Prophylactic Versus Reactive Megestrol Acetate Use for Critical Body Weight Loss in Patients with Pharyngeal and Laryngeal Squamous Cell Carcinoma Undergoing Concurrent Chemoradiotherapy.

This study compared the effects of megestrol acetate (MA) prophylactic (p-MA) versus reactive (r-MA) use for critical body-weight loss (>5% from baseline) during concurrent chemoradiotherapy (CCRT) in patients with advanced pharyngolaryngeal squamous cell carcinoma (PLSCC).Patients receiving CCRT alone in two phase-II trials were included for analyses. Both the p-MA and r-MA cohorts received the same treatment protocol at the same institution, and the critical body-weight loss, survival, and adverse event profiles were compared.The mean (SD) weight loss was 5.1% (4.7%) in the p-MA cohort (n = 54) vs. 8.1% (4.6%) in the r-MA cohort (n = 50) (p = .001). The percentage of subjects with body-weight loss >5% was 42.6% in the p-MA cohort vs. 68.0% in the r-MA cohort (p = .011). Tube feeding was needed in 22.2% of p-MA vs. 62.0% of r-MA patients (p < .001). Less neutropenia (26.0% vs. 70.0% [p < .001]) and a shorter duration of grade 3-4 mucositis (2.4 ± 1.4 vs. 3.6 ± 2.0 wk [p = .009]) were observed with p-MA treatment. Disease-specific survival, locoregional control, or distant metastasis-free survival did not differ. Less competing mortality from secondary primary cancer resulted in a better overall survival trend in the p-MA cohort.p-MA may reduce body-weight loss and improve adverse event profiles during CCRT for patients with PLSCC.

Gonadotropin-releasing hormone antagonist associated with lower cardiovascular risk compared with gonadotropin-releasing hormone agonist in prostate cancer: A nationwide cohort and in vitro study.

BACKGROUND: We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those who receive GnRH antagonist therapy. METHODS: Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages. RESULTS: GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively. CONCLUSION: GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.

Value of early evaluation of treatment response using 18F-FDG PET/CT parameters and the Epstein-Barr virus DNA load for prediction of outcome in patients with primary nasopharyngeal carcinoma.

PURPOSE: To determine the value of early evaluation of response to concurrent chemoradiotherapy (CCRT) using 18F-FDG PET-derived parameters and the Epstein-Barr virus (EBV) DNA titre in outcome prediction in patients with primary nasopharyngeal carcinoma (NPC). METHODS: Sixty patients with primary NPC were prospectively enrolled. All patients underwent 18F-FDG PET/CT before and during CCRT. The plasma EBV DNA titre was measured along with the PET/CT-derived parameters. Changes in EBV DNA titre and PET/CT-derived parameters during CCRT were analysed in relation to response to treatment, recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total lesion glycolysis (TLG) reduction ratio of ≤0.6 and a detectable EBV DNA titre during CCRT were predictors of an unfavourable response to treatment, RFS and OS. In multivariate analysis, a TLG reduction ratio of ≤0.6 predicted incomplete remission (p = 0.002) and decreased RFS (p = 0.003). The proportion of patients with a TLG reduction ratio of >0.6 who achieved a complete response was more than twice that of patients with a TLG reduction ratio of ≤0.6. A detectable EBV DNA titre, a TLG reduction ratio of ≤0.6 and older age were independently associated with a poorer OS (p = 0.037, 0.009 and 0.016, respectively). A scoring system was developed based on these independent predictors of OS. Patients with a score of 1 and 2/3 had poorer survival outcomes than those with a score of 0 (hazard ratio 4.756, p = 0.074, and hazard ratio 18.973, p = 0.001, respectively). This scoring system appeared to be superior to the traditional TNM staging system (p < 0.001 versus p = 0.175). CONCLUSION: Early evaluation of response to CCRT using 18F-FDG PET-derived parameters and the EBV DNA titre can predict outcome in patients with primary NPC. A combination of interim PET parameters and the EBV DNA titre enables better stratification of patients into subgroups with different survival rates.

