Phosphaturic mesenchymal tumor with de novo liver metastases: a case report and literature review.

Phosphaturic mesenchymal tumors (PMTs) are rare tumors that can cause tumor-induced osteomalacia (TIO) through overproduction of FGF23, a peptide hormone that causes renal phosphate wasting and reduced osteoblastic activity. The diagnosis of PMTs can be difficult to make as the presenting symptoms are non-specific. Although PMT is a rare entity, most cases are benign in nature, not requiring further intervention after surgery, as resection is typically curative. Here, we present a unique case of malignant PMT with de novo liver metastasis in a female patient who presented with TIO and underwent surgical resection of her primary lesion with subsequent regression of her liver metastasis. Moreover, we analyze a review of literature and discuss the importance of a timely diagnosis of this rare phenomenon. It is encouraged that providers strongly consider a diagnosis of PMT in patients with otherwise unexplained bone pain, fatigue, weakness, especially if accompanied with hypophosphatemia. Further studies are also warranted to identify prognostic factors that predict a PMT's malignant potential as they may help identify possible therapeutic targets.

Phosphaturic mesenchymal tumor with spread to the liver: A case report and literature review Phosphaturic mesenchymal tumors (PMTs) are rare tumors that can cause bone loss through the excess production of a signal named FGF23. This hormone causes the kidneys to lose phosphate and reduces the body's ability to build new bone. PMTs are incredibly rare and difficult to diagnose especially since the presenting symptoms can be seen in several different diseases. Although PMT is rare, most cases are benign, only requiring surgery. We are presenting a unique case of a patient who presented with PMT in her right thigh and had evidence that the disease spread to her liver. Our patient underwent surgical resection of her thigh lesion and subsequently had improvement of her liver lesion. In our study, we analyze a review of literature and discuss the importance of a timely diagnosis of this rare phenomenon. It is encouraged that providers strongly consider a diagnosis of PMT in patients with otherwise unexplained bone pain, fatigue, weakness, especially if accompanied by low phosphate levels. Further studies are also warranted to identify prognostic factors that predict a PMT's malignant potential as they may help identify possible therapeutic targets.

Therapy With Metronomic Cyclophosphamide (mCyc) for Previously-Treated Metastatic Castrate-Resistant Prostate Cancer (mCRPC).

INTRODUCTION: Despite the introduction of various novel therapies for management of metastatic castrate resistant prostate cancer (mCRPC) in recent decades, available treatment options are finite and remain limited. Multiple historical studies have demonstrated activity and a favorable toxicity profile of oral metronomic cyclophosphamide (mCyc) in prostate cancer (PCa). Unlike the cytotoxic immunosuppressive effects of high-dose intravenously-administered cyclophosphamide, continuous low doses of oral mCyc have a unique immune-stimulatory mechanism of action. MATERIALS AND METHODS: This is a retrospective, multi-institution study of men with 43 patients with mCRPC treated mCyc. Patient demographic information as well as clinical, pathologic, and genomic characteristics of their PCa were extracted. The primary endpoint was the rate of PSA decline by ≥ 50% (ie, PSA50). Additional efficacy and toxicity data as well as cost analysis compared to other commonly used agents in mCRPC was obtained. RESULTS: PSA50 was noted in 20.9% of patients, while an additional 25.6% patients achieved < PSA50 and 6.9% reported improvement in prostate cancer-related symptoms without any PSA reduction. Meanwhile, 9.3% of patients required mCyc dose reduction, 11.6% needed dose interruption due to toxicity, and no treatment discontinuations due to toxicity were observed. mCyc was also cost effective compared to other agents commonly used in mCRPC. CONCLUSIONS: Despite the small sample size and retrospective nature of this dataset, mCyc demonstrated promising rapid activity and a tolerable toxicity profile in a heavily pretreated mCRPC population with aggressive clinical, pathologic, and genomic disease features.

