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Background: While surgery remains the primary treatment for oral squamous cell carcinoma (OCSCC), induction chemotherapy (IC) can be used as a bridging or neoadjuvant therapy. This nationwide study in Taiwan examines the survival outcomes of OCSCC patients who received IC before surgery. Methods: We analyzed data from 29,891 patients with OCSCC. Of these, 29,058 initially underwent surgery (OP group), whereas 833 received IC before surgery (IC + OP group). A propensity score (PS)‐matched analysis (4, 1 ratio, 3260 vs. 815 patients) was performed considering tumor subsite, sex, age, Charlson comorbidity index, clinical T1–T4b tumors, clinical N0–3 disease, and clinical stage I–IV. Results: In the PS‐matched cohort, the 5‐year disease‐specific survival (DSS) and overall survival (OS) rates were 65% and 57%, respectively. When comparing the OP and IC + OP groups, the 5‐year DSS rates were 66% and 62%, respectively (p = 0.1162). Additionally, the 5‐year OS rates were 57% and 56%, respectively (p = 0.9917). No significant intergroup differences in survival were observed for specific subgroups with cT4a tumors, cT4b tumors, cN3 disease, pT4b tumors, and pN3 disease. However, for patients with pT4a tumors, the OP group demonstrated superior 5‐year outcomes compared to the IC + OP group, with a DSS of 62% versus 52% (p = 0.0006) and an OS of 53% versus 44% (p = 0.0060). Notably, patients with cT2–3, cN1, and c‐Stage II disease in the IC + OP group were significantly more likely to achieve pT0–1 status (p < 0.05). Conclusions: Following PS matching, the IC + OP group generally exhibited similar prognosis to the OP group. However, for pT4a tumors, the OP group showed superior 5‐year outcomes. While IC may not universally improve survival, it could be advantageous for patients who respond positively to the treatment. [ABSTRACT FROM AUTHOR]

Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein‐Barr virus (EBV). We envisioned that in‐depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty‐three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep‐sequenced (>1000×) with respect to a panel of 409 cancer‐related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF‐κB, and TGF‐β pathways. In addition, patients harbored CNV among 409 cancer‐related genes and missense mutations in TGF‐β/SMAD signaling were associated with poor overall survival and poor recurrence‐free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD‐dependent TGF‐β signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF‐β‐mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF‐β signaling contributes to exacerbating the NPC pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: We aimed to investigate the prognostic significance of combined pretreatment lymphocyte counts (LCs) and body mass index (BMI) in patients with head and neck cancer (HNC) treated with radiation therapy (RT). Nine hundred and twelve patients with HNC who were treated with RT were retrospectively reviewed. Survival was analyzed by stratifying the patients according to pretreatment LCs and BMI. Patients with low pretreatment LCs and BMI were characterized by a more advanced T stage, fewer nasopharyngeal subsites, less smoking and drinking, and fewer comorbidities. Patients with low pretreatment LCs and BMI had a significantly poorer overall and distant metastasis‐free survival than those with high pretreatment LCs and BMI. No significant differences were observed in terms of local or regional recurrence‐free survival. Combined pretreatment LCs and BMI may be more effective at predicting overall and distant metastasis‐free survival in patients with HNC treated with RT. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to evaluate the recovery kinetics of voice and quality of life (QOL) over time in patients with early glottic cancer who underwent transoral laser microsurgery (TLM). Methods A prospective cohort study was conducted in which acoustic and aerodynamic voice assessments and QOL analyses were done using health-related questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions [EORTC-QLQ-C30] and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35-questions [EORTC-QLQ-H&N35]) were administered at designated times. Results Most voice laboratory parameters worsened during the first month, then recovered to baseline after 6 months. The QLQ-H&N35 speech subscale was significantly improved. Among the voice laboratory parameters, pretreatment harmonics-to-noise ratio was an independent predictor ( P = .041) for improvement on the speech subscale at the endpoint. Conclusion Despite an initial deterioration of voice and QOL in the first month, patients who underwent TLM recovered to a plateau since the sixth month and then to better than preoperative status afterward. A greater improvement in QOL was seen in patients with poorer baseline voice quality. [ABSTRACT FROM AUTHOR]