Clinical utility of simultaneous whole-body 18F-FDG PET/MRI as a single-step imaging modality in the staging of primary nasopharyngeal carcinoma.

PURPOSE: Both head and neck magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) play a crucial role in the staging of primary nasopharyngeal carcinoma (NPC). In this study, we sought to prospectively investigate the clinical utility of simultaneous whole-body 18F-FDG PET/MRI for primary staging of NPC patients. METHODS: We examined 113 patients with histologically confirmed NPC who underwent pretreatment, simultaneous whole-body PET/MRI and PET/CT for primary tumor staging. The images obtained with the different imaging modalities were interpreted independently and compared with each other. RESULTS: PET/MRI increased the accuracy of head and neck MRI for assessment of primary tumor extent in four patients via addition of FDG uptake information to increase the conspicuity of morphologically subtle lesions. PET/MR images were more discernible than PET/CT images for mapping tumor extension, especially intracranial invasion. Regarding the N staging assessment, the sensitivity of PET/MRI (99.5%) was higher than that of head and neck MRI (94.2%) and PET/CT (90.9%). PET/MRI was particularly useful for distinguishing retropharyngeal nodal metastasis from adjacent nasopharyngeal tumors. For distant metastasis evaluation, PET/MRI exhibited a similar sensitivity (90% vs. 86.7% vs. 83.3%), but higher positive predictive value (93.1% vs. 78.8% vs. 83.3%) than whole-body MRI and PET/CT, respectively. CONCLUSIONS: For tumor staging of NPC, simultaneous whole-body PET/MRI was more accurate than head and neck MRI and PET/CT, and may serve as a single-step staging modality.

What should we expect from robotic surgery for second primary oropharyngeal cancer?

The outcomes of second primary oropharyngeal cancer (SPOPC) may not be determined by oropharyngeal cancer but from the other index cancer as well. The management of (SPOPC) remains inconclusive and limited. Transoral robotic surgery (TORS) to maximize the functional outcomes without reducing oncologic effect is suggested as the primary treatment for selected oropharyngeal cancer. This study aimed to evaluate the feasibility and outcomes of TORS for the management of SPOPC. Patients who underwent TORS from January 2011 to June 2015 at a tertian referral center in Taiwan were recruited. Loco-regional status, overall survival (OS), disease-specific survival (DSS), and postoperative functional status were evaluated. Fifteen patients received TORS for SPOPC with curative intent, including eleven with tongue-base carcinomas, and four with tonsil carcinomas. One case was terminated because of inadequate exposure and the other 14 cases were completed with negative pathologic margins. Two-year OS and DSS were 53 and 77%, respectively. Patients with SPOPC occurring within 6 months had poorer outcomes (p = 0.044). The median time to feeding-tube removal was 5 days, and one patient had long-term gastric-tube dependence. Patients of age <65 years with synchronous SPOPC and esophageal cancer as the other index cancer were significant worse in oncologic outcomes. We concluded that TORS is a feasible alternative treatment in selected patients with SPOPC. Patients with metachronous T1-2 SPOPC without an esophageal primary can achieve excellent survival after TORS, while TORS can maximize functional preservation with limited destruction in patients with low life expectancy.

Induction chemotherapy with dose-modified docetaxel, cisplatin, and 5-fluorouracil in Asian patients with borderline resectable or unresectable head and neck cancer.

