Health-related quality of life in advanced gastric/gastroesophageal junction cancer with second-line pembrolizumab in KEYNOTE-061.

BACKGROUND: In the primary analysis population (i.e., PD-L1 combined positive score [CPS] ≥ 1) of the phase 3 KEYNOTE-061 study (NCT02370498), pembrolizumab did not significantly prolong overall survival or progression-free survival. Pembrolizumab had a favorable safety profile in the all-patient population. We present results of prespecified health-related quality of life (HRQoL) analyses. METHODS: HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ gastric cancer questionnaire (QLQ-STO22), and EuroQol 5-dimension, 3-level questionnaire (EQ-5D-3L). Data were analyzed from patients who received ≥ 1 dose of study treatment and who completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 12 least-squares mean (LSM) change in global health status (GHS)/QoL, functional/symptom subscales, and time to deterioration (TTD; ≥ 10-point decrease from baseline) for specific subscales. RESULTS: The HRQoL population included 371 patients (pembrolizumab, n = 188; paclitaxel, n = 183). Compliance and completion rates for all 3 questionnaires were similar in both groups at baseline and week 12. There was no difference in LSM change between groups (- 3.54; 95% CI - 8.92 to 1.84) in GHS/QoL at week 12. LSM change from baseline to week 12 for most QLQ-C30, QLQ-STO22, and EQ-5D-3L subscales indicated some worsening of QoL in both groups. TTD for GHS/QoL, nausea/vomiting, and appetite loss subscales in QLQ-C30 and the pain subscales in QLQ-STO22 were similar between treatment groups. CONCLUSIONS: In this population with advanced gastric and GEJ cancer receiving second-line treatment, HRQoL was similar in patients receiving pembrolizumab and those receiving paclitaxel. CLINICAL TRIAL REGISTRY AND NUMBER: ClinicalTrials.gov, NCT02370498.

A nonparametric method for value function guided subgroup identification via gradient tree boosting for censored survival data.

In randomized clinical trials with survival outcome, there has been an increasing interest in subgroup identification based on baseline genomic, proteomic markers, or clinical characteristics. Some of the existing methods identify subgroups that benefit substantially from the experimental treatment by directly modeling outcomes or treatment effect. When the goal is to find an optimal treatment for a given patient rather than finding the right patient for a given treatment, methods under the individualized treatment regime framework estimate an individualized treatment rule that would lead to the best expected clinical outcome as measured by a value function. Connecting the concept of value function to subgroup identification, we propose a nonparametric method that searches for subgroup membership scores by maximizing a value function that directly reflects the subgroup-treatment interaction effect based on restricted mean survival time. A gradient tree boosting algorithm is proposed to search for the individual subgroup membership scores. We conduct simulation studies to evaluate the performance of the proposed method and an application to an AIDS clinical trial is performed for illustration.

Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.

BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastro-oesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine. METHODS: This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498. FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. INTERPRETATION: Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Quantitative proteomic analysis for novel biomarkers of buccal squamous cell carcinoma arising in background of oral submucous fibrosis.

BACKGROUND: In South and Southeast Asian, the majority of buccal squamous cell carcinoma (BSCC) can arise from oral submucous fibrosis (OSF). BSCCs develop in OSF that are often not completely resected, causing local relapse. The aim of our study was to find candidate protein biomarkers to detect OSF and predict prognosis in BSCCs by quantitative proteomics approaches. METHODS: We compared normal oral mucosa (NBM) and paired biopsies of BSCC and OSF by quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to discover proteins with differential expression. Gene Ontology and KEGG networks were analyzed. The prognostic value of biomarkers was evaluated in 94 BSCCs accompanied with OSF. Significant associations were assessed by Kaplan-Meier survival and Cox-proportional hazards analysis. RESULTS: In total 30 proteins were identified with significantly different expression (false discovery rate < 0.05) among three tissues. Two consistently upregulated proteins, ANXA4 and FLNA, were validated. The disease-free survival was negatively associated with the expression of ANXA4 (hazard ratio, 3.4; P = 0.000), FLNA (hazard ratio, 2.1; P = 0.000) and their combination (hazard ratio, 8.8; P = 0.002) in BSCCs. CONCLUSION: The present study indicates that iTRAQ quantitative proteomics analysis for tissues of BSCC and OSF is a reliable strategy. A significantly up-regulated ANXA4 and FLNA could be not only candidate biomarkers for BSCC prognosis but also potential targets for its therapy.