We aimed to compare the overall survival ( OS) of patients with bone metastases ( BM) from solid tumors after standard-dose radiotherapy ([ RT]; 30 Gy administered in 10 fractions; EQD2Gy = 32.5 Gy) and dose-escalated RT (EQD2Gy > 32.5 Gy). We retrospectively reviewed the clinical charts of 1795 patients (median age, 62.3 years; age range, 18-96 years) with BM from solid tumors who were referred for RT to our institute between 2000 and 2013. These patients were assigned to the standard-dose ( n = 1125; 63%) and dose-escalated ( n = 670; 37%) RT groups. OS, estimated as the duration between the first RT session and death, served as the main outcome measure. The dose-escalated RT group had a significantly better OS than the standard-dose RT group ( P = 0.000). After allowing potential confounders in multivariate analysis, the RT dose retained its independent association with OS (hazard ratio [ HR], 0.837; 95% confidence interval [ CI], 0.753-0.929, P = 0.001). After propensity score matching of the baseline characteristics of both groups, RT dose retained its independent association with OS ( HR, 0.887; 95% CI, 0.737-0.951; P = 0.011) on multivariate analysis. Dose-escalated RT exerted more favorable effects on OS in patients with non-lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis. Dose-escalated RT was significantly associated with better OS in patients with BM from solid malignancies, particularly among those with non-lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Plasma Epstein-Barr virus (EBV) DNA concentrations predict prognosis in patients with nasopharyngeal carcinoma (NPC). Recent evidence also indicates that intratumor heterogeneity on F-18 fluorodeoxyglucose positron emission tomography (18 F-FDG PET) scans is predictive of treatment outcomes in different solid malignancies. Here, we sought to investigate the prognostic value of heterogeneity parameters in patients with primary NPC.Study Design: Retrospective cohort study.Methods: We examined 101 patients with primary NPC who underwent pretreatment 18 F-FDG PET/computed tomography. Circulating levels of EBV DNA were measured in all participants. The following PET heterogeneity parameters were collected: histogram-based heterogeneity parameters, second-order texture features (uniformity, contrast, entropy, homogeneity, dissimilarity, inverse difference moment), and higher-order (coarseness, contrast, busyness, complexity, strength) texture features.Results: The median follow-up time was 5.14 years. Total lesion glycolysis (TLG), tumor heterogeneity measured by histogram-based parameter skewness, and the majority of second-order or higher-order texture features were significantly associated with overall survival (OS) and/or recurrence-free survival (RFS). In multivariate analysis, age (P =.005), EBV DNA load (P = .0002), and uniformity (P = .001) independently predicted OS. Only skewness retained the independent prognostic significance for RFS. Tumor stage, standardized uptake value, or TLG did not show an independent association with survival endpoints. The combination of uniformity, EBV DNA load, and age resulted in a more reliable prognostic stratification (P < .001).Conclusions: Tumor heterogeneity is superior to traditional PET parameters for predicting outcomes in primary NPC. The combination of uniformity with EBV DNA load can improve prognostic stratification in this clinical entity.Level Of Evidence: 4 Laryngoscope, 127:E22-E28, 2017. [ABSTRACT FROM AUTHOR]

Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function. [ABSTRACT FROM AUTHOR]

Previously, a pilot genome-wide association study has identified candidate single nucleotide polymorphism predictors for the therapeutic response of 5-fluorouracil, mitoxantrone and cisplatin (FMP) combination chemotherapy in advanced hepatocellular carcinoma (HCC). Here, we conducted a prospective confirmatory study to examine the predictive value of rs9679162 (located on GALNT14 gene) for the therapeutic responses using a split-dose FMP protocol. One hundred and seven advanced HCC patients receiving split-dose FMP therapy were enrolled. All patients were in Barcelona Clinical Liver Cancer Stage C with either main portal vein thrombosis and/or distant metastasis. Of them, 105 (98.1%) were Child-Pugh classification B. GALNT14 genotype was determined before therapy. Of the patients included, 28 were rs9679162 'TT' and 79 were 'non-TT' ('GG' + 'GT') genotype. The median overall survival, time-to-progression, response rate and disease control rate were ('TT' versus 'non-TT') 6.8 versus 3.9 months ( p < 0.001), 3.9 versus 2.1 months ( p < 0.001), 28.6% versus 10.1% ( p = 0.029) and 35.7% versus 15.2% ( p = 0.030), respectively. Multivariate analysis indicated that rs9679162 genotype was an independent predictor for overall survival ( p = 0.002). Categorical analysis showed that 17 patients with 'TT' genotype, tumor size < 10 cm and neutrophils < 74% had a median overall survival of 25.5 months and a therapeutic response rate of 47.1%. In conclusion, this prospective study confirmed that GALN14 genotype (rs9679162) was an effective predictor for therapeutic outcome in advanced HCC patients treated by FMP chemotherapy. Combining GALNT14 genotype and clinical parameters, a subgroup of patients with excellent outcome was identified. [ABSTRACT FROM AUTHOR]