BACKGROUND/PURPOSE: Significant ethnic differences in susceptibility to the effects of chemotherapy exist. Here, we retrospectively analyzed the safety and efficacy of induction chemotherapy (ICT) with dose-modified docetaxel, cisplatin, and 5-fluorouracil (TPF) in Asian patients with borderline resectable or unresectable head and neck squamous cell carcinoma (HNSCC). METHODS: Based on the incidence of adverse events that occurred during daily practice, TPF90 (90% of the original TPF dosage; docetaxel 67.5 mg/m2 on Day 1, cisplatin 67.5 mg/m2 on Day 1, and 5-fluorouracil 675 mg/m2 on Days 1-5) was used for HNSCC patients who were scheduled to receive ICT TPF. RESULTS: Between March 2011 and May 2014, 52 consecutive patients with borderline resectable or unresectable HNSCC were treated with ICT TPF90 followed by concurrent chemoradiotherapy. Forty-four patients (84.6%) received at least three cycles of ICT TPF90. The most commonly observed Grade 3-4 adverse events included neutropenia (35%), anemia (25%), stomatitis (35%), diarrhea (16%), and infections (13.5%). In an intention-to-treat analysis, the complete and partial response rates after ICT TPF90 were 13.5% and 59.6%, respectively. The complete and partial response rates following radiotherapy and salvage surgery were 42.3% and 25.0%, respectively. The estimated 3-year overall survival and progression-free survival rates were 41% [95% confidence interval (CI): 25-56%] and 23% (95% CI: 10-39%), respectively. The observed median overall survival and progression-free survival were 21.0 months (95% CI: 13.3-28.7 months) and 16.0 months (95% CI: 10.7-21.3 months), respectively. CONCLUSION: TPF90 is a suitable option for Asian patients with borderline resectable or unresectable HNSCC who are scheduled for ICT.

Gemcitabine plus cisplatin for patients with recurrent or metastatic nasopharyngeal carcinoma in Taiwan: a multicenter prospective Phase II trial.

OBJECTIVE: This multicenter Phase II trial evaluated the toxicity/efficacy of gemcitabine plus cisplatin as first-line chemotherapy in patients with recurrent/metastatic nasopharyngeal carcinoma. METHODS: Gemcitabine 1250 mg/m(2) on Days 1 and 8 and cisplatin 75 mg/m(2) on Day 1 were administered at a 3-week interval. The primary endpoint was the response rate. Secondary endpoints included progression-free survival, overall survival, response duration and safety. RESULTS: Fifty-two patients were recruited between 2004 and 2008. The response rate was 51.9% (complete remission rate, 9.6%) in the intent-to-treat group. The median progression-free and overall survivals were 9.8 and 14.6 months, respectively. The major Grade III/IV adverse event was leucopenia (61.6%). The mean number of cycles was 6.63 ± 0.40. The regimen was well-tolerated, although one treatment-related death occurred after severe sepsis from aspiration pneumonia. CONCLUSIONS: Gemcitabine plus cisplatin is an effective, well-tolerated regimen as a first-line treatment for recurrent/metastatic nasopharyngeal carcinoma.

A single nucleotide polymorphism on the GALNT14 gene as an effective predictor of response to chemotherapy in advanced hepatocellular carcinoma.

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.

The antitumor activity of osimertinib plus palbociclib in non-small cell lung cancer patient-derived xenograft (PDX)/2D/3D culture models harboring EGFR amplification and CDKN2A/2B homozygous deletions.

Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations and copy number aberrations were detected by next-generation sequencing and confirmed using polymerase chain reaction (PCR) followed by DNA sequencing, and genomic DNA quantitative PCR. Protein expression was evaluated by immunohistochemistry. Drug sensitivities of PDX/2D/3D models were evaluated by in vivo and in vitro antitumor assays. RNA interference was performed to silence gene expression. Our study found that 44.4 % (4/9) of cases had CDKN2A homozygous deletion (homdel), while 33.3 % (3/9) had CDKN2B homdel. Additionally, 22.2 % (2/9) had amplification (amp) in wildtype CDK4, 44.4 % (4/9) in CDK6, and 44.4 % (4/9) in EGFR. Among the cases, 77.8 % (7/9) lacked CDKN2A, and 33.3 % (3/9) had high CDK4, CDK6, and EGFR had high protein expression. Moreover, 33.3 % (3/9) had KRAS mutations, and 66.7 % (6/9) had TP53 mutations. Antitumor activity of osimertinib plus palbociclib was assessed in four PDX/2D/3D models, two of which had simultaneous EGFR amp and CDKN2A/2B homdel. The data showed that NSCLC with EGFR amp and CDKN2A/2B homdel were sensitive to combined drugs. Additional oncogenic KRAS mutation reduced the drug's antitumor effect. EGFR amp is responsible for osimertinib sensitivity. Osimertinib plus palbociclib effectively treat NSCLC with wildtype EGFR and CDK6 amp and CDKN2A/2B homdel in the absence of oncogenic KRAS mutation.

