Clinical decision pathway and management of locally advanced head and neck squamous cell carcinoma: A multidisciplinary consensus in Asia-Pacific.

OBJECTIVES: To develop consensus on patient characteristics and disease-related factors considered in deciding treatment approaches for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) based on real-world treatment patterns in 4 territories in Asia-Pacific. METHODS: A three-round modified Delphi involving a multidisciplinary panel of HN surgeons, medical oncologists, and radiation oncologists was used. Of 41 panelists recruited, responses of 26 from Australia, Japan, Singapore, and Taiwan were analyzed. All panelists had ≥five years' experience managing LA-HNSCC patients and treated ≥15 patients with LA-HNSCC annually. RESULTS: All statements on definitions of LA-HNSCC, treatment intolerance and cisplatin dosing reached consensus. 4 of 7 statements on unresectability, 2 of 4 on adjuvant chemoradiotherapy, 7 of 13 on induction chemotherapy, 1 of 8 on absolute contraindications and 7 of 11 on relative contraindications to high-dose cisplatin did not reach consensus. In all territories except Taiwan, high-dose cisplatin was preferred in definitive and adjuvant settings for patients with no contraindications to cisplatin; weekly cisplatin (40 mg/m2) preferred for patients with relative contraindications to high-dose cisplatin. For Taiwan, the main treatment option was weekly cisplatin. For patients with absolute contraindications to cisplatin, carboplatin ± 5-fluorouracil or radiotherapy alone were preferred alternatives in both definitive and adjuvant settings. CONCLUSION: This multidisciplinary consensus provides insights into management of LA-HNSCC in Asia-Pacific based on patient- and disease-related factors that guide selection of treatment modality and systemic treatment. Despite strong consensus on use of cisplatin-based regimens, areas of non-consensus showed that variability in practice exists where there is limited evidence.

A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma.

Novel neoadjuvant therapy regimens are warranted for oral squamous cell carcinoma (OSCC). In this phase I trial (NCT04393506), 20 patients with locally advanced resectable OSCC receive three cycles of camrelizumab (200 mg, q2w) and apatinib (250 mg, once daily) before surgery. The primary endpoints are safety and major pathological response (MPR, defined as ≤10% residual viable tumour cells). Secondary endpoints include 2-year survival rate and local recurrence rate (not reported due to inadequate follow-up). Exploratory endpoints are the relationships between PD-L1 combined positive score (CPS, defined as the number of PD-L1-stained cells divided by the total number of viable tumour cells, multiplied by 100) and other immunological and genomic biomarkers and response. Neoadjuvant treatment is well-tolerated, and the MPR rate is 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃10 achieve MPR. Post-hoc analysis show 18-month locoregional recurrence and survival rates of 10.5% (95% CI: 0%-24.3%) and 95% (95% CI: 85.4%-100.0%), respectively. Patients achieving MPR show more CD4+ T-cell infiltration than those without MPR (P = 0.02), and decreased CD31 and ɑ-SMA expression levels are observed after neoadjuvant therapy. In conclusion, neoadjuvant camrelizumab and apatinib is safe and yields a promising MPR rate for OSCC.

Transplantation of oligodendrocyte precursor cells improves locomotion deficits in rats with spinal cord irradiation injury.

Demyelination contributes to the functional impairment of irradiation injured spinal cord. One potential therapeutic strategy involves replacing the myelin-forming cells. Here, we asked whether transplantation of Olig2(+)-GFP(+)-oligodendrocyte precursor cells (OPCs), which are derived from Olig2-GFP-mouse embryonic stem cells (mESCs), could enhance remyelination and functional recovery after spinal cord irradiation injury. We differentiated Olig2-GFP-mESCs into purified Olig2(+)-GFP(+)-OPCs and transplanted them into the rats' cervical 4-5 dorsal spinal cord level at 4 months after irradiation injury. Eight weeks after transplantation, the Olig2(+)-GFP(+)-OPCs survived and integrated into the injured spinal cord. Immunofluorescence analysis showed that the grafted Olig2(+)-GFP(+)-OPCs primarily differentiated into adenomatous polyposis coli (APC(+)) oligodendrocytes (54.6±10.5%). The staining with luxol fast blue, hematoxylin & eosin (LFB/H&E) and electron microscopy demonstrated that the engrafted Olig2(+)-GFP(+)-OPCs attenuated the demyelination resulted from the irradiation. More importantly, the recovery of forelimb locomotor function was enhanced in animals receiving grafts of Olig2(+)-GFP(+)-OPCs. We concluded that OPC transplantation is a feasible therapy to repair the irradiated lesions in the central nervous system (CNS).

