Expression and Functional Contribution of Different Organic Cation Transporters to the Cellular Uptake of Doxorubicin into Human Breast Cancer and Cardiac Tissue

Doxorubicin is a frequently used anticancer drug to treat many types of tumors, such as breast cancer or bronchial carcinoma. The clinical use of doxorubicin is limited by its poorly predictable cardiotoxicity, the reasons of which are so far not fully understood. The drug is a substrate of several efflux transporters such as P-gp or BCRP and was recently reported to be a substrate of cation uptake transporters. To evaluate the potential role of transporter proteins in the accumulation of doxorubicin at its site of action (e.g., mammary carcinoma cells) or adverse effects (e.g., heart muscle cells), we studied the expression of important uptake and efflux transporters in human breast cancer and cardiac tissue, and investigated the affinity of doxorubicin to the identified transporters. The cellular uptake studies on doxorubicin were performed with OATP1A2*1, OATP1A2*2, and OATP1A2*3-overexpressing HEK293 cells, as well as OCT1-, OCT2-, and OCT3- overexpressing MDCKII cells. To assess the contribution of transporters to the cytotoxic effect of doxorubicin, we determined the cell viability in the presence and absence of transporter inhibitors in different cell lines. Several transporters, including P-gp, BCRP, OCT1, OCT3, and OATP1A2 were expressed in human heart and/or breast cancer tissue. Doxorubicin could be identified as a substrate of OCT1, OCT2, OCT3, and OATP1A2. The cellular uptake into cells expressing genetic OATP1A2 variants was markedly reduced and correlated well with the increased cellular viability. Inhibition of OATP1A2 (naringin) and OCT transporters (1-methyl-4-phenylpyridinium) resulted in a significant decrease of doxorubicin-mediated cytotoxicity in cell lines expressing the respective transporters. Similarly, the excipient Cremophor EL significantly inhibited the OCT1-3- and OATP1A2-mediated cellular uptake and attenuated the cytotoxicity of doxorubicin. In conclusion, genetic and environmental-related variability in the expression and function of these transporters may contribute to the substantial variability seen in terms of doxorubicin efficacy and toxicity.

Pulmonary aspergillosis: reports of two cases from a primary care center of Bangladesh

Pulmonary aspergillosis is an uncommon condition and at the same time very much challenging to diagnose and difficult to treat. Here, we present two cases of chronic pulmonary aspergillosis, who presented with with chronic low-grade fever, refractory and distressing cough and haemoptysis. The first patient was diagnosed as having aspergilloma in a pre-existing healed tubercular cavity and the second one with subacute necrotizing pulmonary aspergillosis, which simulated as bronchial carcinoma. BIRDEM Med J 2021; 11(3): 227-230

THE BANALITY OF IMMUNITY, DEATH AND DISTRESS OF TOBACCO SMOKING --("STRIKE THE RIGHT”)

WHO stated that Tobacco Control is "To protect present and future generations from the devastating health, social, environmental and out-turn of exposure to tobacco smoke”. Tobacco plants are indigenous to American abstinent and they knew of its cultivation thousands of years ago. Christopher Columbus brought this plant to European countries. Portuguese traders brought tobacco plants to India Tobacco put to use in the forms of smoking, chewing, or snorting. Bronchial accounts for more than 50% of all male deaths from malignant disease. It is four times more common in men than in women. Cigarette smoking for most cases of bronchial carcinoma, and the increased risk is directly proportional to the amount smoked and to the tar content of the cigarettes. Smoking puffs of any kind, disclosed to nicotine, have pernicious consequences on immune system. Nicotine escalates cortisol concentration, while curtail B cell antibody development and T cells' response to antigens. Smoking bumps one and the other innate and adaptive immunity and operates challenge roles in synchronize immunity

12 × 6 Gy stereotactic radiotherapy for lung tumors. Is there a difference in response between lung metastases and primary bronchial carcinoma?