[Application of the nasolabial fold "smile" incision approach in posterior buccal cancer ablation].

OBJECTIVE: This study investigated the feasibility and clinical result of radical resection of posterior buccal carcinoma by using the facial nasolabial fold "smile" incision approach. METHODS: From August 2016 to March 2017, 23 patients with posterior buccal carcinoma were included in this study and underwent radical surgery. Upon finishing the cervical lymph node dissection, an arc-shaped incision was made at 1 cm lateral to the ipsilateral angulus oris, extending along the nasolabial fold upward to the inferolateral margin of the nasal alar while downward in direct continuity with the neck dissection incision. RESULTS: Satisfactory exposure and easy resection of the primary tumor with negative surgical margin were achieved in all 23 patients. After 12-22 months of follow-up (16.5 months on average), all patients recovered favorably, and no local recurrence or distant metastasis was observed. Mouth opening was restored to normal in all cases. The scars were hidden in the nasolabial fold, thus named "smile" incision. CONCLUSIONS: For posterior buccal cancer patients, the facial "smile" incision approach can satisfy the need of surgical exposure, facilitate operative performance, and preserve the annular integrity of the lips without affecting the radical tumor ablation, thereby maintaining a favorable mouth opening. With these advantages, the "smile" incision approach is considered worthy of being popularized in clinical application.

[BIPADDLED SPLIT PECTORALIS MAJOR MYOCUTANEOUS FLAPS FOR IMMEDIATE RECONSTRUCTION OF ORAL MUCOSAL DEFECTS AND NECK DEFECTS AFTER RESECTION OF RECURRENT ORAL CANCER].

OBJECTIVE: To investigate the feasibility of the bipaddled split pectoralis major myocutaneous flap for immediate reconstruction of oral mucosal defects and neck defects after resection of recurrent oral cancer. METHODS: Six patients with oral mucosal defects combined with neck defects after recurrent oral cancer resection were treated with bipaddled split pectoralis major myocutaneous flap between September 2013 and September 2014. There were 5 males and 1 female with an average age of 54.7 years (range, 45-62 years), including 4 cases of recurrent tongue cancer, 1 case of recurrent mandibular gingival cancer, and 1 case of mouth floor carcinoma. All patients underwent local recurrence at 8 to 14 months after first operation, with no distant metastasis. The defects of the intraoral mucosa was 4.0 cm x 2.5 cm to 6.5 cm x 3.5 cm and the defect of the neck skin was 5.5 cm x 3.5 cm to 7.5 cm x 5.0 cm. The pectoralis major myocutaneous flaps (14.0 cm x 3.5 cm to 17.0 cm x 5.5 cm) were incised at the level of the 3rd to the 4th rib, and then split down along the muscle fiber till about 2 cm away from the thoracoacromial vessels, forming 2 independent skin paddles with 1-2 branch vessels to the pedicles of the distal ones. The distal skin paddles were used for oral reconstruction while the proximal paddles for repair of neck defects. The chest donor sites were sutured directly. RESULTS: Cervical haematoma and infection happened in 1 patient respectively after operation, and were cured after symptomatic treatment. All 6 split pectoralis major myocutaneous flaps with 12 skin paddles completely survived. All patients were followed up 6 to 18 months (mean, 11 months). One patient died of pulmonary metastasis at 8 months after operation and the other 5 survived without relapse or metastasis during follow-up. The intraoral paddles showed good shape with satisfactory speech function and swallowing recovery. The paddles also healed perfectly on the neck with flat outlooks, and all patients obtained full appearance and free movement of the neck. No fistula formed on the submandibular region and neck. CONCLUSION: The bipaddled split pectoralis major myocutaneous flap can complete simultaneous immediate reconstruction of oral mucosal defect and neck defect. It is very useful in the treatment of recurrent oral cancer.