Molecular Diagnosis of Nasopharyngeal Carcinoma: Past and Future.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from the nasopharynx epithelial cells and has been linked with Epstein-Barr virus (EBV) infection, dietary habits, environmental and genetic factors. It is a common malignancy in Southeast Asia, especially with gender preference among men. Due to its non-specific symptoms, NPC is often diagnosed at a late stage. Thus, the molecular diagnosis of NPC plays a crucial role in early detection, treatment selection, disease monitoring, and prognosis prediction. This review aims to provide a summary of the current state and the latest emerging molecular diagnostic techniques for NPC, including EBV-related biomarkers, gene mutations, liquid biopsy, and DNA methylation. Challenges and potential future directions of NPC molecular diagnosis will be discussed.

The synergy of 177Lu-FAPI-46 with tyrosine kinase inhibitor in a sarcoma patient-derived xenograft mouse model.

BACKGROUND: Given the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining 177Lu-FAPI-46 with Pazopanib against this malignancy. METHODS: Patient-derived xenograft (PDX)-bearing mice were randomly divided into three groups: the control group, the 177Lu-FAPI-46 monotherapy group, and the 177Lu-FAPI-46 combined with Pazopanib therapy group. Therapeutic efficacy was regularly monitored. RESULTS: The microPET imaging showed a 0.84-fold decrease in the T/M ratio of 68Ga-FAPI-46 on day 7/8 post combination therapy, while the control group exhibited a 1.23-fold increase. Combination therapy significantly inhibited tumor proliferation, as evidenced by reduced Ki-67 and increased caspase 3 expressions. Notably, there was no significant body weight loss observed in any group. CONCLUSION: This study successfully demonstrated the reduction in FAP expression and suppression of tumor volume in sarcoma PDX following the combination therapy of 177Lu-FAPI-46 with Pazopanib.

Paraneoplastic leukocytosis induces NETosis and thrombosis in bladder cancer PDX model.

Paraneoplastic leukocytosis (PNL) in genitourinary cancer, though rare, can indicate aggressive behavior and poor outcomes. It has been potentially linked to cancer expressing G-CSF and GM-CSF, along with their respective receptors, exerting an autocrine/paracrine effect. In our study, we successfully established four patient-derived xenograft (PDX) lines and related cell lines from urothelial cancer (UC), conducting next-generation sequencing (NGS) for genetic studies. UC-PDX-LN1, originating from bladder cancer, exhibited two druggable targets - HRAS and ERCC2 - responding well to chemotherapy and targeted therapy, though not to tipifarnib, an HRAS inhibitor. Transcriptome analysis post-treatment illuminated potential mechanisms, with index protein analysis confirming their anticancer pathways. Mice implanted with UC-PDX-LN1 mirrored PNL observed in the patient's original tumor. Cytokine array and RT-PCR analyses revealed high levels of G-CSF and GM-CSF in our PDX and cell lines, along with their presence in culture media and tumor cysts.Leukocytosis within small vessels in and around the tumor, associated with NETosis and thrombus formation, suggested a mechanism wherein secreted growth factors were retained, further fueling tumor growth via autocrine/paracrine signaling. Disrupting this cancer cell-NETosis-thrombosis cycle, we demonstrated that anti-neutrophil or anticoagulant interventions enhanced chemotherapy's antitumor effects or prolonged survival in mice, even though these drugs lacked direct antitumor efficacy when used independently. Clinical observations in bladder cancer patients revealed PNL in 1.61% of cases (35/2162) with associated poor prognosis. These findings propose a novel approach, advocating for the combination of anticancer/NETosis/thrombosis strategies for managing UC patients presenting with PNL in clinical settings.

Postradiotherapy Response Assessment Using 18F-FDG PET/CT in Salivary Gland Carcinoma-A Multicenter Study.