Purpose The aim of this study was to evaluate the safety and long-term tumor control after stereotactic radiotherapy (SRT) with 12 × 6 Gy of patients with primary bronchial carcinoma (BC) or with pulmonary metastases (MET) of various solid tumors. Local progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS), and prognostic factors were compared. Methods Between May 2012 and January 2020, 168 patients with 206 pulmonary lesions (170 MET and 36 primary BC) were treated with 12 × 6 Gy (BED10 116 Gy). The irradiated pulmonary MET were from the following cancers: 47 (27.6%) head and neck, 37 (21.8%) rectum or colon, 30 (17.6%) bronchial, 13 (7.6%) malignant melanoma, 9 (5.3%) esophageal, 9 (5.3%) sarcoma, and 25 (14.8%) other. Results The median follow-up was 16.26 months (range: 0.46–89.34) for BC and 19.18 months (0.89–91.11) for MET. Survival rates at 3 years were: OS 43% for BC and 35% for MET; LPFS BC 96% and MET 85%; PFS BC 35% and MET 29%. The most frequently observed grade 3 adverse events (AEs) were pneumonitis (5.9% BC, 4.8% MET), pulmonary fibrosis (2.9% BC, 4% MET), and pulmonary embolism (2.9% BC, 0.8% MET). The favorable prognostic effects on overall survival of patients with MET were female gender (log-rank: p < 0.001), no systemic progression (log-rank; p = 0.048, multivariate COX regression p = 0.039), and malignant melanoma histology (log-rank; p = 0.015, multivariate COX regression p = 0.020). For patients with BC, it was tumor location within the lower lobe (vs. upper lobe, log-rank p = 0.027). LPFS of patients with metastatic disease was beneficially influenced by female gender (log-rank: p = 0.049). Conclusion The treatment concept of 12 × 6 Gy is associated with 96% local progression-free survival for BC and 85% for pulmonary metastases after 3 years. There was no difference in response after SRT of primary lung carcinoma or pulmonary metastases.

Synchronous Association of Squamous Cell Carcinoma of the Larynx and Clear Cell Renal Cell Carcinoma: A Case Report

Laryngeal squamous cell carcinomas represent the most frequent form (over 90%) of laryngeal cancer, but their association with renal tumors is rare; the literature most often reports the synchronous association of carcinoma of the larynx with carcinoma of the upper aerodigestive tract or with bronchial carcinoma. We report the case of a 60-year-old patient, who is followed for a clear cell carcinoma of the kidney, and in whom we made the diagnosis of a squamous cell carcinoma of the larynx. We illustrate through this observation the rarity and the epidemiological profile of this presentation with a broad review of the literature.

An unexpected intracerebral lesion – case report of a superinfected aspergillosis mimicking a brain metastasis

Background Invasive aspergillosis of the central nervous system is a rare but increasingly prevalent disease. We present the unusual case of an immunosuppressed patient suffering from unexpected superinfected invasive aspergillosis with cerebral, pulmonal, and adrenal manifestations, mimicking a metastasized bronchial carcinoma. This report reveals the importance of including aspergillosis in the differential diagnosis of a cerebral mass lesion in the light of unspecific clinical findings. Case presentation A 58-year-old immunocompromised female presented to our emergency department with a single tonic-clonic seizure. Imaging showed a ring enhancing cerebral mass with perifocal edema and evidence of two smaller additional hemorrhagic cerebral lesions. In the setting of a mass lesion in the lung, and additional nodular lesions in the left adrenal gland the diagnosis of a metastasized bronchus carcinoma was suspected and the cerebral mass resected. However, histology did not reveal any evidence for a neoplastic lesion but septate hyphae consistent with aspergillus instead and microbiological cultures confirmed concomitant staphylococcal infection. Conclusions A high index of suspicion for aspergillus infection should be maintained in the setting of immunosuppression. Clinical and radiological findings are often unspecific and even misleading. Definite confirmation usually relies on tissue diagnosis with histochemical stains. Surgical resection is crucial for establishing the diagnosis and guiding therapy with targeted antifungal medications.

Ectopic Cushing’s From Metastatic Prostate Cancer

Objective: Ectopic ACTH production from malignancy is a rare etiology of Cushing’s syndrome. The most common tumors associated with this syndrome include small cell lung cancer, pancreatic neuroendocrine tumors, pheochromoctoma, thymic carcinoma, and bronchial carcinoma. Metastatic prostate cancer does not commonly produce ACTH. Here, we present a rare case of Cushing’s syndrome due to metastatic prostate cancer. Case Report: Patient is a 64 year old man with a 2 year history of castrate-resistant prostate cancer who was admitted for the 2nd time in 1 month for profound weakness and new onset hypokalemia. Initial analysis revealed hypertension with systolic blood pressure in the 150s, potassium in the mid 2s, an ACTH level of &gt;1000pg/mL, and a 24-hr urine cortisol of almost 10,000mcg/24hrs. This was confirmed on repeat analysis. Metyrapone was initiated for treatment of hypercortisolemia and systemic chemotherapy with Cisplatin/Irinotecan was started to treat metastatic prostate cancer. ACTH and 24-hr urine cortisol levels returned to normal within a few weeks of therapy. The patient was able to discontinue Metyrapone following systemic chemotherapy treatment. Subsequent labs following discontinuation of metyrapone confirmed ongoing resolution of hypercortisolemia. Conclusion: This case represents an extremely rare cause of Cushing’s syndrome. Metastatic prostate cancer can rarely produce ACTH and cause clinical Cushing’s syndrome. Ectopic Cushing’s syndrome is often due to very aggressive tumors and is associated with a poor prognosis. Rapid recognition and treatment of this condition can be lifesaving.