Multipaddled anterolateral thigh chimeric flap for reconstruction of complex defects in head and neck.

The anterolateral thigh flap has been the workhouse flap for coverage of soft-tissue defects in head and neck for decades. However, the reconstruction of multiple and complex soft-tissue defects in head and neck with multipaddled anterolateral thigh chimeric flaps is still a challenge for reconstructive surgeries. Here, a clinical series of 12 cases is reported in which multipaddled anterolateral thigh chimeric flaps were used for complex soft-tissue defects with several separately anatomic locations in head and neck. Of the 12 cases, 7 patients presented with trismus were diagnosed as advanced buccal cancer with oral submucous fibrosis, 2 tongue cancer cases were found accompanied with multiple oral mucosa lesions or buccal cancer, and 3 were hypopharyngeal cancer with anterior neck skin invaded. All soft-tissue defects were reconstructed by multipaddled anterolateral thigh chimeric flaps, including 9 tripaddled anterolateral thigh flaps and 3 bipaddled flaps. The mean length of skin paddle was 19.2 (range: 14-23) cm and the mean width was 4.9 (range: 2.5-7) cm. All flaps survived and all donor sites were closed primarily. After a mean follow-up time of 9.1 months, there were no problems with the donor or recipient sites. This study supports that the multipaddled anterolateral thigh chimeric flap is a reliable and good alternative for complex and multiple soft-tissue defects of the head and neck.

[Clinical application of heterogeneous acellular dermal matrix in the surgical treatment of oral submucous fibrosis].

PURPOSE: The aim of this study was to evaluate the clinical effect of heterogeneous acellular dermal matrix in the surgical treatment of advanced oral submucous fibrosis (OSF). METHODS: There were eight patients who had undergone surgical treatment of trismus caused by OSF. Surgery was performed under general anaesthesia given through a nasoendotracheal tube using a fibreoptic bronchoscope. All the fibrous bands on the buccal mucosa were incised and bluntly dissected to stretch the mouth opening. Based on the defect, heterogeneous acellular dermal matrix graft was applied directly on the bilateral wounds. A tie-over dressing technique was used to hold the graft firmly to its bed.The sutures and dressing material were removed on the tenth to fourteenth day after the operation. All the patients were asked to stretch the mouth opening 3 times daily and were followed up for at least 6 months. A modality of medical treatment including multiple micronutrient supplements and steroid injection therapy were carried out if necessary. The changes in the interincisal distances (IDs) were analyzed in the preoperative, intraoperative, and postoperative stages. The data was analyzed with SPSS16.0 software package for one-way ANOVA. RESULTS: The overall success rate was 100% without any or only partial graft loss. There were no immunologic reactions or significant complications.The mean preoperative, intraoperative, and final follow-up interincisal distances were 12.04, 35.46, and 29.33 mm, respectively. Evaluation of the changes in the IDs revealed statistically significant differences between the values recorded at the different stages.(P<0.05). CONCLUSIONS: Heterogeneous acellular dermal matrix may be a valuable biomaterial for repairing oral mucosal defects after surgery on the fibrous bands in patients with advanced OSF through covering and protecting wound surface early,which shortens the healing time of wound, decreases relapse of fibrosis and improve the restricted mouth opening.

[Reconstruction of oral and maxillofacial defects using free anterolateral thigh flaps in patients with malignant tumors].

