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Background: This study compares the outcome of patients suffering from medically refractory classical trigeminal neuralgia (TN) after treatment with radiosurgery using two different shot sizes (5- and 6-mm)., Methods: All patients included in this open, prospective, non-controlled study were treated in a single institution for TN (95 cases in 93 patients) with LINear ACcelerators (LINAC) single-dose radiosurgery using a 5-mm shot (43 cases) or 6-mm shot (52 cases). The target was positioned on the intracisternal part of the trigeminal nerve., Results: The mean Dmax (D0.035) to the brainstem was higher in the 6-mm group: 12.6 vs 21.3 Gy (p < 0.001). Pain relief was significantly better in the 6-mm group: at 12 and 24 months in the 6-mm group the rate of pain-free patients was 90.2 and 87.8%, respectively vs. 73.6 and 73.6% in the 5-mm group (p = 0.045). At 12 and 24 months post-radiosurgical hypoesthesia was more frequent in the 6-mm group: 47.0 and 58% vs.11.3 and 30.8% in the 5-mm group (p = 0.002). To investigate the effect of cone diameter and the dose to the brainstem on outcomes, patients were stratified into three groups: group 1 = 5-mm shot, (all Dmax < 25 Gy, 43 cases), group 2 = 6-mm shot, Dmax < 25 Gy (32 cases), group 3 = 6-mm shot Dmax > 25 Gy (20 cases). At 12 months the rates of hypoesthesia were 11.3, 33.5 and 76.0%, respectively in groups 1, 2 and 3 (p < 0.001) and the rates of recurrence of pain were 26.4, 16.5 and 5%, respectively, (p = 0.11)., Conclusion: LINAC treatment with a 6-mm shot provided excellent control of pain, but increased the rate of trigeminal nerve dysfunction, especially when the maximum dose to the brainstem was higher than 25 Gy., (© 2023. The Author(s).)

Background: To compare the differences in long-term quality of life (QoL) between survivors of paediatric and adult patients with nasopharyngeal carcinoma (NPC) and assess the clinical factors that predict long-term QoL. Methods: We enrolled 420 long-term NPC survivors who were alive for at least 8 years after treatment, including 195 paediatric and 225 adult patients diagnosed and treated with intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Centre (SYSUCC) between 2011 and 2015. Data on clinical factors and EORTC QLQ-C30 were collected from all participants. The QoL of paediatric and adult NPC survivors was compared. Results: The paediatric group had significantly better outcomes in global health status (paediatric: 80.2 ± 12.7; adult: 77.2 ± 11.5; P = 0.027), physical function (paediatric: 98.5 ± 4.6; adult: 95.1 ± 7.0; P < 0.001), role function (paediatric: 97.0 ± 9.2; adult: 90.5 ± 15.2; P < 0.001), social function (paediatric: 96.0 ± 8.9; adult: 93.5 ± 11.8; P = 0.038), insomnia (paediatric: 1.9 ± 7.8; adult: 13.1 ± 22.3; P < 0.001), constipation (paediatric: 1.3 ± 7.5; adult: 8.0 ± 17.4; P < 0.001), diarrhea (paediatric: 0.7 ± 4.6; adult: 2.8 ± 9.3; P = 0.010), and financial difficulties (paediatric: 1.9 ± 7.8; adult: 11.0 ± 19.8; P < 0.001), but poorer cognitive function (paediatric: 88.3 ± 9.9; adult: 93.8 ± 12.6; P < 0.001) than the adult group. Pretreatment clinical factors, including T stage, N stage, and pre-treatment EBV (Epstein-Barr Virus) DNA, showed a strong association with QoL. However, the factors that affected the QoL outcomes differed between the two groups. In survivors of paediatric cancer, global health status/QoL was strongly correlated with T stage (P < 0.001) and clinical stage (P = 0.018), whereas it was strongly correlated with pre-treatment EBV DNA (P = 0.008) in adults. Conclusion: Paediatric survivors of NPC have a significantly better QoL than adult NPC survivors. Moreover, pre-treatment T stage, N stage, and EBV DNA significantly influenced the overall health status of the survivors. These results highlight the need to tailor care to both age groups to promote better long-term health outcomes. [ABSTRACT FROM AUTHOR]