Automated detection and segmentation of thoracic lymph nodes from CT using 3D foveal fully convolutional neural networks

Background In oncology, the correct determination of nodal metastatic disease is essential for patient management, as patient treatment and prognosis are closely linked to the stage of the disease. The aim of the study was to develop a tool for automatic 3D detection and segmentation of lymph nodes (LNs) in computed tomography (CT) scans of the thorax using a fully convolutional neural network based on 3D foveal patches. Methods The training dataset was collected from the Computed Tomography Lymph Nodes Collection of the Cancer Imaging Archive, containing 89 contrast-enhanced CT scans of the thorax. A total number of 4275 LNs was segmented semi-automatically by a radiologist, assessing the entire 3D volume of the LNs. Using this data, a fully convolutional neuronal network based on 3D foveal patches was trained with fourfold cross-validation. Testing was performed on an unseen dataset containing 15 contrast-enhanced CT scans of patients who were referred upon suspicion or for staging of bronchial carcinoma. Results The algorithm achieved a good overall performance with a total detection rate of 76.9% for enlarged LNs during fourfold cross-validation in the training dataset with 10.3 false-positives per volume and of 69.9% in the unseen testing dataset. In the training dataset a better detection rate was observed for enlarged LNs compared to smaller LNs, the detection rate for LNs with a short-axis diameter (SAD) ≥ 20 mm and SAD 5–10 mm being 91.6% and 62.2% (p < 0.001), respectively. Best detection rates were obtained for LNs located in Level 4R (83.6%) and Level 7 (80.4%). Conclusions The proposed 3D deep learning approach achieves an overall good performance in the automatic detection and segmentation of thoracic LNs and shows reasonable generalizability, yielding the potential to facilitate detection during routine clinical work and to enable radiomics research without observer-bias.

A Non-Traumatic Avulsion Fracture of the Lesser Trochanter: Other Diagnosis Not to Be Missed

In adults, an isolated non-traumatic fracture of the lesser trochanter should arouse strong suspicion of an underlying malignant pathology. In this article, we present the case of a 55-year-old male patient who presented with a non-traumatic isolated fracture of the lesser trochanter secondary to a delayed diagnosis of metastases of bronchial carcinoma.

HSV-pneumonitis in a patient with lung cancer receiving check point inhibitors – a case report

Background Herpes simplex virus (HSV) is commonly associated with oro-facial and genital manifestations. It rarely causes encephalitis and even less commonly, in heavily immunosuppressed patients, visceral disease or bronchopneumonitis. We present a case of cytologically-proven, PCR-positive HSV-1 tracheobronchitis and pneumonitis in a patient with less severe immunocompromise. Case presentation A 64 year old white man with steroid-induced diabetes mellitus and progressive small-cell bronchial carcinoma despite chemo- and immunotherapy with two checkpoint inhibitors presented with symptoms of lower respiratory tract infection. Community-acquired pneumonia was suspected and empirical broad-spectrum antibacterial treatment was initiated. Chest CT-scan revealed ground-glass opacities and tree-in bud lesions. Cytology of BAL showed extensive cytopathic effects typically caused by infection with herpes virus and PCR confirmation of HSV-1. Acute phase HSV serology was positive for IgG and borderline for IgM. The patient deteriorated clinically due to tumor progress and infection despite high-dose acyclovir therapy and died 2 weeks after admission. Conclusions We report an unusual case of fatal HSV-1 pneumonitis due to reactivation in a patient with lung cancer, steroid-induced diabetes and treatment with two checkpoint inhibitors. In immunosuppressed patients with non-improving pneumonia invasive diagnostic procedures are warranted including cytology and molecular diagnostics.