Impact of lymph node ratio on the survival of patients with hypopharyngeal squamous cell carcinoma: a population-based analysis.

OBJECTIVE: To analyze the impact of the lymph node ratio (LNR, ratio of metastatic to examined nodes) on the prognosis of hypopharyngeal cancer patients. METHODS: SEER (Surveillance, Epidemiology and End Results)-registered hypopharyngeal cancer patients with lymph node metastasis were evaluated using multivariate Cox regression analysis to identify the prognostic role of the LNR. The categorical LNR was compared with the continuous LNR and pN classifications to predict cause-specific survival (CSS) and overall survival (OS) rates of hypopharyngeal cancer patients. RESULTS: Multivariate analysis of 916 pN+ hypopharyngeal cancer cases identified race, primary site, radiation sequence, T classification, N classification, M classification, the number of regional lymph nodes examined, the continuous LNR (Hazard ratio 2.415, 95% CI 1.707-3.416, P<0.001) and age as prognostic variables that were associated with CSS in hypopharyngeal cancer. The categorical LNR showed a higher C-index and lower Akaike information criterion (AIC) value than the continuous LNR. When patients (n = 1152) were classified into four risk groups according to LNR, R0 (LNR = 0), R1 (LNR ≤ 0.05), R2 (LNR 0.05-0.30) and R3 (LNR >0.30), the Cox regression model for CSS and OS using the R classification had a higher C-index value and lower AIC value than the model using the pN classification. Significant improvements in both CSS and OS were found for R2 and R3 patients with postoperative radiotherapy. CONCLUSIONS: LNR is a significant prognostic factor for the survival of hypopharyngeal cancer patients. Using the cutoff points 0.05/0.30, the R classification was more accurate than the pN classification in predicting survival and can be used to select high risk patients for postoperative treatment.

In vitro and in vivo studies on radiobiological effects of prolonged fraction delivery time in A549 cells.

Intensity-modulated radiation therapy, when used in the clinic, prolongs fraction delivery time. Here we investigated both the in vivoand in vitroradiobiological effects on the A549 cell line, including the effect of different delivery times with the same dose on A549 tumor growth in nude mice. The in vitroeffects were studied with clonogenic assays, using linear-quadratic and incomplete repair models to fit the dose-survival curves. Fractionated irradiation of different doses was given at one fraction per day, simulating a clinical dose-time-fractionation pattern. The longer the interval between the exposures, the more cells survived. To investigate the in vivoeffect, we used sixty-four nude mice implanted with A549 cells in the back legs, randomly assigned into eight groups. A 15 Gy radiation dose was divided into different subfractions. The maximum and minimum tumor diameters were recorded to determine tumor growth. Tumor growth was delayed for groups with prolonged delivery time (40 min) compared to the group receiving a single dose of 15 Gy (P< 0.05), and tumors with a 20 min delivery time had delayed growth compared to those with a 40 min delivery time [20' (7.5 Gy × 2 F) vs 40' (7.5 Gy × 2 F), P= 0.035; 20' (3 Gy × 5 F) vs 40' (3 Gy × 5 F); P= 0.054; 20' (1.67 Gy × 9 F) vs 40' (1.67 Gy × 9 F), P= 0.028]. A prolonged delivery time decreased the radiobiological effects, so we strongly recommend keeping the delivery time as short as possible.

[Clinical analysis of nimotuzumab plus cisplatin and fluorouracil regimen as induction treatment in resectable head and neck squamous cell carcinoma].

