Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report

BACKGROUND Pathological complete response(pCR) is rare in hormone receptor-positive(HR+)HER2-negative breast cancer(BC) treated with either endocrine therapy(ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures.The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced p CR after treatment with palbociclib.CASE SUMMARY We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a p CR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified asendocrine-sensitive, a condition associated with high sensitivity to palbociclib.CONCLUSION This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable.     

Donors with cardiac arrest: improved organ recovery but no preconditioning benefit in liver allografts

BACKGROUND: Historically, organ recovery rates in donors with cardiac arrest (CA) have been low, presumably from hemodynamic instability. We hypothesized that donor resuscitation has improved hemodynamic stability and organ recovery in CA donors, and that CA triggers ischemic preconditioning (IP) in liver grafts. METHODS: A total of 131 donor pairs with and without CA were matched in age, gender, and year of recovery. Hemodynamic stability was determined by vasopressor use. Abdominal and thoracic organs recovered and livers transplanted were compared between the groups. Liver graft function, injury, and IP benefit were examined by comparing liver chemistries after transplantation and postperfusion biopsies between recipients of grafts from both groups (n=40 each). RESULTS:Hemodynamic stability was similar in both groups, but recovery of thoracic organs was significantly lower in CA versus non-CA donors (35 vs. 53%, P<0.01). On the other hand, recovery rates of three or more abdominal organs from CA donors approached those of non-CA donors (77 vs. 87%, not significant). Although significantly fewer livers were transplanted from CA donors (69 vs. 85%, P<0.01), posttransplantation graft function and injury parameters were similar between the two groups, and CA did not appear to trigger IP. CONCLUSION: Compared with historical data, cardiovascular stability and abdominal organ recovery rates have improved considerably in CA donors. Liver grafts from CA donors function similarly to grafts from non-CA donors with no IP from CA. Our data support the increased use of livers and other organs from donors with CA.     

Effect of tegaserod on recto-sigmoid tonic and phasic activity in constipation-predominant irritable bowel syndrome

OBJECTIVES: In irritable bowel syndrome (IBS), the modulation of neural pathways may be altered and we have recently shown that postprandial recto-sigmoid tone modification is impaired. On pathophysiological grounds, we do not know whether this alteration may have a role in symptom onset and, in particular, whether an effective drug, such as tegaserod, can improve this response together with symptom severity. METHODS: Twenty-two female patients with constipation-predominant IBS (IBS-C), diagnosed according to Rome II criteria, were studied. All subjects underwent an evaluation of the presence and severity of IBS symptoms and the recto-sigmoid barostat test to measure fasting and postprandial recto-sigmoid tone and phasic contractility. They were then randomly assigned to receive either tegaserod 6 mg b.i.d (12 patients) or placebo tablets (10 patients) for 4 wk, according to a double-blind protocol. Symptom assessment and recto-sigmoid tone and contractility were re-evaluated at the end of the treatment. RESULTS: Both symptom severity and postprandial modification of recto-sigmoid tone improved only in the tegaserod group and a significant correlation was evident between the improvement of bloating and the improvement of postprandial recto-sigmoid tone modification. No effect of tegaserod on recto-sigmoid motility index or correlation between motility index and symptom improvement was evident. CONCLUSIONS: In IBS-C female patients, the administration of tegaserod improves symptom severity and is accompanied by an improvement of recto-sigmoid tone response to a meal.     

Endoscopic ultrasound-guided vascular interventions: An expanding paradigm

Endoscopic ultrasound(EUS) has expanded its arena from a mere diagnostic modality to an essential therapeutic tool in managing gastrointestinal(GI) diseases. The proximity of the GI tract to the vascular structures in the mediastinum and the abdomen has facilitated the growth of EUS in the field of vascular interventions. EUS provides important clinical and anatomical information related to the vessels’ size, appearance and location. Its excellent spatial resolution, use of colour doppler with o...     

ATG16L1 and NOD2 polymorphisms enhance phagocytosis in monocytes of Crohn’s disease patients

AIM:To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease(CD).METHODS:In this study,we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls.As both autophagy related like 1(ATG16L1)and immunityrelated guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleo-tide-binding ligomerization domain-containing protein2(NOD2)has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction.The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo?Escherichia coli Bioparticles Phagocytosis kit for flowcytometry.RESULTS:In this study,we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity(ratio of mean fluorescence intensity)between the patient groups and the healthy controls.CD patients show a significantly higher phagocytic capacity(ratio mean percentage of phagocytic cells)compared to healthy controls(51.91%±2.85%vs 37.67%±7.06%,P=0.05).The extend of disease was not of influence.However,variants of ATG16L1(WT:2.03±0.19 vs homozygoot variant:4.38±0.37,P<0.009)as well as NOD2(C-ins)(heterozygous variant:42.08±2.94 vs homozygous variant:75.58±4.34(P=0.05)are associated with the phagocytic activity in patients with CD.CONCLUSION:Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants.This could be part of the pathophysiological mechanism resulting in the disease.     

Effect of Propionic and Methylmalonic Acids on the in Vitro Phosphorylation of Intermediate Filaments from Cerebral Cortex of Rats During Development

In this study we investigated the in vivo and in vitro effects of methylmalonic (MMA) and propionic acids (PA), at concentrations usually found in methylmalonic acidemia and propionic acidemia respectively, on the phosphorylation of intermediate filament proteins in cerebral cortex of rats during development. Rats of 9, 12, and 17 days were acutely injected with the acids and sacrificed 90 min after injection. The cerebral cortex was dissected, and slices were incubated with ³²P-orthophosphate. The cytoskeletal fraction was extracted and the radioactivity incorporated into intermediate filament subunits was measured. In addition, cortical slices from nontreated rats of 9, 12, 15, 17, 21, and 60 days of life were incubated with the acids in the presence of ³²P-orthophosphate, the cytoskeletal fraction was extracted and the radioactivity was measured. Results demonstrated that MMA and PA significantly decreased the radioactivity incorporated into intermediate filament proteins at day 12, both in vivo and in tissue slices. In contrast, PA increased the in vitro phosphorylation of the cytoskeletal proteins in slices of 21-day-old animals. It acts through PP2A and PP2B in 12-day-old rats and through PKA and PKCaMII in 21-day-old animals. We propose that alteration of cytoskeletal protein phosphorylation caused by methylmalonic and propionic acids may be related to the neurological dysfunction characteristic of propionic and methylmalonic acidemia.