Diagnosis of osteochondral lesions of the talus on Dual-layer spectral detector CT arthrography: clinical feasibility of virtual noncontrast images.

AIM: To compare the image quality of virtual noncontrast (VNC) and true noncontrast (TNC) CT images and to evaluate the clinical feasibility of VNC CT images for assessing osteochondral lesions of the talus (OLTs). MATERIALS AND METHODS: Forty-five OLT patients who underwent ankle CT arthrography (CTA) using dual-layer spectral detector CT were enrolled. Reconstruction of VNC and three-dimensional volume rendering images was performed. Afterward, image noise, the signal-to-noise ratio (SNR), and the contrast-to-noise ratio (CNR) were measured. For the subjective evaluation, two board-certified musculoskeletal radiologists [R2-1] assessed spatial resolution, overall image quality, and lesion conspicuity. The accuracy rate for OLT grading was determined in 23 patients who underwent arthroscopic surgery. RESULTS: While VNC images showed significantly less noise than TNC images, TNC images showed better SNRs and CNRs (p<.01). In the subjective analysis, TNC images showed better overall image quality (p<.001). For the 3D volume rendering images, VNC images scored significantly higher for lesion conspicuity (p<.001). The accuracy rates of CTA and CTA with VNC images for OLT grading were 79.2% and 83.3%, respectively. Regarding confidence level, when CTA and VNC images were evaluated together, the confidence level was significantly higher than that when only CTA images were evaluated (p<.001). CONCLUSION: VNC imaging can provide better confidence level of OLT grading and evaluation of the integrity of the subchondral bone plate when combined with conventional CTA without additional radiation dose to the patient. In addition, VNC images-based 3D volume rendering reconstruction would be helpful for preoperative planning in OLT patients.

Differentiation between Chondrosarcoma and Synovial Chondromatosis of the Temporomandibular Joint Using CT and MR Imaging.

BACKGROUND AND PURPOSE: Chondrosarcoma and synovial chondromatosis of the temporomandibular joint share overlapping clinical and histopathologic features. We aimed to identify CT and MR imaging features to differentiate chondrosarcoma from synovial chondromatosis of the temporomandibular joint. MATERIALS AND METHODS: The CT and MR images of 12 and 35 patients with histopathologically confirmed chondrosarcoma and synovial chondromatosis of the temporomandibular joint, respectively, were retrospectively reviewed. Imaging features including lesion size, center, enhancement, destruction/sclerosis of surrounding bone, infiltration into the tendon of the lateral pterygoid muscle, calcification, periosteal reaction, and osteophyte formation were assessed. A comparison between chondrosarcoma and synovial chondromatosis was performed with a Student t test for quantitative variables and the Fisher exact test or linear-by-linear association test for qualitative variables. Receiver operating characteristic analysis was performed to determine the diagnostic performance for differentiation of chondrosarcoma and synovial chondromatosis based on a composite score obtained by assigning 1 point for each of 9 imaging features. RESULTS: High-risk imaging features for chondrosarcoma were the following: lesion centered on the mandibular condyle, destruction of the mandibular condyle, no destruction/sclerosis of the articular eminence/glenoid fossa, infiltration into the tendon of the lateral pterygoid muscle, absent or stippled calcification, periosteal reaction, internal enhancement, and size of ≥30.5 mm. The best cutoff value to discriminate chondrosarcoma from synovial chondromatosis was the presence of any 4 of these high-risk imaging features, with an area under the curve of 0.986 and an accuracy of 95.8%. CONCLUSIONS: CT and MR imaging features can distinguish chondrosarcoma from synovial chondromatosis of the temporomandibular joint with improved diagnostic performance when a subcombination of 9 imaging features is used.

[Value of dual-layer spectral detector CT in preoperative prediction of lymph node metastasis of gastric cancer].

