Splenic metastases in a large unselected autopsy series

We analyzed the files of all autopsies performed at the Institute of Pathology of the Philipps-University Marburg between 1980 and 1999 with respect to the presence of splenic metastasis. The total number of autopsies within the study period was 8,563. In 1,898 cases, a solid malignant tumor (1,774 carcinomas, 36 sarcomas, 27 malignant melanomas) was diagnosed. Metastasis to the spleen occurred in 57 cases (3.0%). Compared to the whole study population, patients with splenic metastasis were significantly younger (59 years vs. 67 years, p<0.05) and had significantly more metastastic sites (median: 6 vs. median:1, p<0.05). This underlines the assumption that splenic metastasis is associated with a worse prognosis. Lung cancer, cutaneous malignant melanoma, and breast cancer were the most frequent primary tumors, accounting for 24.6%, 15.8%, and 12.3% of all spleen metastases, respectively. Patients with testicular germ cell tumors (patients: 9, spleen metastasis: 4), malignant melanoma (patients: 27, spleen metastasis: 9, 33%), and small cell lung cancer (patients: 106, spleen metastasis: 8, 7.5%) had the highest frequency of splenic involvement. Most (n=48) metastases were detected macroscopically, the remaining ones were micrometastases (n=2), small tumor cell clusters, and single tumor cells within sinusoids (n=7). The present study underlines the importance of spleen metastasis as an indicator of poor prognosis. There are, however, various aspects as to the detection and morphology of spleen metastasism, which merit further scrutiny.     

Anti-SARS-CoV-2 activity of targeted kinase inhibitors: Repurposing clinically available drugs for COVID-19 therapy

Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. This study supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response.     

Improved formulation of photosensitizer chlorin e6 polyvinylpyrrolidone for fluorescence diagnostic imaging and photodynamic therapy of human cancer.

An improved formulation of the photosensitizer chlorin e6 (Ce6) in combination with the hydrophilic polymer polyvinylpyrrolidone (PVP) was investigated for its potential clinical applications in fluorescence diagnosis and photodynamic therapy (PDT) of cancer. This study reports the comparative preclinical biodistribution and efficacy of Ce6 delivered with or without PVP versus dimethyl sulfoxide (DMSO). The safety and fluorescence pharmacokinetics of Ce6-PVP in humans was also accessed. Biodistribution results showed that Ce6-PVP had higher tumor to normal tissue ratio compared to the other formulations. The sensitivity and specificity derived from the area under the receiver operating characteristics curves showed that the formulations were able to discriminate tumor from peritumoral muscle in the following order: Ce6-PVP>Ce6>Ce6-DMSO. In vitro PDT results showed that Ce6-PVP was found to induce selective phototoxicity in leukemic cells compared to peripheral mononuclear blood cells. In addition, in vivo light irradiation at 1h after Ce6-PVP was found to induce greater tumor necrosis without causing animal toxicity. In patients, preferential accumulation of Ce6-PVP was observed in angiosarcoma lesions compared to normal skin following intravenous administration. In conclusion, PVP significantly enhanced the Ce6 concentration in tumors compared with Ce6 alone and increased the therapeutic index of PDT without any side effects in animal model. No serious adverse events were observed in human as well.     

Use of automated external defibrillators by a U.S. airline

BACKGROUND: Passengers who have ventricular fibrillation aboard commercial aircraft rarely survive, owing to the delay in obtaining emergency care and defibrillation. METHODS: In 1997, a major U.S. airline began equipping its aircraft with automated external defibrillators. Flight attendants were trained in the use of the defibrillator and applied the device when passengers had a lack of consciousness, pulse, or respiration. The automated external defibrillator was also used as a monitor for other medical emergencies, generally at the direction of a passenger who was a physician. The electrocardiogram that was obtained during each use of the device was analyzed by two arrhythmia specialists for appropriateness of use. We analyzed data on all 200 instances in which the defibrillators were used between June 1, 1997, and July 15, 1999. RESULTS: Automated external defibrillators were used for 200 patients (191 on the aircraft and 9 in the terminal), including 99 with documented loss of consciousness. Electrocardiographic data were available for 185 patients. The administration of shock was advised in all 14 patients who had electrocardiographically documented ventricular fibrillation, and no shock was advised in the remaining patients (sensitivity and specificity of the defibrillator in identifying ventricular fibrillation, 100 percent). The first shock successfully defibrillated the heart in 13 patients (defibrillation was withheld in 1 case at the family's request). The rate of survival to discharge from the hospital after shock with the automated external defibrillator was 40 percent. A total of 36 patients either died or were resuscitated after cardiac arrest. No complications arose from use of the automated external defibrillator as a monitor in conscious passengers. CONCLUSIONS: The use of the automated external defibrillator aboard commercial aircraft is effective, with an excellent rate of survival to discharge from the hospital after conversion of ventricular fibrillation. There are not likely to be complications when the device is used as a monitor in the absence of ventricular fibrillation.     

