Pre-diagnosis Multidisciplinary Tumor Board and Time to Staging in Lung Cancer: The Case Western MetroHealth Experience.

Introduction National guidelines support the discussion of cancer patients by multidisciplinary tumor boards (MTB). We researched whether early pre-diagnosis multidisciplinary tumor board discussions are associated with shorter times to staging in lung cancer. Methods We reviewed our institution's lung cancer and MTB registries to retrospectively study if an early discussion at pre-diagnostic MTB (pd-MTB) influenced the timeliness of diagnostic evaluation. Over 14 months, 161 consecutive patients with a diagnosis of lung cancer were included. Fifty-five patients were presented at pd-MTB while 106 (controls) patients were not. The primary outcome was the difference in the time interval from suspicious imaging (Ix) to completion of staging (Sx). Outcomes were adjusted for key confounders with a multiple regression analysis. Results For stages I, II, and III lung cancer, where time to therapy matters, early discussion of patients with nodules suspicious for malignancy at pd-MTB was associated with no time delays when compared to patients who were not discussed in pd-MTB. The mean time intervals for imaging to staging (with standard deviations) are 65 days in controls (sd = 42.67) and 75 days (sd = 58.27) in tumor board cases (p=0.39). Adjusting for confounders with a multiple regression analysis among all stages revealed a similar lack of difference in time intervals to diagnosis, staging, and therapy. Conclusion Our stage I-III lung cancer cases (pd-MTB) completed staging in a timely manner, similar to controls (no pd-MTB). The severity of illness at presentation and the availability of diagnostic services and others likely influence the results. Our manuscript shares important numerical data on timelines during cancer diagnosis and treatment. Using this data, prospective registries examining the process workflow may help standardize cancer quality goals and maximize referrals from primary-care/specialty providers. The key findings in our study create a paradigm for future studies to create and achieve "door-to-balloon" time targets for lung cancer care (akin to cardiac care) across different styles of tumor boards.

The functional characterization of long noncoding RNA SPRY4-IT1 in human melanoma cells.

Expression of the long noncoding RNA (lncRNA) SPRY4-IT1 is low in normal human melanocytes but high in melanoma cells. siRNA knockdown of SPRY4-IT1 blocks melanoma cell invasion and proliferation, and increases apoptosis. To investigate its function further, we affinity purified SPRY4-IT1 from melanoma cells and used mass spectrometry to identify the protein lipin 2, an enzyme that converts phosphatidate to diacylglycerol (DAG), as a major binding partner. SPRY4-IT1 knockdown increases the accumulation of lipin2 protein and upregulate the expression of diacylglycerol O-acyltransferase 2 (DGAT2) an enzyme involved in the conversion of DAG to triacylglycerol (TAG). When SPRY4-IT1 knockdown and control melanoma cells were subjected to shotgun lipidomics, an MS-based assay that permits the quantification of changes in the cellular lipid profile, we found that SPRY4-IT1 knockdown induced significant changes in a number of lipid species, including increased acyl carnitine, fatty acyl chains, and triacylglycerol (TAG). Together, these results suggest the possibility that SPRY4-IT1 knockdown may induce apoptosis via lipin 2-mediated alterations in lipid metabolism leading to cellular lipotoxicity.

During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor apoprotein supports cell cycling through the retinoic acid receptor α1 apoprotein.

INTRODUCTION: Current hormonal adjuvant therapies for breast cancer including tamoxifen treatment and estrogen depletion are overall tumoristatic and are severely limited by the frequent recurrence of the tumors. Regardless of the resistance mechanism, development and progression of the resistant tumors requires the persistence of a basal level of cycling cells during the treatment for which the underlying causes are unclear. METHODS: In estrogen-sensitive breast cancer cells the effects of hormone depletion and treatment with estrogen, tamoxifen, all-trans retinoic acid (ATRA), fulvestrant, estrogen receptor α (ER) siRNA or retinoic acid receptor α (RARα) siRNA were studied by examining cell growth and cycling, apoptosis, various mRNA and protein expression levels, mRNA profiles and known chromatin associations of RAR. RARα subtype expression was also examined in breast cancer cell lines and tumors by competitive PCR. RESULTS: Basal proliferation persisted in estrogen-sensitive breast cancer cells grown in hormone depleted conditioned media without or with 4-hydroxytamoxifen (OH-Tam). Downregulating ER using either siRNA or fulvestrant inhibited basal proliferation by promoting cell cycle arrest, without enrichment for ErbB2/3+ overexpressing cells. The basal expression of RARα1, the only RARα isoform that was expressed in breast cancer cell lines and in most breast tumors, was supported by apo-ER but was unaffected by OH-Tam; RAR-ß and -γ were not regulated by apo-ER. Depleting basal RARα1 reproduced the antiproliferative effect of depleting ER whereas its restoration in the ER depleted cells partially rescued the basal cycling. The overlapping tamoxifen-insensitive gene regulation by apo-ER and apo-RARα1 comprised activation of mainly genes promoting cell cycle and mitosis and suppression of genes involved in growth inhibition; these target genes were generally insensitive to ATRA but were enriched in RAR binding sites in associated chromatin regions. CONCLUSIONS: In hormone-sensitive breast cancer, ER can support a basal fraction of S-phase cells (i) without obvious association with ErbB2/3 expression, (ii) by mechanisms unaffected by hormone depletion or OH-Tam and (iii) through maintenance of the basal expression of apo-RARα1 to regulate a set of ATRA-insensitive genes. Since isoform 1 of RARα is genetically redundant, its targeted inactivation or downregulation should be further investigated as a potential means of enhancing hormonal adjuvant therapy.