Objective: To investigate the value of dual-layer spectral detector CT(SDCT) in preoperative prediction of lymph node (LN) metastasis of gastric cancer. Methods: From January 2019 to January 2021, the clinical and imaging data of 130 gastric cancer patients(93 males and 37 females, aged from 37 to 84 years)confirmed by pathology in the Zhongshan hospital of Xiamen University were retrospectively collected. According to the status of lymph node metastasis, those patients were divided into metastatic LNs group (n=104) and nonmetastatic LNs group (n=26). The maximum diameter of gastric cancer on spectral CT images, CT Values of lesions in 40, 50, 60, 70. KeV monoenergetic image of arterial and Venous phase (CT40 keV, CT50 keV, CT60 keV, CT70 keV), iodine concentration (IC) and effective atomic number (Zeff) were measured, then the normalized IC(NIC) and spectral curve(K(40-70)) value were calculated. The differences of each parameter derived from spectral CT between the two groups were compared, and a logistic regression model was constructed. The ROC curves and area under the curve (AUC) were conducted to evaluate the diagnostic performance of each parameter and Delong test was used to compare the difference of each AUC. Results: Compared to nonmetastatic LNs group, metastatic LNs group had higher maximum diameter of tumor, CT40 keV, CT50 keV, CT60 keV, CT70 keV, IC, NIC, Zeff, and K(40-70) values on venous phase (the representative parameter is Zeff: 8.4 (8.2, 8.5) vs 8.2 (8.1, 8.3)) (all P<0.05). The proportion of patients with lower histology differentiated degree, higher T grade and positive carcino embryonic antigen (CEA)were higher than that in nonmetastatic LNs (the representative parameter was CEA: 34.6%(36/104) vs 7.7%(2/26) (all P<0.05). The regression model constructed by CEA and Zeff had the highest predictive value in predicting metastatic LNs, with an AUC of 0.835(0.759-0.894), sensitivity and specificity of 83.65% and 73.08%, respectively. Conclusion: SDCT quantitative parameters on venous phase and CEA facilitate the accurate prediction of metastatic LNs in patients with gastric cancer, and the multi-parameter regression model has the highest diagnostic performance.

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients.

BACKGROUND: Nivolumab plus ipilimumab demonstrated clinically meaningful improvement in efficacy versus chemotherapy with a manageable safety profile in patients with advanced non-small cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% or <1% in Part 1 of CheckMate 227. Here we report efficacy and safety results for the Asian subpopulation. METHODS: Patients with stage IV/recurrent NSCLC were randomized 1 : 1 : 1 to nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy (PD-L1 ≥1%) or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Overall survival (OS), progression-free survival, objective response rate, duration of response, and safety were evaluated among patients in Japan, South Korea, and Taiwan. RESULTS: In the Asian subpopulation with PD-L1 ≥1%, 81 patients received nivolumab plus ipilimumab and 81 received chemotherapy. Median OS was not reached with nivolumab plus ipilimumab versus 24.8 months with chemotherapy; 3-year OS rate was 53% versus 37% [hazard ratio (HR), 0.72; 95% confidence interval (CI) 0.47-1.11]. The 3-year progression-free survival rate was 26% versus 7% (HR, 0.65; 95% CI 0.45-0.96), objective response rate was 56% versus 37%, and median duration of response was 29.0 months (95% CI 15.0 months-not reached) versus 6.9 months (95% CI 3.9-11.1 months). Similar results were observed regardless of tumor PD-L1 expression and in Japanese patients. Grade 3-4 treatment-related adverse events occurred in 40% of patients receiving nivolumab plus ipilimumab and 36% receiving chemotherapy, in the overall Asian subpopulation (tumor PD-L1 expression ≥1% and <1%); no new safety signals were identified. CONCLUSIONS: At 3-year follow-up, nivolumab plus ipilimumab provided durable long-term efficacy benefits versus chemotherapy regardless of tumor PD-L1 expression in the Asian subpopulation, including Japanese patients. Consistent with findings for all randomized patients, these data support the use of nivolumab plus ipilimumab as first-line treatment of Asian patients with advanced NSCLC.

Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

Imaging features of synovial chondromatosis of the temporomandibular joint: a report of 34 cases.

