Management of Dyspnea in Advanced Cancer: ASCO Guideline.

PURPOSE To provide guidance on the clinical management of dyspnea in adult patients with advanced cancer. METHODS ASCO convened an Expert Panel to review the evidence and formulate recommendations. An Agency for Healthcare Research and Quality (AHRQ) systematic review provided the evidence base for nonpharmacologic and pharmacologic interventions to alleviate dyspnea. The review included randomized controlled trials (RCTs) and observational studies with a concurrent comparison group published through early May 2020. The ASCO Expert Panel also wished to address dyspnea assessment, management of underlying conditions, and palliative care referrals, and for these questions, an additional systematic review identified RCTs, systematic reviews, and guidelines published through July 2020. RESULTS The AHRQ systematic review included 48 RCTs and two retrospective cohort studies. Lung cancer and mesothelioma were the most commonly addressed types of cancer. Nonpharmacologic interventions such as fans provided some relief from breathlessness. Support for pharmacologic interventions was limited. A meta-analysis of specialty breathlessness services reported improvements in distress because of dyspnea. RECOMMENDATIONS A hierarchical approach to dyspnea management is recommended, beginning with dyspnea assessment, ascertainment and management of potentially reversible causes, and referral to an interdisciplinary palliative care team. Nonpharmacologic interventions that may be offered to relieve dyspnea include airflow interventions (eg, a fan directed at the cheek), standard supplemental oxygen for patients with hypoxemia, and other psychoeducational, self-management, or complementary approaches. For patients who derive inadequate relief from nonpharmacologic interventions, systemic opioids should be offered. Other pharmacologic interventions, such as corticosteroids and benzodiazepines, are also discussed

Solitary splenic metastasis from ovarian carcinosarcoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Metastatic tumors to the spleen are rare but are usually found in conjunction with metastasis to other organs. The most common sources of splenic metastasis are breast, lung and colorectal cancers as well as melanoma and ovarian carcinoma. A solitary carcinosarcoma metastasis to the spleen of any origin is very rare. To the best of our knowledge, there are fewer than 30 reported cases of ovarian primary tumors with solitary metastasis to the spleen, and only three solitary primary carcinosarcomas to the spleen have been reported, of which one is female. We present what is, to the best of our knowledge, the first case of a solitary metastatic carcinosarcoma to the spleen arising from a primary ovarian carcinsarcoma.</p> <p>Case presentation</p> <p>A 72-year-old Hispanic woman status post-total abdominal hysterectomy for ovarian carcinosarcoma presented with complaints of early satiety and abdominal pain for the past two months with a 30-lb unintentional weight loss. An initial computed tomographic scan of her abdomen and pelvis revealed a 30 cm × 27 cm splenic mass with displacement of the left kidney, stomach and liver. The patient was found to have a solitary metastatic carcinosarcoma of the spleen with biphasic epithelial (carcinomatous) and mesenchymal (sarcomatous) elements consistent with carcinosarcoma.</p> <p>Conclusion</p> <p>Carcinosarcoma of the spleen is a rare tumor. Carcinosarcomas are a biphasic neoplasm comprising malignant epithelial and mesenchymal components arising from a stem cell capable of differentiation. They can arise anywhere in the female genital tract, most commonly from the endometrium. Even though it is rare, carcinosarcomas can metastasize to the spleen. This unique case of a solitary splenic metastasis from ovarian carcinosarcoma has particular interest in medicine, especially for the specialties of surgical oncology, pathology and hematology/oncology.</p

Conditional Inactivation of Brca1, p53 and Rb in Mouse Ovaries Results in the Development of Leiomyosarcomas

Epithelial ovarian cancer (EOC) is thought to arise in part from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. To generate a model in which Brca1-mediated transformation can be studied, we previously inactivated Brca1 alone in murine OSE, which resulted in an increased accumulation of premalignant changes, but no tumor formation. In this study, we examined tumor formation in mice with conditionally expressed alleles of Brca1, p53 and Rb, alone or in combination. Intrabursal injection of adenovirus expressing Cre recombinase to inactivate p53 resulted in tumors in 100% of mice. Tumor progression was accelerated in mice with concomitant inactivation of Brca1 and p53, but not Rb and p53. Immunohistologic analyses classified the tumors as leiomyosarcomas that may be arising from the ovarian bursa. Brca1 inactivation in primary cultures of murine OSE cells led to a suppression of proliferation that could be rescued by concomitant inactivation of p53 and/or Rb. Brca1-deficient OSE cells displayed an increased sensitivity to the DNA damaging agent cisplatin, and this effect could be modulated by inactivation of p53 and/or Rb. These results indicate that Brca1 deficiency can accelerate tumor development and alter the sensitivity of OSE cells to chemotherapeutic agents. Intrabursal delivery of adenovirus intended to alter gene expression in the ovarian surface epithelium may, in some strains of mice, result in more rapid transformation of adjacent cells, resulting in leiomyosarcomas

NRF2 Activation Restores Disease Related Metabolic Deficiencies in Olfactory Neurosphere-Derived Cells from Patients with Sporadic Parkinson's Disease

Extent: 14p.Background: Without appropriate cellular models the etiology of idiopathic Parkinson’s disease remains unknown. We recently reported a novel patient-derived cellular model generated from biopsies of the olfactory mucosa (termed olfactory neurosphere-derived (hONS) cells) which express functional and genetic differences in a disease-specific manner. Transcriptomic analysis of Patient and Control hONS cells identified the NRF2 transcription factor signalling pathway as the most differentially expressed in Parkinson’s disease. Results: We tested the robustness of our initial findings by including additional cell lines and confirmed that hONS cells from Patients had 20% reductions in reduced glutathione levels and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium, inner salt] metabolism compared to cultures from healthy Control donors. We also confirmed that Patient hONS cells are in a state of oxidative stress due to higher production of H2O2 than Control cultures. siRNA-mediated ablation of NRF2 in Control donor cells decreased both total glutathione content and MTS metabolism to levels detected in cells from Parkinson’s Disease patients. Conversely, and more importantly, we showed that activation of the NRF2 pathway in Parkinson’s disease hONS cultures restored glutathione levels and MTS metabolism to Control levels. Paradoxically, transcriptomic analysis after NRF2 pathway activation revealed an increased number of differentially expressed mRNAs within the NRF2 pathway in L-SUL treated Patient-derived hONS cells compared to L-SUL treated Controls, even though their metabolism was restored to normal. We also identified differential expression of the PI3K/AKT signalling pathway, but only post-treatment. Conclusions: Our results confirmed NRF2 as a potential therapeutic target for Parkinson’s disease and provided the first demonstration that NRF2 function was inducible in Patient-derived cells from donors with uniquely varied genetic backgrounds. However, our results also demonstrated that the response of PD patient-derived cells was not co-ordinated in the same way as in Control cells. This may be an important factor when developing new therapeutics.Anthony L. Cook, Alejandra M. Vitale, Sugandha Ravishankar, Nicholas Matigian, Greg T. Sutherland, Jiangou Shan, Ratneswary Sutharsan, Chris Perry, Peter A. Silburn, George D. Mellick, Murray L. Whitelaw, Christine A. Wells, Alan Mackay-Sim and Stephen A. Woo