Background: To assess the feasibility and benefit of integrating four-dimensional (4D) Positron Emission Tomography (PET) - computed tomography (CT) for liver stereotactic body radiation therapy (SBRT) planning., Methods: 8 patients with 14 metastases were accrued in the study. They all underwent a non-gated PET and a 4D PET centered on the liver. The same CT scan was used for attenuation correction, registration, and considered the planning CT for SBRT planning. Six PET phases were reconstructed for each 4D PET. By applying an individualized threshold to the 4D PET, a Biological Internal Target Volume (BITV) was generated for each lesion. A gated Planning Target Volume (PTVg) was created by adding 3 mm to account for set-up margins. This volume was compared to a manual Planning Target Volume (PTV) delineated with the help of a semi-automatic Biological Target Volume (BTV) obtained from the non-gated exam. A 5 mm radial and a 10 mm craniocaudal margins were applied to account for tumor motion and set-up margins to create the PTV., Results: One undiagnosed liver metastasis was discovered thanks to the 4D PET. The semi-automatic BTV were significantly smaller than the BITV (p = 0.0031). However, after applying adapted margins, 4D PET allowed a statistically significant decrease in the PTVg as compared to the PTV (p = 0.0052)., Conclusions: In comparison to non-gated PET, 4D PET may better define the respiratory movements of liver targets and improve SBRT planning for liver metastases. Furthermore, non respiratory-gated PET exams can both misdiagnose liver metastases and underestimate the real internal target volumes.

Radiotherapy and targeted therapy are essential treatments for patients with brain metastases from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the combination of radiotherapy and targeted therapy still needs to be investigated, and neurotoxicity induced by radiotherapy for brain metastases has also become an important issue of clinical concern. It remained unclear how to achieve the balance of efficacy and toxicity with the application of new radiotherapy techniques and new targeted therapy drugs. This article reviews the benefits and potential risk of combining radiotherapy and targeted therapy for HER2-positive breast cancer with brain metastases. [ABSTRACT FROM AUTHOR]

Background: Tumor-associated neutrophils (TANs) in the tumor microenvironment are prognostic biomarkers in many malignancies. However, it is unclear whether TANs can serve as a prognostic marker for clinical outcomes in patients with glioblastoma (GBM), as classified according to World Health Organization Classification of Tumors of the Central Nervous System, fifth edition (CNS5). In the present study, we analyzed correlations of TANs and peripheral blood neutrophils prior to radiotherapy with overall survival (OS) in GBM (CNS5). Methods: RNA-seq expression profiles of patients with newly diagnosed GBM (CNS5) were extracted from The Cancer Genome Atlas (TCGA), and The Chinese Glioma Genome Atlas (CGGA). TAN infiltration was inferred using CIBERSORTx algorithm. Neutrophil counts prior to radiotherapy in newly diagnosed GBM (CNS5) were obtained from the First Affiliated Hospital of Fujian Medical University. The prognostic value of TANs and peripheral blood neutrophils before radiotherapy was investigated using Kaplan-Meier analysis and Cox proportional hazards models. The robustness of these findings was evaluated by sensitivity analysis, and E values were calculated. Results: A total of 146 and 173 individuals with GBM (CNS5) were identified from the TCGA and CGGA cohorts, respectively. High infiltration of TANs was of prognostic of poor OS in TCGA (HR = 1.621, 95% CI: 1.004–2.619) and CGGA (HR = 1.546, 95% CI: 1.029–2.323). Levels of peripheral blood neutrophils before radiotherapy (HR = 2.073, 95% CI: 1.077–3.990) were independently associated with poor prognosis. Sensitivity analysis determined that the E-value of high TANs infiltration was 2.140 and 2.465 in the TCGA and CGGA cohorts. Conclusions: TANs and peripheral blood neutrophil levels before radiotherapy are prognostic of poor outcomes in GBM (CNS5). [ABSTRACT FROM AUTHOR]