PURPOSE: To explore the value of free anterolateral thigh flaps in the reconstruction of oral and maxillofacial defects following radical resection of malignant tumors. METHODS: Seventy-six cases of oral and maxillofacial malignant tumor from December 2007 to June 2009, including 32 tongue carcinomas, 16 buccal carcinomas, 10 carcinomas of floor of mouth, 9 gingival carcinomas, 8 oropharyngeal carcinomas and 1 skin carcinoma, underwent radical resection. Free anterolateral thigh flaps were used to reconstruct the defects. The postoperative effect and flap success rate were evaluated. RESULTS: Among 76 cases, 74 flaps survived completely with satisfied configuration, only 2 flaps had complete necrosis. The survival rate was 97.3%. No complications were observed in the donor site. CONCLUSIONS: The free anterolateral thigh flap is an ideal choice for reconstruction of oral and maxillofacial defects, as it has many advantages such as reliable blood supply, large size available, and little donor site morbidity.

[Construction of eukaryotic expression vector of major histocompatibility complex class I -related chain A and establishment of its stable transfected Tca8113-Tb cell line].

OBJECTIVE: To construct the eukaryotic expression vector, encoding major histocompatibility complex class I-related chain A gene (MICA), for the further research of transfecting Tca8113-Tb cell line(a metastatic cell line of brain metastasis from human tongue cancer Tca8113 cells in nude mouse), and to establish a stable MICA overexpression oral squamous cell line. METHODS: cDNA of MICA gene from pCMV-SPORT6-MICA was amplified by PCR, and subcloned into eukaryotic expression vector pEGFP-N1 marked with green fluorescent protein (GFP). The recombinant plasmid was sequenced and transfected into Tca8113-Tb cell line by lipofectamine 2000. After screen culture by G418, stable tranfected Tca8113-Tb cell line was established using definite dilution method. The expressions of GFP protein was viewed directly with fluorescence microscopy and the overexpression of MICA was identified by RT-PCR, real time PCR and immunocytochemistry. RESULTS: The MICA gene was amplified by PCR and then cloned into the vector, whose sequence was identical to that in the GenBank. The transfected cells showed the expression of GFP. And the overexpression of MICA gene in transfected cells was detected by RT-PCR, real time PCR and immunocytochemistry. CONCLUSION: The recombinant eukaryotic expression vector pEGFP-N1-MICA has been constructed successfully and stably expressed in Tca8113-Tb cell line, providing a foundation for further studies on the function of MICA in vitro.

[Molecules of G(2)/M phase and the phosphorylation of survivin in the carcinogenesis of oral submucosal fibrosis].

OBJECTIVE: To determine the expression of Cyclin B1, p34(cdc2) and the phosphorylation of survivin (p-survivin) in oral squamous cell carcinoma and oral submucosa fibrosis (OSF), and to discuss their possible role in carcinogenesis of OSF. METHODS: The expression of Cyclin B1, p34(cdc2) and p-survivin were analyzed by Western blotting assay in 10 cases of normal oral mucosa epithelium, 40 cases of OSF epithelium and 42 cases of oral squamous cell carcinoma (OSCC) originated from OSF, respectively. Immunoprecipitation was used to confirm the relationship between the p34(cdc2) and survivin. RESULTS: The expression of Cyclin B1, p34(cdc2), p-p34(cdc2) and p-survivin in OSF group were significantly higher than those in normal group (P < 0.05). The expression of these molecules showed significant different (P < 0.05) between the OSF and OSCC originated from OSF, but there was no significant difference among the early stage, the moderately advanced stage and the advanced stage of OSF. Immunoprecipitation assay confirmed the combination of p34(cdc2) and survivin. CONCLUSIONS: The important molecules in G(2)/M phase-Cyclin B1, p34(cdc2) and p-survivin may play a key role during the mitosis and proliferation of OSF, which will be helpful in early diagnosis and therapy of carcinogenesis of OSF.