Real world experience: Examining outcomes using letermovir for CMV prophylaxis in high-risk allogeneic hematopoietic stem cell patients in the setting of using T-cell depletion as GVHD prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) infection significantly impacts the morbidity and mortality of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Despite monitoring and pharmacologic prophylaxis with drugs such as valganciclovir or ganciclovir, rates of early CMV reactivation have continually persisted, contributing to increased rates of morbidity and mortality in allogeneic-HSCT patients. This study evaluates the outcomes of letermovir in preventing CMV reactivation and CMV-related complications in HSCT recipients with initiation of therapy at +21 days in high-risk patients. METHODS: We retrospectively analyzed adult patients at University of Southern California (USC) Norris Cancer Hospital who received allogeneic-HSCT from 2018 to 2020 with subsequent serial CMV monitoring and treatment. CMV reactivation was determined in patients if they had clinically significant serum CMV viremia (viremia requiring treatment) or organ involvement by day+100. Primary endpoint assessed was day+100 rates of CMV reactivation. Secondary end-points included 1-year OS, 1-year RFS, and incidence of GVHD. Descriptive statistics were used to compare characteristics between groups used in this study, with a significance level of α = 0.05. RESULTS: Between 2018 and 2020, 116 adult HSCT recipients were reviewed. 51% were male and 49% were female; donor sources consisted of 27% match related donor (MRD) 28% match-unrelated donor (MUD), and 45% haploidentical donor. Of the 116 patients, 92 were identified as high-risk for CMV reactivation. 71 patients received letermovir prophylaxis, and 21 patients received no prophylaxis. In high-risk patients, after adjusting for GVHD status and transplant type, patients that received letermovir had no statistically significant difference of having D + 100 CMV reactivation compared to patients that did not receive letermovir. 1.02 (95% CI: 0.35, 3.20) (p = 0.97). Moreover, there were no statistically significant difference observed between letermovir treatment and 1-year OS, 1-year RFS, and incidence of GVHD. CONCLUSION: Patients in the high-risk letermovir group had outcomes that were comparable to the lower risk "non-letermovir" group. There was no significant difference in CMV D + 100 reactivation between high-risk patients who did not receive letermovir compared to the patients who did. While other studies have shown that early initiation of letermovir may be associated with improved outcomes, our study shows that the use of letermovir with initiation at 21 days may not necessarily translate to improved secondary outcomes such as overall survival. Further prospective studies evaluating the time of initiating therapy and outcomes are needed.

A83-01 inhibits TGF-ß-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells.

PURPOSE: The aim of this study is to investigate the mechanisms of interactions between TGF-ß and Wnt/ß-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment. METHODS: The effect of TGF-ß on Wnt/ß-catenin signaling pathway was examined by using a human Wnt/ß-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay. RESULTS: HER2-overexpressing breast cancer cells treated with TGF-ß have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF-ß-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and ß-catenin pathways. The TGF-ß-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-ß regulating Wnt3 during EMT. Subsequently, TGF-ß-induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/ß-catenin signaling were repressed by the shRNA treatment. TGF-ßR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-ß-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-ß-induced cell invasion significantly in both trastuzumab responsive and resistant cells. CONCLUSIONS: Our data demonstrated an important interdependence between TGF-ß and Wnt/ß-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-ß-induced EMT. A83-01 could inhibit the TGF-ß-initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment.

Aberrant Phosphorylation of SMAD4 Thr277-Mediated USP9x-SMAD4 Interaction by Free Fatty Acids Promotes Breast Cancer Metastasis.

Obesity increases the risk of distant metastatic recurrence and reduces breast cancer survival. However, the mechanisms behind this pathology and identification of relevant therapeutic targets are poorly defined. Plasma free fatty acids (FFA) levels are elevated in obese individuals. Here we report that TGFß transiently activates ERK and subsequently phosphorylates SMAD4 at Thr277, which facilitates a SMAD4-USP9x interaction, SMAD4 nuclear retention, and stimulates TGFß/SMAD3-mediated transcription of Twist and Snail. USP9x inhibited the E3 ubiquitin-protein ligase TIF1γ from binding and monoubiquitinating SMAD4, hence maintaining the SMAD4 nuclear retention. FFA further facilitated TGFß-induced ERK activation, SMAD4 phosphorylation, and nuclear retention, promoting TGFß-dependent cancer progression. Inhibition of ERK and USP9x suppressed obesity-induced metastasis. In addition, clinical data indicated that phospho-ERK and -SMAD4 levels correlate with activated TGFß signaling and metastasis in overweight/obese patient breast cancer specimens. Altogether, we demonstrate the vital interaction of USP9x and SMAD4 for governing TGFß signaling and dyslipidemia-induced aberrant TGFß activation during breast cancer metastasis. Cancer Res; 77(6); 1383-94. ©2017 AACR.

Combination treatment with flavonoid morin and telomerase inhibitor MST­312 reduces cancer stem cell traits by targeting STAT3 and telomerase.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. The malignant CRC that undergoes metastasis in the advanced stage is usually refractory to existing chemotherapy and shows a poor prognosis. However, to date, efficient targeted-therapy for metastatic CRC is ill-defined. We tested the hypothesis that combined treatment of flavonoid morin and telomerase inhibitor MST­312 may reduce the cancer stem cell (CSC) traits. To characterize CSC phenotype, we performed the CD133/CD44 subpopulation profiling, tumorsphere formation assay, cell invasion assay and wound healing assay. We have examined the augmenting effects of the combined treatment of morin and MST­312 for 5-FU (5-fluorouracil) efficacy in human colorectal cancer. Morin and MST­312 combined treatment reduced CD133 (+) and CD44 (+) subpopulations in human colorectal and breast cancer cells, respectively. Tumorsphere formation and cell invasiveness were decreased with the morin and MST­312 combination treatment. Consistent with these data, morin and MST­312 treatment decreased the wound healing capacity of human breast cancer cells. Stress and apoptosis antibody arrays revealed that there were specific upregulated and downregulated proteins resulting from different treatments. Phosphorylation levels of BAD, p53 and Chk1 were enhanced upon morin/MST­312 treatments in HT-29 cells, whereas caspase-3 cleavage level and expression of IκBα were downregulated by combined morin/MST­312 treatment in SW620 cells. Finally, morin and MST­312 co-treatment further augmented the 5-FU efficacy, chemosensitizing the 5-FU resistant human colorectal cancer cells. Taken together, our study suggests that novel targeted-therapy can be implemented by using flavonoid morin and telomerase inhibitor MST­312 for improved cancer prognosis.