Oncogenic N-/KRAS mutations were frequently associated with MLL/AF10 in acute myeloid leukemia with myeloid sarcoma (MS). To study the cooperating leukemogenesis by MLL/AF10 and KRAS mutation, we retrovirally transduced MLL/AF10(OM-LZ) and KRASG12C into mouse bone marrow cells and generated two immortalized cell lines. The cells carrying cooperating MLL/AF10(OM-LZ) and KRASG12C had immature myelomonocytic phenotypes. Compared to a previously established cell line carrying MLL/AF10(OM-LZ) alone, cooperation of MLL/AF10(OM-LZ) with KRASG12C blocked the cells at a more immature myelomonocytic stage with reduced expression of monocyte/macrophage markers. The mice transplanted with the cells carrying cooperating MLL/AF10(OM-LZ) and KRASG12C, liked those transplanted with the cells carrying MLL/AF10(OM-LZ) alone, induced myeloproliferative disease-like myeloid leukemia, but in a shorter latency and formed multiple MS at the adipose tissues of skin, peritoneum and intraperitoneal cavity. Cooperation of MLL/AF10(OM-LZ) with KRASG12C increased cell adhesion via upregulation of an adhesion G-protein-coupled receptor Gpr125. Knockdown of Gpr125 in the cells by short hairpin RNA reduced cell aggregation and diminished MS formation in the transplanted mice. Our results indicated that upregulation of Gpr125 by cooperating MLL/AF10(OM-LZ) and KRASG12C promoted cell adhesion and contributed to the MS formation. [ABSTRACT FROM AUTHOR]

Background To investigate the pretreatment copy number and the clearance rate of plasma Epstein-Barr virus (EBV) DNA as novel prognostic outcome markers for metastatic nasopharyngeal carcinoma (NPC). Methods Seventy-three patients with metastatic NPC were treated at outpatient department. Plasma EBV DNA concentrations and half-life values of plasma viral clearance rates, were determined by real-time quantitative polymerase chain reaction. Results Treatment response evaluated after 3 to 6 months of treatment showed that the overall response rate was 53.5%. The pretreatment plasma EBV DNA concentrations and the half-life of plasma EBV DNA clearance rates had significant effects on treatment response and overall survival prediction. In the chemotherapy regimen, gemcitabine plus cisplatin had a better treatment outcome than the cisplatin plus oral UFT and calcium folinate-based regimens. Conclusions The pretreatment plasma EBV DNA copy number and their clearance rates are significant predictors for NPC treatment outcome. © 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Several mouse models studying the MLL fusion-induced leukemic transformation showed that a myeloproliferation stage precedes leukemia or occurred as the only phenotype of hematological disorder in mice. We established 6 MLL/AF10(OM-LZ)-immortalized cell lines by retrovirally transducing the fusion gene into bone marrow cells from B6 or congenic GFP-B6 mice. Immunophenotypic and cytological analyses revealed that the immortalized cell lines could be divided into 2 types. Type I had a high percentage of cells expressing monocytic lineage marker CD115 in the medium containing IL3 and could terminally differentiate into granulocytes and monocytes in response to granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) treatments, respectively. On the other hand, type II had a low percentage of cells expressing CD115. The type II cell lines could not differentiate into granulocytes by G-CSF treatment and died rapidly in response to M-CSF treatment. Transplantation of both types I and II cells induced lethal myeloproliferative disease (MPD)-like myeloid leukemia in most of the sublethally irradiated B6 mice. Flow cytometric analysis of GFP and lineage markers of the peripheral blood cells from MPD mice revealed that the monocytes and granulocytes were generated not only from the donor cells but also from the host cells. RT-PCR analysis revealed that the MLL/AF10(OM-LZ)-immortalized cells expressed mRNAs encoding colony-stimulating factors (CSFs) of M-CSF and GM-CSF and inflammatory cytokines of IL-1α, IL-1β and TNF-α. Our results showed that the MLL/AF10(OM-LZ)-immortalized cells could induce host cell proliferation in the transplanted mice, probably through stimulation by CSFs or cytokines produced by the donor cells. [ABSTRACT FROM AUTHOR]

Prostate cancer is initially responsive to hormonal therapy, but cancers inevitably progress in an androgen-independent fashion with virtually all tumors evolving into more aggressive androgen refractory disease. Immunohistological comparisons of cyclooxygenase 2 (COX-2) expressions in 3 pairs of prostate cancer patients before and after the combined androgen blockade (CAB) therapy show elevated COX-2 expressions. This observation from clinical specimens is further supported by in vitro laboratory data using human prostate cancer cells in which the antiandrogen hydroxyflutamide (HF) induced COX-2 expression, and androgen suppressed COX-2 expression. By applying knockdown and overexpression strategies to modulate AR expression in prostate cancer cells, we confirmed that androgen/AR signal suppressed, and HF induced COX-2 expression at both protein and mRNA levels. COX-2 promoter reporter assay indicated that the suppression of COX-2 by androgen/AR is at the transcriptional level via modulation of NF-κB signals. Treatment of LNCaP and LAPC4 cells with 1 μM HF in the presence of 1 nM DHT, which mimics the CAB therapy condition, promotes cell growth, and this growth induction can be suppressed via adding the COX-2 specific inhibitor, NS398. This suggests that HF promoted prostate cancer cell growth is COX-2 dependent and this HF-COX-2 activation pathway can account for one reason of CAB therapy failure. Together, these findings provide a possible explanation how CAB with antiandrogen HF therapy might fail and provide a potential new therapeutic approach to battle prostate cancer via combination of CAB therapy with COX-2 inhibitor(s). © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]