PURPOSE: This multicenter study investigates the efficacy of 18F-FDG PET/CT in postradiotherapy (post-RT) response evaluation in salivary gland carcinoma (SGC). METHODS: We retrospectively reviewed 115 SGC patients who underwent definitive or adjuvant RT followed by 18F-FDG PET/CT between 2004 and 2021. Most tumors were parotid gland malignancies (50%). The most common histological subtypes were adenoid cystic (29%) and mucoepidermoid carcinomas (18%). RESULTS: The median follow-up was 65 months. Post-RT anatomic images (CT/MRI) revealed complete response (CR) in 51 patients (44%). Among 53 patients with partial response or stable disease, only 17 (32%) patients experienced locoregional recurrence, with a 5-year locoregional control rate of 69%. Post-RT 18F-FDG PET/CT documented metabolic CR in 81 patients (70%). Metabolic complete responders had significantly higher 5-year locoregional control (90% vs 43%), distant metastasis-free survival (80% vs 48%), progression-free survival (76% vs 24%), and overall survival rates (89% vs 42%) compared with non-complete responders (all P < 0.001), as confirmed in both univariate and multivariate analyses. It identified additional viable tumors in 18 cases (16%) and facilitated salvage local therapies in 7 patients (6%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of post-RT 18F-FDG PET/CT were 63%, 91%, 70%, 88%, and 84%, respectively, in predicting locoregional recurrence. 18F-FDG PET/CT showed significantly higher sensitivity (88% vs 36%, P = 0.011) in tumors with pre-RT SUVmax ≥7.39 compared with those with SUVmax <7.39. CONCLUSIONS: Post-RT 18F-FDG PET/CT demonstrates high negative predictive value and specificity, with metabolic CR predicting excellent outcomes. Additionally, it exhibits higher sensitivity for high-SUVmax SGC, facilitating early detection of viable tumors.

Prognostic impact of bridge or neoadjuvant induction chemotherapy in patients with resected oral cavity cancer: A nationwide cohort study.

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.

Involvement of Gpr125 in the myeloid sarcoma formation induced by cooperating MLL/AF10(OM-LZ) and oncogenic KRAS in a mouse bone marrow transplantation model.

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.

Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis.

UNLABELLED: Early reports suggested androgen/androgen receptor (AR) signals promote hepatocarcinogenesis. However, all antiandrogen clinical trials failed in advanced hepatocellular carcinoma (HCC) without reasonable explanations. We examined AR functions in HCC cancer metastasis in this study. We examined hepatic AR roles in HCC metastasis by comparing liver hepatocyte AR knockout and wildtype in a carcinogen-induced HCC mouse model. We examined tumor histology, cancer metastatic risks, and cancer survival in vivo, as well as cell anoikis and migration using primary hepatic tumor culture in vitro. We also examined therapeutic potentials of AR expression combined with the molecular targeting agent sorafenib in an HCC metastasis mouse model. We found a novel cancer phenotype in which mice lacking hepatic AR developed more undifferentiated tumors and larger tumor size at the metastatic stage. These mice also died earlier with increased lung metastasis, suggesting that hepatic AR may play dual yet opposite roles to promote HCC initiation but suppress HCC metastasis. Mechanistic dissection found that hepatic AR could enhance anoikis and suppress migration of HCC cells by way of suppression of p38 phosphorylation/activation and the nuclear factor kappa B (NF-κB)/matrix metallopeptidase 9 (MMP9) pathway, respectively. In addition, the in vivo preclinical trials concluded that a combination therapy of increased AR expression and reduced multiple-kinase inhibitor (sorafenib) exhibited better therapeutic efficacy. CONCLUSION: Our study demonstrates that AR could orchestrate intrahepatic signaling hierarchies and cellular behaviors, consequently affect HCC progression. Results from combination therapy shed light on developing new therapeutic paradigms for battling HCC at later metastatic stages.

Overexpression of Lgr5 correlates with resistance to 5-FU-based chemotherapy in colorectal cancer.