Identification of Novel Biomarkers for Metastatic Colorectal Cancer Using Angiogenesis-Antibody Array and Intracellular Signaling Array.

Colorectal cancer (CRC) is one of the three leading causes for cancer mortality. CRC kills over 600,000 people annually worldwide. The most common cause of death from CRC is the metastasis to distant organs. However, biomarkers for CRC metastasis remain ill-defined. We compared primary and metastatic CRC cell lines for their angiogenesis-protein profiles and intracellular signaling profiles to identify novel biomarkers for CRC metastasis. To this end, we used primary and metastatic CRC cell lines as a model system and normal human colon cell line as a control. The angiogenesis profiles two isogenic CRC cell lines, SW480 and SW620, and HT-29 and T84 revealed that VEGF was upregulated in both SW620 and T84 whereas coagulation factor III, IGFBP-3, DPP IV, PDGF AA/AB, endothelin I and CXCL16 were downregulated specifically in metastatic cell lines. Furthermore, we found that TIMP-1, amphiregulin, endostatin, angiogenin were upregulated in SW620 whereas downregulated in T84. Angiogenin was downregulated in T84 and GM-CSF was also downregulated in SW620. To induce CRC cell metastasis, we treated cells with pro-inflammatory cytokine IL-6. Upon IL-6 treatment, epithelial-mesenchymal transition was induced in CRC cells. When DLD-1 and HT-29 cells were treated with IL-6; Akt, STAT3, AMPKα and Bad phosphorylation levels were increased. Interestingly, SW620 showed the same signal activation pattern with IL-6 treatment of HT-29 and DLD-1. Our data suggest that Akt, STAT3, AMPKα and Bad activation can be biomarkers for metastatic colorectal cancer. IL-6 treatment specifically reduced phosphorylation levels of EGFR, HER2 receptor, Insulin R and IGF-1R in receptor tyrosine kinase array study with HT-29. Taken together, we have identified novel biomarkers for metastatic CRC through the angiogenesis-antibody array and intracellular signaling array studies. Present study suggests that those novel biomarkers can be used as CRC prognosis biomarkers, and as potential targets for the metastatic CRC therapy.

The prevalence and characteristics of tinnitus in the youth population of the United States.

OBJECTIVES/HYPOTHESIS: To evaluate the prevalence, characteristics, and associated risk factors of tinnitus in U.S. adolescents. STUDY DESIGN: Cross-sectional analyses of U.S. representative demographic and audiometric data, the National Health and Nutrition Examination Survey (NHANES) 2005 to 2008. METHODS: The study population consisted of 3,520 individuals aged 12 to 19 years with complete tinnitus-related data. Tinnitus was defined as the presence of ringing or buzzing in the ears lasting for at least 5 minutes during the preceding 12 months. In addition, we defined a chronic tinnitus subgroup as being bothered by tinnitus for more than 3 months. Demographic and other data regarding tinnitus, smoking, body mass index (BMI), anemia, hypertension, history of ear infections, tympanostomy tube placement, otoscopy, tympanometry and hearing thresholds, history of firearm use, and recreational and occupational exposure to noise were extracted and analyzed. RESULTS: Overall, tinnitus lasting 5 minutes or more in the preceding 12 months was reported by 7.5% of the 12- to 19-year-old population. This represents about 2.5 million adolescents in the United States. The prevalence of chronic tinnitus was 4.7%, corresponding to about 1.6 million adolescents in the United States. Multivariable-adjusted analysis revealed that both overall and chronic tinnitus were associated with female gender, low income, exposure to passive smoking, type A tympanogram, and occupational and recreational noise exposure. History of ≥ 3 ear infections and history of tympanostomy tube placement were associated only with overall tinnitus. CONCLUSIONS: Tinnitus afflicts a substantial portion of the youth population. Further investigation of the association between tinnitus and the identified risk factors is warranted.

Genetics of hearing loss: where are we standing now?

Hearing loss (HL) is the most common sensory impairment and is caused by a broad range of inherited to environmental causes. Inherited HL consists 50-60% of all HL cases. The inherited form of HL is further classified to different categories. More than 300 syndromes and 40 genes have been identified to result in different levels of HL. Although several diagnostic or screening tests have been developed, yet there are controversies around their use.