OBJECTIVE: A phase II study was conducted to test the efficacy and toxicity of the combination of cisplatin, 5-Fu and nimotuzumab, as induction treatment of resectable head and neck squamous cell carcinoma (HNSCC). METHODS: Forty cases of resectable HNSCC were treated with nimotuzumab (400 mg on day 1) combined with PF regimens (cisplatin 75 mg/m² on days 1 and 5-Fu 750 mg/m² on days 1-5 q3wks). After 2 cycles, an organ-preservation local therapy (surgery or radiotherapy) was recommended. The primary endpoints of this study were overall response rate, pathologic complete response and safety of the induction treatment. Mean age of 40 patients was 54 years old, of them 9 patients with oropharyngeal cancer (22.5%), 16 hypopharyngeal cancer (40.0%), 10 laryngeal cancer (25.0%), and 5 oral cancer (12.5%). RESULTS: With a 2-cycle induction treatment, 34 (85.0%) patients achieved complete or partial response. Twenty-four patients (60.0%) got downstage, with T downstage in 21 (52.5%) patients and N downstage in 8 (20.0%) patients. Totally 27 patients got surgery after the induction treatment, of them 20 patients (74.1%) preserved organ functions. Four patients' primary tumors (10.0% in all 40 patients and 14.8% in operated 27 patients) showed pathologically complete responses. The toxicity was mild and manageable. The most common grade 3/4 toxicities were neutropenia (5.0%), nausea/vomiting (2.5%), stomatitis (2.5%) and thrombocytopenia (2.5%). One patient got grade 2 renal insufficiency and one patient got grade 1 skin rash. CONCLUSION: For resectable HNSCC, nimotuzumab plus PF regimen as induction treatment is highly effective for preserving the organ function and the toxicities are well tolerable.

Predictive index for lymph node management of major salivary gland cancer.

OBJECTIVES/HYPOTHESIS: To find the risk factors of lymph node (LN) metastasis of salivary gland cancer and draw a scheme for LN management. STUDY DESIGN: Hospital-based retrospective study. METHODS: The records of salivary gland cancer patients treated at the Department of Head and Neck Surgery, Cancer Hospital, Fudan University, were entered in a database, and 219 consecutive patients with carcinomas of major salivary glands primarily operated on between January 1998 and January 2011 were chosen for univariate and multivariate analysis to identify risk factors for LN involvement. RESULTS: Fifty-eight (26.5%) patients had LN involvement. Factors associated with cervical LN involvement on univariate analysis included pathologic type, male sex, shorter duration of preoperative course, facial paralysis, advanced T stage, and major nerve, soft tissue, lymphatic/vascular (L/V), neural/perineural, and extracapsular invasion. Multivariate analysis identified major nerve invasion, histologic type, L/V invasion, and extracapsular invasion as significant factors for LN involvement. The proportion of patients with LN involvement with low (105), middle (61), high (34), and super high (19) predictive index scores based on the four risk factors were 3.8%, 27.9%, 55.9%, and 94.7%, respectively. CONCLUSIONS: A predictive index using the clinicopathologic factors described in this report can effectively stratify patients into risk groups for nodal metastasis. Comprehensive management based on this risk index should improve treatment outcomes for patients with salivary gland cancer.

Comparison of the NCI-CTCAE version 4.0 and version 3.0 in assessing chemoradiation-induced oral mucositis for locally advanced nasopharyngeal carcinoma.

