Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines. The interaction was characterized by combination index analysis, platinum accumulation and DNA platination were determined using flameless atomic absorption spectrometry, and protein expression was assessed with Western blot. In the sensitive A2780 ovarian carcinoma and H520 squamous cell lung carcinoma cell lines, sorafenib induced downregulation of Na⁺,K⁺-ATPase. In A2780 cells, the kinase inhibitor also decreased the expression of copper transporter 1 (CTR1). As a result, sorafenib treatment led to a diminished cellular accumulation of cisplatin and carboplatin and to a decrease in DNA platination in these cell lines. This was not the case in the cisplatin-resistant A2780cis ovarian carcinoma and H522 lung adenocarcinoma cell lines featuring lower basal expression of the above-mentioned transporters. In all cell lines studied, an antagonistic interaction between platinum drugs and sorafenib was found. Our results suggest that sorafenib impairs cisplatin and carboplatin uptake through downregulation of CTR1 and/or Na⁺,K⁺-ATPase resulting in reduction of DNA platination. This effect is not observed in cancer cells with defects in platinum accumulation.     

Pathological fracture in paediatric bone tumours and tumour-like lesions: A predictor of benign lesions?

Objective:To determine the incidence and causes of pathological fractures in paediatric bone tumours and tumour-like lesions, and to determine if they are predictive of benign lesions.Methods and materials:Retrospective review of children with suspected bone tumours referred to a specialist musculoskeletal oncology service between September 2019 and August 2020. Data recorded included patient age and gender, lesion location, the presence of a pathological fracture on the initial plain radiograph, and the final diagnosis made either by image-guided biopsy/curettage or based on typical imaging features.Results:231 patients were included with 233 lesions (138 males and 93 females with mean age 10.5 years, range 3 months–18 years). Final diagnosis was based on histology in 85 (36.5%) cases and imaging in 148 (63.5%) cases, 52 (22.3%) lesions classed as non-neoplastic, 139 (59.7%) as benign and 42 (18%) as malignant. Pathological fractures were seen in 41 cases (17.6%) at presentation, involving the humerus in 19 (46.3%), the femur in 14 (34.1%), the tibia in 3 (7.3%), the fibula and radius in two each (4.9%) and the second toe proximal phalanx in 1 (2.4%) (p < 0.001). The commonest underlying lesions included simple bone cyst (n = 17; 41.5%) and non-ossifying fibroma (n = 10; 24.4%). Only 4 cases (9.75%) were malignant, one case each of osteosarcoma, Ewing sarcoma, leukaemia and BCOR undifferentiated round cell sarcoma. Pathological fracture occurred in 27.7% of non-malignant lesions and 9.5% of malignant lesions, this difference being statistically significant (p < 0.001).Conclusion:Pathological fractures were seen in 17.6% of paediatric bone tumours, tumour-like lesions, being significantly associated with humeral location and non-malignant diagnosis.Advances in knowledge:Demonstrates the frequency, location and underlying diagnosis of pathological fractures in paediatric bone tumour and tumour-like lesions.     

An unusual approach to the spontaneous rupture of hepatocellular carcinoma

Our aim is to describe an unusual approach to the spontaneous rupture of a large hepatocellular carcinoma (HCC). A 45-year-old man, Hepatitis C virus (+) (HCV+), complaining of abdominal pain. During the investigation, a tumor affecting liver segments V, VI, VII and VIII, with the presence of fluid within the peritoneal cavity, suggesting hemoperitoneum, was found. The patient was submitted to an exploratory laparotomy, revealing a large hepatic tumor mass with capsule rupture in segment V, biopsy verified the diagnosis of HCC. After one week, a superselective chemoembolization of the nutrient artery of the tumor was performed; one month later, the patient was submitted to an embolization of the right portal branch, aimed at causing hypertrophy of the left lateral portion of the liver. A right hepatectomy was performed, as well as a nodulectomy in segment II, without complications along the 40 days subsequent to the portal embolization. The patient is currently on his 53rd postoperative month and evidences no tumor recurrence to the moment. Although the spontaneous rupture of HCC is uncommon, it can be today treated by combining interventionist radiology procedures and conventional liver resections, offering the patient a better chance of survival.     

A Corynebacterium striatum endocarditis on a carrier of pacemaker

We report a new case of a Corynebacterium striatum endocarditis on a carrier of a pacemaker. Corynebacterium striatum was isolated from blood culture, the pulse generator and the pacing lead. A literature review of Corynebacterium striatum endocarditis on a carrier of pacemaker was conducted.     

A mathematical model for shortening waiting time in pancreas-kidney transplantation

AIM: To simulate a hypothetical increase of 50% in the number of pancreas-kidney (PK) transplantations using less-than-ideal donors by a mathematical model. METHODS: We projected the size of the waiting list by taking into account the incidence of new patients per year, the number of PK transplantations carried out in the year and the number of patients who died on the waiting list or were removed from the list for other reasons. These variables were treated using a model developed elsewhere. RESULTS: We found that the waiting list demand will meet the number of PK transplantation by the year 2022. CONCLUSION: In future years, it is perfectly possible to minimize the waiting list time for pancreas transplantation through expansion of the donor pool using less-than-ideal donors.     

Avulsion traumatique du triceps brachial chez un bodybuilder

Ruptures of the elbow triceps are rare lesions that occur during the practice of sport. They usually occur as an indirect protection mechanism after a severe fall on the hand, since the elbow is being in extension or in a slight flexion. The authors report the case of a bodybuilder, victim of a trauma during the practice of the sport bench, causing an avulsion of the elbow triceps. An urgent surgery provided good results.     

Does intrathymic injection of alloantigen-presenting cells before islet allo-transplantation prolong graft survival?

Abstract Current immunosuppressive agents have potentially dangerous side-effects, are nonspecific and most are also diabetogenic. We investigated tolerance induction with intrathymic injection of purified antigen-presenting cells (APC) plus a single dose of anti-lymphocyte serum (ALS) intraperitoneally before allogeneic islet transplantation in the rat model WAG to Lewis (RT1^u to RT1¹. Purified donor APC [non-parenchymal cells (NPC) or dendritic cells (DC)] were prepared from liver and spleen, respectively. Isograft function for more than 120 days proved that islet isolation, purification and transplantation procedures were adequate. A total of WAG DC (4 times 10⁵) or NPC (2 times 10⁶) in 20 μl were injected into both lobes of the thymus of 140–210 g Lewis recipients followed by a single injection of ALS. Three days later, diabetes was induced with streptozotocin (60 mg/kg). Four days later allogeneic islets were grafted into the liver by intraportal injection of 3000 WAG islets. Control animals ( n = 8) received 20 μ saline intrathymically instead of APC. Graft function was assessed by blood glucose measurements with glucose levels above 15 mmol/l on 3 consecutive days defined as graft rejection. Animals given DC ( n = 9) or NPC ( n = 8) intrathymically plus 1 ml of ALS, rejected their grafts in an accelerated fashion with a median survival time (MST) of 3 days. However, control animals rejected their grafts with a MST of 7 days, but with two animals surviving for more than 2 months. In conclusion, intrathymic inoculation with purified APC plus a single dose of ALS did not prolong allogeneic islet graft function but induce? accelerated rejection of the islet allografts.