Osimertinib has demonstrated efficacy for patients with epidermal growth factor receptor (EGFR) T790M positive non-small cell lung cancer (NSCLC) in clinical trials. However, data on the effectiveness of osimertinib in real-world settings remain scarce.

Objectives To analyze prevalence of HPV DNA, HPV genotype distribution, prognostic factors and long-term outcomes of vulvar carcinoma. Methods We retrospectively reviewed medical records of patients with vulvar carcinoma who received primary surgeries between 1985 and 2014 in a single institution. General polymerase chain reaction (PCR) SPF1/GP6+ followed by revert-blot detection was performed for human papillomavirus (HPV) genotyping. E6 type-specific PCR of the top-5 prevalent types was performed to reconfirm HPV-negative status. P16INK4a immunohistochemistry staining was performed. Univariate and multivariate analyses were performed to identify predictors of clinical outcomes of squamous cell carcinomas (SCCs). Results A total of 150 vulvar carcinoma patients eligible for analysis were retrieved. Medial follow up time was 71.4 months (0.2–341.8 months). One hundred and twenty-nine patients (86.0%) were diagnosed as SCC. In SCC specimens, HPV DNA sequences were detected in 56.6%, and 14.3% of non-SCC vulvar cancer (n = 21) were HPV positive. The leading 4 types were HPV16 (54.0%), HPV58 (15.8%), HPV52 (6.6%), and HPV18 (5.3%). HPV-positivity was associated with better 5-year cancer-specific survival (CSS) (P = 0.037). In multivariable analysis, older age (continuous, hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.03–1.08, P <0.001), advanced International Federation of Gynecology and Obstetrics (FIGO) stage (III-IV vs I-II, HR 3.86 95%CI 2.01–7.42, P <0.001) were independent adverse predictors of CSS, while p16-positivity (0.36, 95%CI 0.19–0.69, P =0.002) was related to better prognosis. Conclusion Advanced FIGO stage and older age were significant adverse predictors, while p16-positivity was a significant factor of better prognosis.

The epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism of drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The third generation irreversible EGFR inhibitor HS-10296 has been shown to be safe and effective against both EGFR TKI-sensitizing and T790M resistance mutations in preclinical studies. A Phase I, open-label, multi-center clinical trial was conducted in patients with locally advanced or distant metastatic NSCLC who have progressed following prior therapy with EGFR TKIs. The study was consisted of dose-escalation cohorts (55, 110, 220 and 260 mg) and dose-expansion cohorts (55, 110 and 220 mg) with once daily oral administration of HS-10296. In each expansion cohort, tumor biopsies were collected for central determination of EGFR T790M status. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy of HS-10296. A total of 117 patients (median age 60) received at least one dose of HS-10296 across multiple sites in China (43 patients), Taiwan (69 patients) and the United States (5 patients). Maximum tolerated dose(MTD)has not been reached in this study. The most common adverse events were grade1/2 rash, pyrexia, upper respiratory tract infection, constipation, diarrhoea and blood creatine phosphokinase elevation. Drug-related serious adverse events were anemia (0.8%), blood creatinine elevation (0.8%), anemiarhabdomyolysis (0.8%) and blood creatine phosphokinase elevation (0.8%) occurred mainly in the cohorts with higher doses at 220 mg or 260 mg, respectively. These data demonstrated favorable tolerability and safety of HS-10296 in patients enrolled. The pharmacokinetics of HS-10296 was dose proportional and the plasma half-life was 30.7∼37.5 hours. Among 82 evaluable patients (18 in escalation cohorts and 64 in expansion cohorts) with the EGFR T790M mutation, the overall objective response rate (ORR) was 52.4% (43/82; 95% CI, 41.6 to 63.3), while disease control rate (DCR) was 91.5% (75/82; 95% CI, 85.4 to 97.5). 110mg cohort showed better DCR (97.2% VS. 86.1%) than 55mg cohort. Phase II study is ongoing with the dose at 110 mg. HS-10296 has the potential to provide clinical benefit to locally advanced or distant metastatic NSCLC patients with EGFR T790M mutation who had disease progression following prior therapy with EGFR TKIs. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

BACKGROUND: Esophageal cancer is commonly treated with surgery, concurrent chemoradiotherapy (CCRT), or a combination of both. The correlation between the hematological parameters during CCRT and early survival of esophageal cancer has not been fully evaluated. MATERIALS AND METHODS: We analyzed the records of 65 esophageal cancer patients treated by CCRT between 2007 and 2010 retrospectively. The association between CCRT-associated myelosuppression, demographic variables, and survival rates were analyzed by univariate and multivariate analysis. RESULTS: The univariate analysis showed that tumor extent of T3-4, a higher stage of tumor, a lower albumin level, grade 3 or higher anemia and thrombocytopenia, and interruptions in treatment affected survival rates. Further, the multivariate analysis revealed that stage IV (P = 0.030) is an independently negative prognostic factor for a one-year survival rate. Stage IV (P = 0.035), tumor extent of T3-4 (P = 0.002), and grade 3-4 thrombocytopenia (P = 0.015) are independently negative prognostic factors for a two-year survival rate. CONCLUSIONS: Severe decrease in platelet count during CCRT independently affects survival of esophageal cancer patients in addition to stage of the tumor.