To compare the role of CTCAE version 4.0 (v4.0) and version 3.0 (v3.0) in assessing chemoradiation-induced oral mucositis (OM) for locally advanced nasopharyngeal carcinoma (LA-NPC). Patients with LA-NPC were recruited into the study. All eligible participants received docetaxel and cisplatin-based induction chemotherapy followed by intensity modulated radiation therapy concurrent with cisplatin. OM was assessed before and weekly during radiotherapy (RT), using CTCAE v3.0 (clinical exam) and v4.0 separately. OM-related quality of life (QOL) was also evaluated in these patients with the EORTC Quality of Life Questionnaire - Head and Neck module (QLQ-H&N35). From June 2010 to February 2011, 23 eligible patients were enrolled. A highly significant correlation (rho=0.838, p=0.000) and a non-significant difference (p=0.167) in OM grades were found between the two CTCAE versions. However, the trend lines showed that the mean grade determined by CTCAE v3.0 reached a plateau while the mean grade determined by v4.0 continued to increase after the fourth week during RT. Changing trends of several QOL subscale mean scores were similar to that of OM mean grade evaluated by CTCAE v4.0. Both grades of the two CTCAE versions were significantly and positively correlated with scores of several QOL subscales. Nonetheless, the correlation coefficients related to CTCAE v4.0 were higher than those related to v3.0 (rho: 0.727-0.865 versus 0.727-0.778). CTCAE v4.0 could serve as a good surrogate for v3.0 (clinical exam) in assessing chemoradiation-induced oral mucositis. Moreover, CTCAE v4.0 has a few subtle advantages over v3.0 under some circumstances such as delegating QOL. However, there is still no "gold standard" assessment scale for oral mucositis. Therefore, the appropriate tool should be carefully chosen according to the purpose of assessment.

The in vivo study on the radiobiologic effect of prolonged delivery time to tumor control in C57BL mice implanted with Lewis lung cancer.

BACKGROUND: High-precision radiation therapy techniques such as IMRT or sterotactic radiosurgery, delivers more complex treatment fields than conventional techniques. The increased complexity causes longer dose delivery times for each fraction. The purpose of this work is to explore the radiobiologic effect of prolonged fraction delivery time on tumor response and survival in vivo. METHODS: 1-cm-diameter Lewis lung cancer tumors growing in the legs of C57BL mice were used. To evaluate effect of dose delivery prolongation, 18 Gy was divided into different subfractions. 48 mice were randomized into 6 groups: the normal control group, the single fraction with 18 Gy group, the two subfractions with 30 min interval group, the seven subfractions with 5 min interval group, the two subfractions with 60 min interval group and the seven subfractions with 10 min interval group. The tumor growth tendency, the tumor growth delay and the mice survival time were analyzed. RESULTS: The tumor growth delay of groups with prolonged delivery time was shorter than the group with single fraction of 18 Gy (P < 0.05). The tumor grow delay of groups with prolonged delivery time 30 min was longer than that of groups with prolonged delivery time 60 min P < 0.05). There was no significant difference between groups with same delivery time (P > 0.05). Compared to the group with single fraction of 18 Gy, the groups with prolonged delivery time shorten the mice survival time while there was no significant difference between the groups with prolonged delivery time 30 min and the groups with prolonged delivery time 60 min. CONCLUSIONS: The prolonged delivery time with same radiation dose shorten the tumor growth delay and survival time in the mice implanted with Lewis lung cancer. The anti-tumor effect decreased with elongation of the total interfractional time.

Paclitaxel with cisplatin in concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma.

The aim of this study was to evaluate the efficacy and the toxicity of paclitaxel and cisplatin in patients in concurrent radiotherapy for locally advanced nasopharyngeal carcinoma, and to see whether such a regime would be better tolerated than high dose cisplatin plus fluoracil in Chinese patients. Thirty-one patients with locally advanced nasopharyngeal carcinoma were enrolled. Patients were scheduled to receive two courses of concomitant chemotherapy, starting on day 1 and then day 28 during radiotherapy (70-76 Gy in 35-38 fractions in 7-7.5 weeks). Chemotherapy was given by intravenous infusion, paclitaxel 120 mg/m(2) in 3 h, cisplatin 75 mg/m(2) (25 mg/m(2) days 1-3). Adjuvant therapy was paclitaxel 135 mg/m(2) in 3 h, cisplatin 75 mg/m(2) (25 mg/m(2) days 1-3) on weeks 3, 6, 9 after radiotherapy. All patients completed radiotherapy, but for concomitant chemoradiotherapy, 20 of the 31 patients completed the 2 cycles of chemotherapy, while the other 11 could only receive 1 cycle due to various reasons. The median follow-up was 40 months, 2 patients developed locoregional recurrences, one of whom in the cervical lymph nodes, the other in the nasopharynx. The 3-year overall survival rate was 83.9% and the distant metastasis rate at 3 years was 13.6%. Grade 3-4 toxicities were neutropenia 12.9%, anaemia 6.45%, thrombocytopenia 3.22%, severe arrhythmia 3.2%, and hypersensitivity reaction 3.2%. In conclusion, paclitaxel with cisplatin as concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma is feasible, safe, and might improve regional control and survival rates in Chinese patients.