AIM: To investigate the imaging features of synovial chondromatosis of the temporomandibular joint (TMJ), which is a rare benign arthropathy with cartilaginous proliferation. MATERIALS AND METHODS: Computed tomography and magnetic resonance imaging examinations of 34 patients with histopathologically confirmed primary synovial chondromatosis of the TMJ were reviewed retrospectively. Imaging features including the lesion epicentre, destruction/sclerosis of surrounding bone, calcification, periosteal reaction, osteophyte, lesion size, and joint space dimensions were assessed. RESULTS: Thirty-one of thirty-four patients (91.2%) showed the superior joint space as the lesion epicentre. For the mandibular condyle, more than one-third of patients (14/34; 41.2%) showed no destruction, and more than half of patients (19/34; 55.9%) showed no sclerosis. Conversely, >70% of patients showed destruction and sclerosis of the articular eminence/glenoid fossa, while >80% of patients (28/34; 82.4%) presented with various calcifications, including the ring-and-arc (9/34; 26.5%) and popcorn (13/34; 38.2%) types. The mean joint space on the affected side was significantly larger than that of the unaffected side (p<0.001). More than three-fourths of patients (76.9%) experienced no interval increase in lesion size during an average of 1.6 years of follow-up. CONCLUSION: Synovial chondromatosis of the TMJ demonstrated several imaging features, including the lesion centre being located in the superior joint space, resultant articular eminence/glenoid fossa-oriented bone changes, ring-and-arc and popcorn calcification, joint space widening, and self-limiting growth. These imaging features may be helpful in differentiating synovial chondromatosis from other lesions of the TMJ.

Liposomal irinotecan plus fluorouracil/leucovorin versus FOLFIRINOX as the second-line chemotherapy for patients with metastatic pancreatic cancer: a multicenter retrospective study of the Korean Cancer Study Group (KCSG).

BACKGROUND: There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy. PATIENTS AND METHODS: From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study. RESULTS: There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL. CONCLUSIONS: Second-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.

Light quantum control of persisting Higgs modes in iron-based superconductors.

The Higgs mechanism, i.e., spontaneous symmetry breaking of the quantum vacuum, is a cross-disciplinary principle, universal for understanding dark energy, antimatter and quantum materials, from superconductivity to magnetism. Unlike one-band superconductors (SCs), a conceptually distinct Higgs amplitude mode can arise in multi-band, unconventional superconductors  via strong interband Coulomb interaction, but is yet to be accessed. Here we discover such hybrid Higgs mode and demonstrate its quantum control by light in iron-based high-temperature SCs. Using terahertz (THz) two-pulse coherent spectroscopy, we observe a tunable amplitude mode coherent oscillation of the complex order parameter from coupled lower and upper bands. The nonlinear dependence of the hybrid Higgs mode on the THz driving fields is distinct from any known SC results: we observe a large reversible modulation of resonance strength, yet with a persisting mode frequency. Together with quantum kinetic modeling of a hybrid Higgs mechanism, distinct from charge-density fluctuations and without invoking phonons or disorder, our result provides compelling evidence for a light-controlled coupling between the electron and hole amplitude modes assisted by strong interband quantum entanglement. Such light-control of Higgs hybridization can be extended to probe many-body entanglement and hidden symmetries in other complex systems.

A preliminary evaluation of the circulating leptin/adiponectin ratio in dogs with pituitary-dependent hyperadrenocorticism and concurrent diabetes mellitus.