Postoperative endophthalmitis caused by sequestered Acinetobacter calcoaceticus

PURPOSE:To describe postoperative endophthalmitis caused by sequestered Acinetobacter calcoaceticus.METHOD:Case report. A 40-year-old woman developed recurrence of inflammation after extracapsular cataract extraction with intraocular lens (IOL) implantation. At last recurrence, the capsular bag was studded with white deposits. Intraocular lens was removed along with capsular bag during pars plana vitrectomy.RESULTS:The capsular bag, when cultured, grew A calcoaceticus. The media remained clear with no evidence of recurrence of infection over a 3-month follow-up. CONCLUSION:Postoperative endophthalmitis similar to that caused by sequestered Propionibacterium acnes can be caused by A calcoaceticus.     

Mucinous cancers have fewer genomic alterations than more common classes of breast cancer

Mucinous cancers of the breast are distinguished histologically by their abundant pools of mucin and low degree of nuclear pleomorphism. Relative to the more common breast cancers of no distinctive type (ductal carcinoma), mucinous cancers have a relatively favorable prognosis. In a study of chromosomal changes in mucinous cancers, we evaluated the extent of loss of heterozygosity (LOH) at chromosomal regions commonly deleted in usual infiltrating ductal carcinoma, including markers on chromosomal arms 1p, 1q, 3p, 6q, 8p, 9p, 11p, 11q, 13q, 16q, 17p, and 17q. Remarkably, we found an average frequency of LOH of only 1.9 of these 12 chromosomal arms in 18 cases of mucinous carcinoma, compared to an average frequency of LOH of 6.4 of these same chromosomal arms in cases of infiltrating ductal cancer. In three of the 18 cases of mucinous carcinoma studied, including one case with regional lymph node metastases, no LOH was seen at any of the 12 chromosomal regions studied. We considered the possibility of other chromosomal loci being more commonly affected in mucinous cancers and conducted comparative genomic hybridization on six of the cases. These studies demonstrated a low overall frequency of genomic copy number changes (mean of 3.1 changes per case) and failed to reveal any other chromosomal locus with frequent losses that had not been evaluated by microsatellite analysis. Together, these data indicate that mucinous cancers of the breast do not have the extensive genomic alterations that are typically found in more common variants of breast cancer. Thus, mucinous cancers most likely have less genetic instability than most other forms of breast cancer and the molecular pathogenesis of this form of breast cancer is likely to be substantially different than that of usual ductal breast cancer.     

Lysophosphatidic acid induces glycodelin gene expression in cancer cells

Glycodelin is a glycoprotein that has been suggested to be important in normal pregnancy and in malignancy. The regulation of its synthesis has not been studied. In this study, we report the induction of glycodelin gene expression by lysophosphatidic acid (LPA). We studied the effect of LPA (5, 10 and 25 microM) on glycodelin production in breast (MDA-MB-231), cervical (Hela), endometrial (RL-95), ovarian cancer (OVCAR-3) and erythroleukemia (K562) cells. There was a dose-dependent (5-25 microM) induction of glycodelin gene and protein expression in these cell types. LPA is a mimic of phorbol myristate acetate (PMA) action and is found to be elevated in high concentrations in the serum of cancer subjects. As glycodelin is an angiogenic protein with a potential immunosuppressive role, control of LPA synthesis might offer a potential target for intervention.     

Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma

The pathological distinction between malignant pleural mesothelioma (MPM)and adenocarcinoma (ADCA) of the lung can be cumbersome using established methods. We propose that a simple technique, based on the expression levels of a small number of genes, can be useful in the early and accurate diagnosis of MPM and lung cancer. This method is designed to accurately distinguish between genetically disparate tissues using gene expression ratios and rationally chosen thresholds. Here we have tested the fidelity of ratio-based diagnosis in differentiating between MPM and lung cancer in 181 tissue samples (31 MPM and 150 ADCA). A training set of 32 samples (16 MPM and 16 ADCA) was used to identify pairs of genes with highly significant, inversely correlated expression levels to form a total of 15 diagnostic ratios using expression profiling data. Any single ratio of the 15 examined was at least 90% accurate in predicting diagnosis for the remaining 149 samples (e.g., test set). We then examined (in the test set) the accuracy of multiple ratios combined to form a simple diagnostic tool. Using two and three expression ratios, we found that the differential diagnoses of MPM and lung ADCA were 95% and 99% accurate, respectively. We propose that using gene expression ratios is an accurate and inexpensive technique with direct clinical applicability for distinguishing between MPM and lung cancer. Furthermore, we provide evidence suggesting that this technique can be equally accurate in other clinical scenarios.