Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Local delivery of magnetic resonance (MR) contrast agent in kidney using thermosensitive liposomes and MR imaging-guided local hyperthermia: a feasibility study in vivo.

PURPOSE: To investigate the feasibility of local delivery of a magnetic resonance (MR) contrast agent in vivo using paramagnetic thermosensitive liposomes and infrared (IR) laser-induced local hyperthermia under real-time MR thermometry on rabbit kidney. MATERIALS AND METHODS: Respiratory gated, radio frequency (RF)-spoiled gradient-echo sequences were used for precise MR temperature mapping (SD = 1 degrees C). In vivo heating experiments confirmed local release of MR contrast agent from liposomes. RESULTS: T1 decreased from 800 msec to about 500 msec, as measured after tissue cooling, in those locations where the renal parenchyma was heated above the phase transition temperature of the liposome membrane. CONCLUSION: The release of MR contrast agent has been demonstrated in rabbit kidney in vivo. This may be used as a reporter for simultaneous release of therapeutic agents.

Balloon angioplasty of the femoro-popliteal segment: follow up results from southern India.

BACKGROUND: Disease of the femoral and popliteal arteries, though one of the commonest manifestations of atherosclerosis, is under-recognized because the morbidity it produces is less catastrophic than coronary or cerebrovascular arterial involvement. Percutaneous transluminal angioplasty is performed for femoro-popliteal lesions at different centres in India, but post-angioplasty follow up data are scarce. We present our results after femoro-popliteal balloon angioplasty in 140 lesions. METHODS: Between 1986 and 1993, 140 femoro-popliteal angioplasties were performed in 119 patients with symptomatic limb ischaemia. Seventy-one per cent of patients had claudication and the others also had tissue loss. Eighty-two per cent of the lesions were occlusions. The average length of the lesions was 10.7 cm. Conventional wire-balloon angioplasty was performed in 128 lesions; in 12 others, laser-assisted balloon angioplasty was performed using an Nd-YAG laser thermal probe. Patients were followed up at regular intervals for any recurrence of symptoms and for objective evidence of restenosis or re-occlusion. RESULTS: Despite a technical success in 83% of the lesions, cumulative primary patency calculated by the life-table method showed a slow decline which plateaued at 40% after 36 months. Long occlusions and multifocal stenoses showed shorter cumulative patency following angioplasty (27 months and 5.8 months respectively). Extensive luminal irregularity due to post-angioplasty intimal flaps was reduced by using warm contrast for balloon dilatation in 16 patients. In 14 patients who had repeat angioplasty for restenosis, the secondary patency showed a satisfactory figure of 84% at 60 months. CONCLUSION: Percutaneous transluminal angioplasty is a satisfactory alternative to surgery in femoro-popliteal stenotic or occlusive disease. Regular follow up of such patients is essential in the first three years because re-occlusion can occur. We found that patency remained fairly constant after 36 months. Repeated angioplasty can maintain patency in patients with restenosis.

Focal occlusive disease of the common femoral artery: a report of 20 cases.

Occlusive disease localized to the common femoral artery without contiguous involvement of the external iliac and superficial femoral arteries is distinctly uncommon in vascular surgical practice. Twenty patients with focal occlusive disease in 21 common femoral arteries are featured in this report. All except one had severe disabling symptoms: Fontaine classification was stage I in one patient, stage IIb in 13, and stage III in six patients. The probable aetiology, based on clinical features and angiographic observations, was identified as atherosclerosis (nine cases), thromboangiitis obliterans (three) and Takayasu's arteritis (two). Histological features of mucoid vasculopathy, a novel disorder, was seen in one patient while no specific aetiology was evident in five patients. Associated lesions were seen in fourteen patients: aortoiliac in one, femoropopliteal in seven (without any continuity to the common femoral lesion), internal iliac in three and tibial in three. Balloon angioplasty of the common femoral artery lesions was attempted in 14 patients with successful outcome in nine. Three patients (including two with failed balloon angioplasty), underwent thromboendarterectomy and two bypass procedures (iliofemoral, one; femoropopliteal, one). Late reocclusion occurred in one patient each in the angioplasty and surgical groups. There were no procedure-related complications in either group.

Percutaneous transluminal angioplasty of the subclavian artery in nonspecific aortoarteritis: results of long-term follow-up.

PURPOSE: The results of percutaneous transluminal angioplasty (PTA) of the subclavian artery in nonspecific aortoarteritis (Takayasu disease) are analyzed. PATIENTS AND METHODS: Twenty-four patients (15 men, nine women; age range, 18-47 years; mean, 37.1 years) with occlusive disease in 26 subclavian arteries, had symptoms due to vertebrobasilar insufficiency, upper limb claudication, or both. Aortography revealed stenosis in 19 arteries and occlusion in seven. The lesions were focal in 14 arteries (< 3 cm) and extensive in 12. Associated lesions involved the brachiocephalic artery in three patients, carotid arteries in five patients, and renal arteries in five patients. RESULTS: Initial technical and clinical success was achieved in 21 of 26 arteries (81%, 17 of 19 stenoses and four of seven occlusions). The maximum follow-up was 82 months (mean, 26 months), during which time restenosis occurred in six arteries, all of which had extensive lesions. The cumulative primary, secondary, and overall patencies were 64%, 82%, and 65%, respectively, as analyzed by means of the life-table method. The cumulative patencies for short- and long-segment lesions were 100% and 50%, respectively (P = .0113). Minor complications were observed in four of 26 procedures (15%) and included vasospasm (three patients) and transient loss of consciousness (one patient). There were no major complications. CONCLUSIONS: PTA is useful for treatment of occlusive disease of the subclavian artery in nonspecific aortoarteritis. The procedure is simple and associated with minimal morbidity. Long-term results are excellent in focal lesions but are less durable in the presence of more extensive disease.