Leptin and adiponectin are thought to modulate insulin sensitivity and pancreatic ß-cell function, but there is limited information regarding the adipokine status of hyperglycemic dogs with hyperadrenocorticism. This study aimed to determine whether alterations in the leptin/adiponectin ratio, insulin sensitivity, and/or pancreatic ß-cell function are associated with diabetes mellitus (DM) in dogs with pituitary-dependent hyperadrenocorticism (PDH). A total of 48 client-owned dogs were included in this prospective observational study: 20 dogs with PDH (10 normoglycemic and 10 with DM), 15 dogs with DM, and 13 healthy dogs. The serum concentrations of leptin, adiponectin, resistin, interleukin (IL)-1ß, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF)-α were measured, and homeostatic model assessment indices (HOMAs) were calculated and compared among the groups. Serum leptin was significantly higher in PDH dogs with and without DM than in healthy and DM dogs, and it was lower in DM dogs than in PDH dogs without DM. Serum adiponectin was significantly lower in PDH dogs with DM than in healthy and PDH dogs, and it was significantly lower in DM dogs than in healthy dogs. Serum IL-10 was significantly higher in PDH dogs with DM than in healthy and PDH dogs without DM. The leptin/adiponectin ratio was significantly higher in PDH dogs with DM than in normoglycemic PDH dogs. Serum IL-6 concentrations were significantly higher in DM dogs than in healthy dogs. Serum IL-1ß concentration was significantly higher in DM dogs than in healthy dogs and PDH dogs with DM and without DM. Serum TNF-α and IL-18 concentrations were not different among groups. The HOMAß-cell function was significantly lower in PDH dogs with DM than in normoglycemic PDH dogs, while HOMAinsulin sensitivity was significantly lower in PDH dogs with DM than in healthy dogs. These results suggest that adipokine dysregulation, a reduction in insulin sensitivity, and a further impairment in pancreatic ß-cell function might predispose PDH dogs to DM. Further longitudinal study will be necessary to confirm this result.

A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial☆.

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.

Imaging features of chondrosarcoma of the temporomandibular joint: report of nine cases and literature review.

AIM: To investigate the imaging features of chondrosarcoma of the temporomandibular joint (TMJ) and review the literature. MATERIALS AND METHODS: Computed tomography (CT), magnetic resonance imaging (MRI), and integrated positron-emission tomography (PET)/CT images of nine patients with histopathologically confirmed chondrosarcoma of the TMJ were reviewed retrospectively. Imaging features regarding the direction of lesion growth, bone destruction, infiltration into the tendon of the lateral pterygoid muscle (LPM) in the pterygoid fovea, enhancement pattern, calcification, periosteal reaction, markedly hyperintense T2 signal area, and qualitative PET signal intensity were evaluated. RESULTS: Seven of nine patients (77.8%) presented with lesion growth that was outward from the medulla of the mandibular condyle. Infiltration into the tendon of LPM in the pterygoid fovea was observed in all cases, and 77.8% (7/9) of them demonstrated >50% infiltration. All the lesions showed a mixed peripheral and internal enhancement, and revealed a markedly hyperintense T2 signal intensity area, which showed no enhancement. Although five of nine cases demonstrated higher FDG uptake compared with that of the liver, the other four cases showed less FDG uptake than that of the liver. CONCLUSION: Chondrosarcoma of the TMJ demonstrated several imaging features, including outward growth from the mandibular condyle, resultant infiltration into the tendon of LPM in the pterygoid fovea, various patterns of internal enhancement, and a markedly hyperintense T2 signal intensity area. These imaging features may be helpful to differentiate chondrosarcoma from other lesions of the TMJ.

A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy.

BACKGROUND: Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear. PATIENTS AND METHODS: This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H1 = 30%) for the BM cohort and overall survival (OS) (H1 = 5 months) for the LM cohort. RESULTS: The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months [95% confidence interval (CI) 5.0-16.6]; the median OS was 16.9 months [95% CI 7.9-not reached (NR)]. In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1-NR); the median PFS was 8.0 months (95% CI 7.2-NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n = 18, P = 0.39) and LM (n = 17, P = 0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P = 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1-2. CONCLUSION: Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.

Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial.