The correlation evaluation of a tumor tracking system using multiple external markers.

The purpose of this study is to evaluate the correlations between external markers and internal targets for radiation therapy of lung cancer patients. Using an infrared camera system coupled with a clinical simulator, the simultaneous motions of multiple external markers and an internal target were obtained. The correlation between external and internal signals was analyzed using a cross-covariance function. A linear regression model was employed to generate a composite signal from multiple external markers in order to predict the internal target motion. The external and internal signals, and their correlations, demonstrated a wide range of variation with respect to marker location, motion dimension, and breathing pattern. The performance of the composite signal indicates that when more external signals were taken into account, the mean correlation between the composite signal and internal signal was improved. This implies that a combination of multiple external signals might be an improved way to predict internal target motion. Also, since the characteristics of respiratory signals can vary significantly, certain methods of preprocessing and external signal combination are necessary.

Adaptive prediction of internal target motion using external marker motion: a technical study.

An adaptive prediction approach was developed to infer internal target position by external marker positions. First, a prediction model (or adaptive neural network) is developed to infer target position from its former positions. For both internal target and external marker motion, two networks with the same type are created. Next, a linear model is established to correlate the prediction errors of both neural networks. Based on this, the prediction error of an internal target position can be reconstructed by the linear combination of the prediction errors of the external markers. Finally, the next position of the internal target is estimated by the network and subsequently corrected by the reconstructed prediction error. In a similar way, future positions are inferred as their previous positions are predicted and corrected. This method was examined by clinical data. The results demonstrated that an improvement (10% on average) of correlation between predicted signal and real internal motion was achieved, in comparison with the correlation between external markers and internal target motion. Based on the clinical data (with correlation coefficient 0.75 on average) observed between external marker and internal target motions, a prediction error (23% on average) of internal target position was achieved. The preliminary results indicated that this method is helpful to improve the predictability of internal target motion with the additional information of external marker signals. A consistent correlation between external and internal signals is important for prediction accuracy.

The change of adrenergic receptor-adenyl cyclase system on myocardial ischemic preconditioning in rats / 中国应用生理学杂志

<p><b>AIM</b>To study the varies and effects of ischemic preconditioning of myocardium on every part of adrenergic receptor-adenyl cyclase system in rats in vivo.</p><p><b>METHODS</b>SD rats were randomly divided into three groups: CON group (n = 6), IP group (n = 12) and I/R group (n = 12). Surgical procedure included intermittent left coronary artery occlusion and reperfusion. After the procedure, the hearts were extracted. We analyzed the infarct size by TTC staining, measured serum myocardial enzymes, studied the beta-AR Bmax and KD by radioligand binding assay of receptors (RAB), and checked the activity of AC and the content of cAMP by radioimmunoassay (RIA).</p><p><b>RESULTS</b>Infarct area were much smaller in IP group than in I/R group (P < 0.05). CK, CK-MB, LDH were significantly higher in I/R group (P < 0.01). The Bmax of beta-AR in IP group were much higher than in I/R group (P < 0.01). No difference of KD could be seen between IP and I/R group. In IP group, the activity of AC and the content of cAMP were higher than I/R group (P < 0.05).</p><p><b>CONCLUSION</b>Ischemic preconditioning can protect the heart from necrosis and reduce endo-enzyme leakage. Ischemic preconditioning can increase the density of beta-AR, the activity of AC and the content of cAMP, which shows that the system of adrenergic receptor-adenyl cyclase system probably takes part in the protection of IP.</p>