Since we found patients with adenocarcinomas/adenosquamous carcinomas (AC/ASC) of cervix primarily treated with radiotherapy (RT) had inferior outcome than those with squamous cell carcinomas (SCC), this study was aimed to investigate if same conclusion can be obtained from patients who were primarily treated with radical hysterectomy (RAH) and received adjuvant RT or concurrent chemoradiation (CCRT) due to presence of risk factors. Three hundred and eighteen FIGO IB-IIB cervical cancer patients (SCC: 202; AC/ASC: 116) treated by RAH and adjuvant RT/CCRT between 1998 and 2008 were reviewed. The indication for adjuvant RT was the presence of at least one of the following risk factors: deep stromal invasion (DSI), positive resection margin, parametrial invasion or lymph node (LN) metastasis. Adjuvant CCRT was administered in 65 (32%) patients with SCC, and in 80 (69%) with AC/ASC. The median follow-up time was 7.1 years (range, 0.6 - 13 years). The treatment failure was found in 39 (19.3%) and 39 (33.6%) patients with SCC and AC/ASC, respectively. The 5-year relapse-free survival rates for AC/ASC and SCC group were 83.4% and 66.5%, respectively (p = 0.000). Distant metastasis was the major failure pattern in both histological types. After univariate and multivariate analysis, prognostic factors for local recurrence were younger age (p = 0.014), parametrial invasion (p = 0.037), AC/ASC histology (p = 0.043) and positive resection margin (p = 0.052), and for distant recurrence were parametrial invasion (p = 0.000), LN metastasis (p = 0.001) and AC/ASC histology (p = 0.003). Patients were further stratified into high- and low- risk group; the former had the presences of parametrial invasion or LN metastasis, and the latter had only DSI or positive resection margin. Patients with AC/ASC showed significantly higher recurrence rate than those with SCC for both group. Adjuvant CCRT did not achieve better survival outcome than RT alone. Similar to that found in patients primarily treated by RT, higher recurrence rate in AC/ASC histology than in SCC histology was also found in cervical cancer patients treated by RAH and RT/CCRT. Development of effective chemotherapeutic agent to enhance radiotherapy and eradicate distant metastasis in patients with AC/ASC is needed.

This study aimed to investigate if MRI and ultrasound can be used to evaluate vascular functions during tumor development and predict responses of radiotherapy (RT) and chemotherapy. A murine cell line TRAMP C-1 grown in thigh of male C57Bl/6J mice was used as a tumor model. Vascular function was monitored at 2–3 days interval after tumor inoculation by dynamic contrast enhanced-MRI (DCE-MRI), using a 7-Tesla magnet with the contrast agent gadolinium (Gd)-DTPA, and by high frequency Power Doppler ultrasound imaging. Single-dose 25 Gy RT was given to tumors at indicated time and growth delay was measured. The drug distribution in tumors was assessed by injecting Doxorubicin (Dox), a chemotherapeutic agent with autofluorescence. The Ktrans signal obtained from DCE-MRI remained high and evenly distributed among whole tumor from Day 3 to 9. However, more than 50% decrease of mean ktrans was found after Day 9, and this decrease is more obvious in the central core than peripheral region at Day 12 and 15. In histologic examination, barely necrotic areas can be identified in tumors up to Day 15, even in the central core. The microvascular density, as recognized by anti-CD31, was not decreased and the vascular structure was well reserved among whole tumor. Flow velocity measured from color Doppler also showed higher flow in the peripheral region than core region from Day 9 to 15. The tumors were irradiated with single-dose of 25 Gy at Day 5, 7 (before functional switch), and 10 (after functional imaging), respectively. The tumor doubling time is 1.75 days for control TRAMP-C1 tumors grown in vivo; and the growth delay was 3 weeks for tumors irradiated at Day 10, but only 1 week for those irradiated at Day 7 or 5. Further studies showed the 2-week difference in growth delay between tumors irradiated at Day 10 and 7 is not solely due to the differences in cell burden; the functional switch in vascular function might play an important role. Mice were injected with DOX and concentrations of Dox were higher in tumors at Day 7 than those at Day 10. Apoptotic index after Dox treatment was also higher in tumors at Day 7 than those at Day 10. A switch of vascular function during the tumor development occurs prior to the histological changes, which can be detected by DCI-MRI and high frequency Doppler ultrasound. The time coincidence of functional switch with prolonged growth delay after RT and low drug concentration suggests it might affects tumor radiosensitivity and distribution of chemotherapeutic agent. These two imaging modalities have the potential to be clinical tools to predict radiation and chemotherapy responses.