BACKGROUND: Treatment options are limited for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) following progression after first-line platinum-based therapy, particularly in Asian countries. PATIENTS AND METHODS: In this randomised, open-label, phase III trial, we enrolled Asian patients aged ≥18 years, with histologically or cytologically confirmed recurrent/metastatic HNSCC following first-line platinum-based therapy who were not amenable for salvage surgery or radiotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. Patients were randomised (2 : 1) to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week), stratified by ECOG performance status and prior EGFR-targeted antibody therapy. The primary end point was progression-free survival (PFS) assessed by an independent central review committee blinded to treatment allocation. RESULTS: A total of 340 patients were randomised (228 afatinib; 112 methotrexate). After a median follow-up of 6.4 months, afatinib significantly decreased the risk of progression/death by 37% versus methotrexate (hazard ratio 0.63; 95% confidence interval 0.48-0.82; P = 0.0005; median 2.9 versus 2.6 months; landmark analysis at 12 and 24 weeks, 58% versus 41%, 21% versus 9%). Improved PFS was complemented by quality of life benefits. Objective response rate was 28% with afatinib and 13% with methotrexate. There was no significant difference in overall survival. The most common grade ≥3 drug-related adverse events were rash/acne (4% with afatinib versus 0% with methotrexate), diarrhoea (4% versus 0%), fatigue (1% versus 5%), anaemia (<1% versus 5%) and leukopenia (0% versus 5%). CONCLUSIONS: Consistent with the phase III LUX-Head & Neck 1 trial, afatinib significantly improved PFS versus methotrexate, with a manageable safety profile. These results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for certain patients with recurrent or metastatic HNSCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01856478.

Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial.

BACKGROUND: Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs. PATIENTS AND METHODS: In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1) or XELOX (capecitabine 1000 mg/m2, twice daily, on days 1-14 and oxaliplatin 130 mg/m2 on day 1) as first-line treatment, given every 3 weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate. RESULTS: In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3 months for the GEMOX group and 5.8 months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was -12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001). CONCLUSION: XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (number NCT01470443).

Alcohol consumption and the risk of incident pulmonary embolism in US women and men.

Essentials The association of moderate alcohol consumption with pulmonary embolism (PE) risk remains unclear. In three large US cohorts, we evaluated the association of alcohol consumption with PE risk. We found no evidence of an association of alcohol consumption amount or frequency with PE risk. Secondary analyses of type and heavy episodic drinking also yielded null findings. SUMMARY: Background Moderate alcohol consumption has been variably associated with hemostatic and fibrinolytic factor levels, but the association between alcohol consumption and the risk of incident pulmonary embolism (PE) remains uncertain. Objective To evaluate alcohol consumption amount and frequency in relation to PE risk. Methods Nurses' Health Study (NHS), NHS II and Health Professionals Follow-Up Study participants free of venous thromboembolism (VTE) at baseline (n = 217 442) reported alcohol consumption by type, quantity and frequency, every 2-4 years. Incident PE cases were identified by self-report and confirmed for participants without cancer. In this cohort study, we used Cox proportional hazards models to estimate multivariable-adjusted hazard ratios (HRs) for PE associated with alcohol consumption amount and, separately, frequency. Secondary analyses evaluated alcohol type and heavy episodic drinking in relation to PE risk, and amount and frequency in relation to medical record-confirmed idiopathic PE and any self-reported VTE risk. Cohort-specific analyses were pooled using random-effects meta-analysis. Results During ≥ 20 years of follow-up, we identified 1939 PE events. We found no strong evidence of an association between PE risk and alcohol consumption amount (pooled HRadj for 5.0-14.9 g day-1 vs. abstention = 0.97 [95% CI, 0.79, 1.20]) or frequency (pooled HRadj for 5-7 drinking days per week vs. abstention = 1.04 [95% CI, 0.88, 1.23]). Secondary analyses of type, heavy episodic drinking, idiopathic PE and VTE also yielded null findings. Conclusions Among three large prospective cohorts of US men and women, we found no evidence of an association between the amount or frequency of alcohol consumption and PE risk.

Influences of age and sex on the validity of bone scintigraphy for the diagnosis of temporomandibular joint osteoarthritis.