BACKGROUND: The leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) is an adult intestinal stem cell marker frequently detected in human colorectal cancers (CRCs). However, the value of Lgr5 level in CRC prognosis and treatment prediction has not been well characterized. METHODS: We examined Lgr5 expression in 384 formalin-fixed paraffin-embedded CRC specimens from 296 CRC patients, including 64 patients treated with 5-fluorouracil (5-FU)-based chemotherapy. The effects of Lgr5 on cell proliferation, survival, and drug resistance were examined in cultured CRC cells. RESULTS: Elevated expression of Lgr5 was observed in CRC tissues, and Lgr5 protein levels were significantly correlated with an advanced American Joint Committee on Cancer stage (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and distant metastasis (P < 0.001). High expression levels of Lgr5 were significantly associated with shorter disease-free survival (P < 0.001) and shorter cancer-specific survival (P = 0.007) in CRC patients. Among the chemotherapy-treated subgroups, patients with low Lgr5 level showed a better response rate (65 %) than patients with high Lgr5 level (37 %) towards 5-FU-based treatment (P = 0.025). In cultured CRC cell lines, knocking down Lgr5 suppressed cell proliferation and colony formation ability, while it enhanced apoptosis and rendered cells more sensitive to chemotherapeutic agents. In contrast, overexpression of Lgr5 increased cell proliferation and enhanced chemoresistance. CONCLUSION: These results suggest that elevated Lgr5 level is associated with CRC progression and treatment response and has the potential to serve as a therapeutic target in CRC patients.

Recombinant lipidated FLIPr effectively enhances mucosal and systemic immune responses for various vaccine types.

Formyl peptide receptor-like 1 inhibitor protein (FLIPr) is an immune evasion protein produced by Staphylococcus aureus, and FLIPr is a potential vaccine candidate for reducing Staphylococcus aureus virulence and biofilm formation. We produced recombinant lipidated FLIPr (rLF) to increase the immunogenicity of FLIPr and showed that rLF alone elicited potent anti-FLIPr antibody responses to overcome the FLIPr-mediated inhibition of phagocytosis. In addition, rLF has potent immunostimulatory properties. We demonstrated that rLF is an effective adjuvant. When an antigen is formulated with rLF, it can induce long-lasting antigen-specific immune responses and enhance mucosal and systemic antibody responses as well as broad-spectrum T-cell responses in mice. These findings support further exploration of rLF in the clinic as an adjuvant for various vaccine types with extra benefits to abolish FLIPr-mediated immunosuppressive effects.

Prognostic value of interim CT-based peritumoral and intratumoral radiomics in laryngeal and hypopharyngeal cancer patients undergoing definitive radiotherapy.

BACKGROUND AND PURPOSE: We aimed to investigate the prognostic value of peritumoral and intratumoral computed tomography (CT)-based radiomics during the course of radiotherapy (RT) in patients with laryngeal and hypopharyngeal cancer (LHC). MATERIALS AND METHODS: A total of 92 eligible patients were 1:1 randomly assigned into training and validation cohorts. Pre-RT and mid-RT radiomic features were extracted from pre-treatment and interim CT. LASSO-Cox regression was used for feature selection and model construction. Time-dependent area under the receiver operating curve (AUC) analysis was applied to evaluate the models' prognostic performances. Risk stratification ability on overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method and Cox regression. The associations between radiomics and clinical parameters as well as circulating lymphocyte counts were also evaluated. RESULTS: The mid-RT peritumoral (AUC: 0.77) and intratumoral (AUC: 0.79) radiomic models yielded better performance for predicting OS than the pre-RT intratumoral model (AUC: 0.62) in validation cohort. This was confirmed by Kaplan-Meier analysis, in which risk stratification depended on the mid-RT peritumoral (p = 0.009) and intratumoral (p = 0.003) radiomics could be improved for OS, in comparison to the pre-RT intratumoral radiomics (p = 0.199). Multivariate analysis identified mid-RT peritumoral and intratumoral radiomic models as independent prognostic factors for both OS and PFS. Mid-RT peritumoral and intratumoral radiomics were correlated with treatment-related lymphopenia. CONCLUSION: Mid-RT peritumoral and intratumoral radiomic models are promising image biomarkers that could have clinical utility for predicting OS and PFS in patients with LHC treated with RT.