatinine, 140.3 µmol/L) and ABOc recipients (creatinine, 140.2 µmol/L) (P = 0.99), with no significant change over the study period in either group (Δcreatinine, -0.83 vs 6.6 µmol/L) (P = 0.59). There was no transplant glomerulopathy in biopsies from either group. Interstitial fibrosis (IF) and tubular atrophy (TA) was present in 7 (28%) of 25 ABOi compared with 7 (20.6%) of 34 ABOc (P = 0.52). Progression of IF/TA from implantation was noted in 6 (24%) of 25 ABOi and 6 (17.6%) of 34 ABOc, respectively. C4d staining without antibody-mediated rejection was present in 13 (52%) 25 early posttransplant biopsies from ABOi recipients by immunohistochemistry, but in only 4 (16%) of 25 at 12 months. CONCLUSIONS: ABO-incompatible renal transplant performed with antibody removal and conventional immunosuppression continues to provide excellent patient and graft survival, and stable renal function over 4 years. Coupled with absent transplant glomerulopathy and low rates of progressive IF/TA on earlier biopsies, this suggests that ABOi with conventional immunosuppression and antibody removal, without rituximab or splenectomy, can achieve long-term outcomes comparable to ABO-compatible transplantation.

Carpal tunnel syndrome in fabry disease.

Carpal tunnel syndrome (CTS) is a common peripheral mononeuropathy affecting up to 4% of the general population, typically women in late middle age. The incidence in patients with Fabry disease (FD) is unclear, but may affect 25% of patients with this X-linked lysosomal storage disease. We report three cases of CTS in young Caucasian male patients with classical FD, who developed CTS symptoms with supportive nerve conduction study (NCS) findings. Two patients had bilateral CTS and two had evidence of concurrent ulnar nerve neuropathy on NCS, suggesting a systemic process contributed to nerve compression. All were receiving enzyme replacement therapy (ERT) and had a moderate burden of FD complications. It is possible that an increase in connective tissue in the intracarpal canal in FD patients may be incited by injury to fibroblasts, via either accumulation of globotriaosylceramide (GL3) or local ischaemia through endothelial injury. The former hypothesis may be a more plausible explanation for the development of CTS, as histology of the flexor retinaculae from our patients has demonstrated fibroblasts with characteristic vacuolation and excessive myxomatous stroma, despite endothelial clearance of GL3 in these patients receiving ERT. CTS should not be overlooked in FD patients and young patients presenting with CTS should be evaluated for an underlying systemic or genetic disorder. Surgical carpal tunnel decompression was effective in our patients, already troubled by long-standing acroparesthesia, in providing sustained relief of symptoms.

Sweet's syndrome associated with cellulitis.

A 38-year-old woman developed an acute, painful cutaneous eruption on her lower legs, neck, chest and fingers while receiving a number of oral and intravenous antibiotics for left leg cellulitis caused by trauma. Clinically and histopathologically, she was diagnosed with Sweet's syndrome with typical pseudovesicular skin changes in conjunction with erythema nodosum-like lesions on her lower legs. She responded quickly to oral prednisolone. We propose Staphylococcal cellulitis as a cause of Sweet's syndrome.

Multiple periungual pyogenic granulomas following systemic 5-fluorouracil.

A 65-year-old man presented with a 7-month history of eight bleeding periungual lesions on both feet. The clinical diagnosis of multiple pyogenic granulomas was confirmed by histological examination. Historically, the pyogenic granulomas appeared 3 months after commencing 5-fluorouracil chemotherapy for rectal carcinoma, suggesting a possible causative relationship. Chemotherapy was ceased by the supervising oncologist. Resolution occurred after two lesions had been treated with curettage and diathermy, and the remaining lesions with occlusive dressings over Kenacomb ointment (triamcinolone acetonide 0.1%, neomycin sulphate 0.25%, gramicidin 0.025%, nystatin 100,000 U/g) topically twice daily for a period of 3 months.