Bone scintigraphy has been used for the diagnosis of early-stage temporomandibular joint (TMJ) osteoarthritis (OA) owing to its high sensitivity. However, the diagnostic value of bone scintigraphy may be compromised when applied to patients in an age range with high bone metabolism rates. The aim of this study was to investigate the validity of bone scintigraphy as an appropriate diagnostic modality for TMJ OA. A total of 406 subjects (145 male, 261 female; age range 14-87 years) were selected, and all subjects underwent both bone scintigraphy and computed tomography (CT). The diagnosis of TMJ OA was confirmed with CT. Images obtained with bone scintigraphy were analyzed by visual and quantitative methods using the TMJ-to-skull ratio. The TMJ-to-skull ratio was significantly higher during adolescence and elderly adulthood, but differences between the sexes were not significant. The diagnostic value of the TMJ-to-skull ratio was lower in elderly adulthood in both males and females. The diagnostic utility of visual assessment was also compromised during late adulthood in both males and females. Thus bone scintigraphy has little value in the detection of TMJ OA, because the results could be influenced by age-related bone metabolism rates.

Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Risk factors to predict the development of chronic kidney disease in patients with lupus nephritis.

Objectives We analyzed the clinical follow-up results of 88 lupus nephritis patients to find prognostic factors for the development of chronic kidney disease in ethnically homogeneous Korean patients with biopsy-proven lupus nephritis. Methods Sociodemographic, clinical, laboratory, and treatment-related data at the time of kidney biopsy and during follow-up were obtained. Renal biopsy specimens were reclassified according to the International Society of Pathology/Renal Pathology Society classification, separately, by two renal pathologists blinded to the previous classification. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model to identify independent risk factors for chronic kidney disease in lupus nephritis patients. Results Eighteen of 88 patients (20.5%) developed chronic kidney disease during a mean follow-up of 47.6 months (range: 12-96 months). Patients who developed chronic kidney disease were older at onset of lupus nephritis, had less education, and were more likely to have hypertension; they had lower serum albumin levels, lower platelet levels, higher serum creatinine levels, lower estimated glomerular filtration rate, higher chronicity index, and lower frequency of anti-ribosomal P antibodies, and they were less likely to be in complete remission in the first year. In stepwise multivariable analyses, hypertension, lower glomerular filtration rate, and failure to achieve complete remission in the first year of treatment were significant predictors of the development of chronic kidney disease in lupus nephritis patients. Conclusions These findings suggest that patients with hypertension and decreased kidney function at the onset of lupus nephritis and showing a poor response to immunosuppressive drugs in the first year should be monitored carefully and managed aggressively to avoid deterioration of kidney function.

Polycystic ovary syndrome with hyperandrogenism as a risk factor for non-obese non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with polycystic ovary syndrome (PCOS). However, most studies investigated the prevalence of NAFLD in obese PCOS patients. AIM: To compare the prevalence of non-obese NAFLD in women with or without PCOS, and to assess an independent association between PCOS and NAFLD in a non-obese Asian cohort. METHODS: This was a case-control study using a prospective PCOS cohort. After subjects with other potential causes of chronic liver disease were excluded, 275 non-obese women with PCOS and 892 non-obese controls were enrolled. NAFLD was determined by hepatic ultrasonography. Main outcomes were the prevalence of NAFLD on hepatic ultrasonography between non-obese women with or without PCOS, and an independent association between non-obese NAFLD and PCOS. RESULTS: Non-obese women with PCOS had a significantly higher prevalence of NAFLD than those without PCOS (5.5% vs. 2.8%, P = 0.027). PCOS was associated with non-obese NAFLD (odds ratio: 2.62, 95% confidence intervals: 1.25-5.48) after adjustment for age and body mass index (BMI). In women with PCOS, the level of androgenicity represented by free testosterone or free androgen index was associated with NAFLD after adjustment for age, BMI, lipid profile, insulin resistance or glycaemic status. CONCLUSIONS: Non-obese NAFLD is more prevalent in women with polycystic ovary syndrome than in those without. In non-obese patients with polycystic ovary syndrome, hyperandrogenemia may be an independent risk factor for non-obese NAFLD.