Purpose/Objective(s)To study the prognostic value of the genotypes of human papillomavirus (HPV) in patients with advanced cervical cancer after radiotherapy with/without concurrent chemotherapy.Materials/MethodsA total of 327 patients with advanced squamous cell carcinoma of the cervix, which was defined as FIGO III/IVa or positive lymph nodes (AJCC 2002 Stage III–IVa), between August 1993 and May 2000 were eligible for this study. Their DNA was extracted from paraffin embedded specimens and used as a template for the amplification of the L1 open reading frame of HPV. Resultant amplifiers were then hybridized with the Easychip HPV Blot membrane, which detects 38 types of HPV. Data of treatment outcome were analyzed by the Kaplan-Meier survival analysis and Cox regression hazard model.ResultsA total of 22 types of HPV were detected and only 4 patients (1.2%) had negative HPV tumors. The leading 8 types were: HPV 16 (38.5%), HPV 58 (26.9%), HPV 18 (18%), HPV 33 (15.6%), HPV 39 (7%), HPV 52 (6.1%), HPV 31 (4.3%), and HPV 45 (2.1%). These types belong to two high-risk HPV species: Alpha 7 (18, 39, 45) and Alpha 9 (16, 31, 33, 52, 58). Among the 323 HPV-positive specimens, 89 (27.5%) contained two or more types of HPV. At the endpoint (July 31, 2008) of the follow-up analysis, 106 patients were still alive after a median follow-up of 35.3 months (range, 1–170 months). The 5-year overall-survival rate and disease-specific survival (DSS) rate for the entire cohort were 41.9% and 51.5%, respectively. On univariate and multivariate analysis, age, and the level of SCC-Ag were confirmed as prognostic indicators for overall survival and DSS. Concurrent cisplatin-based chemotherapy increased the 5-year DSS from 47.5% to 56.4%; however, this improvement did not achieve statistic significance (p = 0.0889). Individual HPV genotypes were not a crucial prognostic factor in patients with advanced cervical cancer. Interestingly, the benefit of combining chemotherapy with radiotherapy was only significant in patients with HPV Alpha 7 species infection. In this subgroup, the 5-year DSS for patients with chemotherapy was 60.3%, compared to 36.8% for the ones without chemotherapy (p = 0.0348). In patients without Alpha 7 species, the 5-year DSS for the ones with chemotherapy and without chemotherapy were 55.3% and 50.5% (p = 0.433), respectively. The improvement of DSS by chemotherapy mainly resulted from the better local control (5-year local control rates: 70.2% vs. 50.6%; p = 0.08); the metastasis-free rates were similar in both treatment groups (64.3% vs. 57.1%; p = 0.266).ConclusionsThe HPV genotype is a useful biomarker to predict survival benefit from concurrent chemoradiotherapy in patients with advanced squamous cell carcinoma of cervix, although it may not be a significant prognostic factor in this patient group. Purpose/Objective(s)To study the prognostic value of the genotypes of human papillomavirus (HPV) in patients with advanced cervical cancer after radiotherapy with/without concurrent chemotherapy. To study the prognostic value of the genotypes of human papillomavirus (HPV) in patients with advanced cervical cancer after radiotherapy with/without concurrent chemotherapy. Materials/MethodsA total of 327 patients with advanced squamous cell carcinoma of the cervix, which was defined as FIGO III/IVa or positive lymph nodes (AJCC 2002 Stage III–IVa), between August 1993 and May 2000 were eligible for this study. Their DNA was extracted from paraffin embedded specimens and used as a template for the amplification of the L1 open reading frame of HPV. Resultant amplifiers were then hybridized with the Easychip HPV Blot membrane, which detects 38 types of HPV. Data of treatment outcome were analyzed by the Kaplan-Meier survival analysis and Cox regression hazard model. A total of 327 patients with advanced squamous cell carcinoma of the cervix, which was defined as FIGO III/IVa or positive lymph nodes (AJCC 2002 Stage III–IVa), between August 1993 and May 2000 were eligible for this study. Their DNA was extracted from paraffin embedded specimens and used as a template for the amplification of the L1 open reading frame of HPV. Resultant amplifiers were then hybridized with the Easychip HPV Blot membrane, which detects 38 types of HPV. Data of treatment outcome were analyzed by the Kaplan-Meier survival analysis and Cox regression hazard model. ResultsA total of 22 types of HPV were detected and only 4 patients (1.2%) had negative HPV tumors. The leading 8 types were: HPV 16 (38.5%), HPV 58 (26.9%), HPV 18 (18%), HPV 33 (15.6%), HPV 39 (7%), HPV 52 (6.1%), HPV 31 (4.3%), and HPV 45 (2.1%). These types belong to two high-risk HPV species: Alpha 7 (18, 39, 45) and Alpha 9 (16, 31, 33, 52, 58). Among the 323 HPV-positive specimens, 89 (27.5%) contained two or more types of HPV. At the endpoint (July 31, 2008) of the follow-up analysis, 106 patients were still alive after a median follow-up of 35.3 months (range, 1–170 months). The 5-year overall-survival rate and disease-specific survival (DSS) rate for the entire cohort were 41.9% and 51.5%, respectively. On univariate and multivariate analysis, age, and the level of SCC-Ag were confirmed as prognostic indicators for overall survival and DSS. Concurrent cisplatin-based chemotherapy increased the 5-year DSS from 47.5% to 56.4%; however, this improvement did not achieve statistic significance (p = 0.0889). Individual HPV genotypes were not a crucial prognostic factor in patients with advanced cervical cancer. Interestingly, the benefit of combining chemotherapy with radiotherapy was only significant in patients with HPV Alpha 7 species infection. In this subgroup, the 5-year DSS for patients with chemotherapy was 60.3%, compared to 36.8% for the ones without chemotherapy (p = 0.0348). In patients without Alpha 7 species, the 5-year DSS for the ones with chemotherapy and without chemotherapy were 55.3% and 50.5% (p = 0.433), respectively. The improvement of DSS by chemotherapy mainly resulted from the better local control (5-year local control rates: 70.2% vs. 50.6%; p = 0.08); the metastasis-free rates were similar in both treatment groups (64.3% vs. 57.1%; p = 0.266). A total of 22 types of HPV were detected and only 4 patients (1.2%) had negative HPV tumors. The leading 8 types were: HPV 16 (38.5%), HPV 58 (26.9%), HPV 18 (18%), HPV 33 (15.6%), HPV 39 (7%), HPV 52 (6.1%), HPV 31 (4.3%), and HPV 45 (2.1%). These types belong to two high-risk HPV species: Alpha 7 (18, 39, 45) and Alpha 9 (16, 31, 33, 52, 58). Among the 323 HPV-positive specimens, 89 (27.5%) contained two or more types of HPV. At the endpoint (July 31, 2008) of the follow-up analysis, 106 patients were still alive after a median follow-up of 35.3 months (range, 1–170 months). The 5-year overall-survival rate and disease-specific survival (DSS) rate for the entire cohort were 41.9% and 51.5%, respectively. On univariate and multivariate analysis, age, and the level of SCC-Ag were confirmed as prognostic indicators for overall survival and DSS. Concurrent cisplatin-based chemotherapy increased the 5-year DSS from 47.5% to 56.4%; however, this improvement did not achieve statistic significance (p = 0.0889). Individual HPV genotypes were not a crucial prognostic factor in patients with advanced cervical cancer. Interestingly, the benefit of combining chemotherapy with radiotherapy was only significant in patients with HPV Alpha 7 species infection. In this subgroup, the 5-year DSS for patients with chemotherapy was 60.3%, compared to 36.8% for the ones without chemotherapy (p = 0.0348). In patients without Alpha 7 species, the 5-year DSS for the ones with chemotherapy and without chemotherapy were 55.3% and 50.5% (p = 0.433), respectively. The improvement of DSS by chemotherapy mainly resulted from the better local control (5-year local control rates: 70.2% vs. 50.6%; p = 0.08); the metastasis-free rates were similar in both treatment groups (64.3% vs. 57.1%; p = 0.266). ConclusionsThe HPV genotype is a useful biomarker to predict survival benefit from concurrent chemoradiotherapy in patients with advanced squamous cell carcinoma of cervix, although it may not be a significant prognostic factor in this patient group. The HPV genotype is a useful biomarker to predict survival benefit from concurrent chemoradiotherapy in patients with advanced squamous cell carcinoma of cervix, although it may not be a significant prognostic factor in this patient group.

Differential cross sections and photon-beam asymmetries have been measured for the gamma n -> K+Sigma(-) and gamma p -> K+Sigma(0) reactions separately using liquid deuterium and hydrogen targets with incident linearly polarized photon beams of E-gamma=1.5-2.4 GeV at 0.6 < cos Theta(K)(cm)< 1. The cross section ratio of sigma(+)(K)Sigma(-)/sigma(+)(K)Sigma(0), expected to be 2 on the basis of the isospin 1/2 exchange, is found to be close to 1. For the K+Sigma(-) reaction, large positive asymmetries are observed, indicating the dominance of K-* exchange. The large difference between the asymmetries for the K+Sigma(-) and K+Sigma(0) reactions cannot be explained by simple theoretical considerations based on Regge model calculations.