Natural history of aortoarteritis: an angiographic study in 26 survivors.

The natural history of aortoarteritis was angiographically studied in 26 surviving patients (19 female; 7 male). The interval between the initial and current angiographic study was 38-228 months (mean -84.46 months). All patients underwent panaortography during both studies and one patient also underwent pulmonary angiography. The lesions were extensive involving the ascending, arch and the descending thoracic and/or the abdominal aorta (Type III) in 15 patients; localized to the arch alone (Type I) in five patients and to the descending thoracic and/or abdominal aorta in five patients (Type II). Pulmonary angiography in the solitary patient with clinical features of pulmonary hypertension showed occlusion of the lower lobe branch of the right pulmonary artery. The lesions were occlusive in 19 patients, aneurysmal in one patient and mixed in six patients. While four patients developed fresh lesions in the follow-up period, two showed progression of existing lesions and one revealed partial thrombosis of an aneurysm. Persistently elevated erythrocytic sedimentation rate (> 40 mm) was identified as a reliable indicator for activity of inflammatory process and disease progression. The stable nature of the lesions in 20 out of 26 patients in this study indicates a non-progressive course in the healed stage of aortoarteritis and suggests a conservative approach to the management of this disease in all patients except those with severe, life-threatening manifestations.

Role of angiographic catheters in surgery of popliteal arteriovenous fistulas.

A 50-year-old woman with a chronic, traumatic popliteal arteriovenous fistula was treated surgically by closure of the fistula. Placement of an angiographic catheter across the fistula into the venous sac immediately before surgery helped to locate the fistula accurately and quickly at operation. This simple manoeuvre will facilitate surgical treatment, particularly in cases of long-standing, chronic arteriovenous fistulas.

Endovascular management of carotid cavernous fistulae: observation on angiographic and clinical results.

Twenty-five patients with carotid cavernous fistulae (CCFs) were managed at our institute during a five-year period. Transarterial and transvenous treatment of traumatic carotid cavernous fistulae using the detachable balloon technique was performed in 21 patients resulting in angiographic and clinical cure in 20 patients and fatal outcome in one patient following venous rerouting. Surgical ligation of the infraclinoid internal carotid artery was needed in one patient. Preservation of the carotid artery was possible in 16 patients. Four patients with spontaneous CCFs were advised digital compression of carotid arteries resulting in complete closure of the fistula in one and considerable clinical improvement in two patients. One patient required transarterial obliteration of the fistula via the middle meningeal artery by means of a platinum coil and normal butyl cyanoacrylate (NBCA) resulting in total radio anatomical cure.

Aortoarteritis of abdominal aorta: an angiographic profile in 110 patients.

The angiographic appearances in 110 patients (49 males, 61 females, age range 11-46 years, mean 27.8 years) with aortoarteritis involving the abdominal aorta and/or its branches were analysed. There were 41 aneurysms of the abdominal aorta in 37 patients and eight aneurysms of its branches in as many patients. In 50 patients, 53 obstructive lesions involved the abdominal aorta and were classified as stenoses of focal, segmental and diffuse types and total occlusions. Branch obstructions (182 lesions in 85 patients) affected in order of frequency, the renal, superior mesenteric, coeliac, iliac and the inferior mesenteric arteries. Mesenteric arterial lesions were significantly more common in males (P = 0.01). Collateral circulation through a prominent mesenteric arcade was a distinctive angiographic feature in 28 patients. Computed tomography done in four patients showed peri-adventitial thickening and layered thrombus within aneurysms in three patients, and luminal occlusion of the upper abdominal aorta in one patient. Angiographic appearances in aortoarteritis of the abdominal aorta are characteristic and sufficiently distinctive for definitive diagnosis and appropriate management.

Syringohydromyelia: radiological evaluation of 82 patients in a developing country.

A series of 82 patients presenting with syringohydromyelia and confirmed at operation were studied by conventional radiological techniques and computed tomography (CT). Cord collapse was demonstrated in 71% of the patients with wide bony canals and only 11% of patients with normal bony canals. It was most reliably shown with high resolution CT. Intrathecal CT metrizamide myelography (CTMM) failed to demonstrate contrast percolation into many cavities shown in the plain scans. Obliteration of the subarachnoid space at C1-2 levels appreciated in the plain scans strongly indicated coexisting tonsillar herniation, making CTMM unnecessary. In almost all patients, CTMM was found to be non-contributory if the high resolution plain CT scan failed to reveal cord cavitation.

Aneurysmal form of aortoarteritis (Takayasu's disease): analysis of thirty cases.

The clinical and radiological features, and outcome of 30 patients including 22 females, with the aneurysmal form of aortoarteritis were analysed. The average age at diagnosis was 27.4 +/- 7.2 years. Features which indicated the diagnosis of aneurysmal aortoarteritis included young age, female sex, characteristic location, associated stenotic lesions and the presence of multiple aneurysms. There were 41 fusiform and 18 saccular aneurysms, mostly located in the descending aorta. Diffuse dilatation (n = 24) was seen mainly in the ascending aorta. Two patients had dissecting aneurysms, while one patient had an aneurysm of the left main coronary artery. Both these lesions are rare in aortoarteritis. The aneurysmal form was associated with a higher incidence of aortic incompetence (P less than 0.01) and elevated ESR (P less than 0.001) as compared to the more common non-aneurysmal form. The average follow-up period was 59.7 (+/- 48.1) months. The event-free survival rate was 82.9% at 5 years, similar to that seen in the non-aneurysmal form. These data should be useful to the clinician in the diagnosis and management of the aneurysmal form of aortoarteritis.