Background: The traditional Chinese medicine (TCM) formula 01 for nasopharyngeal carcinoma (NPC01) is used in the management of head and neck cancers (HNCs), but whether NPC01 has an impact on the HR-QOL of patients with HNCs is unknown. Methods: This was a retrospective study of patients with HNCs who were treated between January 2019 and January 2020 at the Head & Neck Cancer Center of Tianjin Medical University Cancer Institute & Hospital. The patients were grouped according to whether they received NPC01 or not (controls). All patients routinely completed the EORTC QLQ-C30 and QLQ-H&N35 modules before and after 3 months of systemic treatment. Health economics were collected. Results: The patients who received NPC01 were older than the controls (48.6 ± 11.4 vs. 43.4 ± 8.8 years, P = 0.004). All other characteristics were comparable between the two groups (all P > 0.05). In EORTC QLQ-C30, physical functioning (P = 0.03), fatigue (P = 0.04), pain (P = 0.02), appetite loss (P = 0.02), and constipation (P = 0.01) scores were improved more in the NPC01 group than in controls. In EORTC H&N35, the scores for pain (P = 0.02), swallowing (P = 0.01), and dry mouth (P = 0.02) were better in the NPC01 group than in controls. The NPC01 cost was 38.94 RMB/patient compared with 12.81 RMB/patient for regular follow-up, but considering insurance coverage, the financial burden was not higher. Conclusions: The results suggest that NPC01 improves HNCs-related symptoms and HR-QOL. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests a merging role of immunothrombosis in the formation of arterial thrombosis. Our study aims to investigate its relevance in stroke patients.Methods: We compared the peripheral immunological profile of stroke patients vs. healthy controls. Serum samples were functionally analyzed for their formation and clearance of Neutrophil-Extracellular-Traps. The composition of retrieved thrombi has been immunologically analyzed.Results: Peripheral blood of stroke patients showed significantly elevated levels of DNAse-I (p < 0.001), LDG (p = 0.003), CD4 (p = 0.005) as well as the pro-inflammatory cytokines IL-17 (p < 0.001), INF-γ (p < 0.001) and IL-22 (p < 0.001) compared to controls, reflecting a TH1/TH17 response. Increased counts of DNAse-I in sera (p = 0.045) and Neutrophil-Extracellular-Traps in thrombi (p = 0.032) have been observed in patients with onset time of symptoms longer than 4,5 h. Lower values of CD66b in thrombi were independently associated with greater improvement of NIHSS after mechanical thrombectomy (p = 0.045). Stroke-derived neutrophils show higher potential for Neutrophil-Extracellular-Traps formation after stimulation and worse resolution under DNAse-I treatment compared to neutrophils derived from healthy individuals.Conclusions: Our data provide new insight in the role of activated neutrophils and Neutrophil-Extracellular-Traps in ischemic stroke. Future larger studies are warranted to further investigate the role of immunothrombosis in the cascades of stroke.Trial Registration: DRKS, DRKS00013278, Registered 15 November 2017, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013278. [ABSTRACT FROM AUTHOR]

Background: Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients.Methods: This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate.Discussion: The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale.Trial Registration: The study was prospectively registered at clinicaltrials.gov ( NCT04679454 ). [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemoradiotherapy (nCRT) prior to surgery is the standard treatment for patients with locally advanced rectal cancer (LARC), while parts of them show poor therapeutic response accompanied by therapy adverse effects. Predictive biomarkers for nCRT response could facilitate the guidance on treatment decisions but are still insufficient until now, which limits the clinical applications of nCRT in LARC patients. Methods: In our study, 37 formalin-fixed paraffin-embedded tumor biopsies were obtained from patients with LARC before receiving 5-fluorouracil based nCRT. Proteomics analyses were conducted to identify the differentially expressed proteins (DEPs) between total responders (TR) and poor responders (PR). The DEPs were validated via ROC plotter web tool and their predictive performance was evaluated by receiver operating characteristic analysis. Functional enrichment analyses were performed to further explore the potential mechanisms underlying nCRT response. Results: Among 3,998 total proteins, 91 DEPs between TR and PR were screened out. HSPA4, NIPSNAP1, and SPTB all with areas under the curve (AUC) ~ 0.8 in the internal discovery cohort were independently validated by the external mRNA datasets (AUC ~ 0.7), and their protein levels were linearly correlated with the graded responses to nCRT in the internal cohort. The combination of HSPA4 and SPTB could distinctly discriminate the TR and PR groups (AUC = 0.980, p < 0.0001). Moreover, multiple combinations of the three proteins realized increased specificity and/or sensitivity, while achieving favorable predictive value when moderate responders were introduced into the ROC analysis. Pathways including DNA damage repair, cell cycle, and epithelial mesenchymal transition were involved in nCRT response according to the enrichment analysis results. Conclusions: HSPA4, SPTB and NIPSNAP1 in tumor biopsies and/or their optional combinations might be potential predictive markers for nCRT response in patients with LARC. The DEPs and their related functions have implications for the potential mechanisms of treatment response to nCRT in patients with LARC. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen.Methods: This is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life.Discussion: The expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance.Trial Registration: chictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study. [ABSTRACT FROM AUTHOR]

Cancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using "liquid biopsies" to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis. [ABSTRACT FROM AUTHOR]

Background: To compare the prognostic value of 7th and 8th editions of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system for patients with nonmetastatic nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy and simultaneous integrated boost- intensity-modulated radiation therapy (SIB-IMRT).Methods: Patients with NPC (n = 300) who received SIB-IMRT were included. Survival by T-classification, N-classification, and stage group of each staging system was assessed.Results: For T-classification, nonsignificant difference was observed between T1 and T3 and between T2 and T3 disease (P = 0.066 and 0.106, respectively) for overall survival (OS) in the 7th staging system, whereas all these differences were significant in the 8th staging system (all P < 0.05). The survival curves for disease-free survival (DFS) and locoregional recurrence-free survival (LRRFS) in both staging systems were similar, except for the comparison of T2 and T4 disease for LRRFS (P = 0.070 for 7th edition; P = 0.011 for 8th edition). For N-classification, significant differences were observed between N2 and N3 diseases after revision (P = 0.046 and P = 0.043 for OS and DFS, respectively). For staging system, no significant difference was observed between IVA and IVB of 7th edition.Conclusion: The 8th AJCC staging system appeared to have superior prognosis value in the SIB-IMRT era compared with the 7th edition. [ABSTRACT FROM AUTHOR]

Background: The incidence of anal squamous cell carcinoma (SCC) has been steadily growing globally in the past decade. Clinical data on anal SCC from China are rare. We conducted this study to describe the clinical and epidemiological characteristics of anal SCC in China and explore prognostic factors of outcomes among patients with anal SCC.Methods: We audited demographic characteristics, relevant symptoms, risk factors, treatment modalities and outcomes for patients diagnosed with anal SCC at 11 medical institutions in China between January 2007 and July 2018.Results: A total of 144 patients (109 females) were diagnosed with SCC during this period. Median age at initial diagnosis was 52.0 (interquartile range: 46.0-61.8) years. The most common symptoms were bleeding (n = 93, 64.6%), noticing a lump (n = 49, 34.0%), and pain (n = 47, 32.6%). The proportion of patients at the American Joint Committee on Cancer (AJCC) stages I-IV were 10 (6.9%), 22 (15.3%), 61 (42.4%) and 8 (5.6%), respectively, and AJCC stages in 43 (29.9%) patients were unknown. Thirty-six patients (25.0%) underwent abdominoperineal resection initially. Univariable analysis showed that T stage predicted recurrence-free survival (RFS) (Hazard ratio [HR] = 3.03, 95% Confidence interval [CI]: 1.10-8.37, p = 0.032), and age group (HR = 2.90, 95% CI: 1.12-7.49, p = 0.028), AJCC stage (HR = 4.56, 95% CI: 1.02-20.35, p = 0.046), and N stage (HR = 3.05, 95% CI: 1.07-8.74, p = 0.038) predicted overall survival (OS).Conclusions: T stage was identified as prognostic factor of RFS, and age, AJCC stage, and N stage were identified as prognostic factors of OS. Improving symptom awareness and earlier presentation among patients potentially at risk for anal SCC should be encouraged. Familiarity with the standard treatment among health care providers in China should be further improved. [ABSTRACT FROM AUTHOR]

Background: To explore the efficacy and safety of Transcatheter rectal arterial chemoembolization with oxaliplatin and S-1 concurrent chemoradiotherapy as neoadjuvant therapy for locally advanced rectal cancer.Methods: This s a prospective, monocentric, non-randomized clinical study, a total of 95 patients were enrolled and assigned to two groups: an investigational group (n = 50) receiving transcatheter rectal arterial chemoembolization (TRACE) with oxaliplatin and preoperative radiotherapy plus S-1 concurrent chemotherapy (NATRACE-CRT), followed by surgery, a control group (n = 45) receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy plus capecitabine based chemotherapy (NA-CRT), followed by surgery. The primary endpoint was postoperative pathological regression rate which evaluated by tumor regression grade (TRG) according to the 7th edition of the American Joint Committee on Cancer (AJCC) standard, and the secondary endpoints included objective response rate (ORR) and toxicity, as well as surgical complications, and postoperative tumor downstaging.Results: Compared with NA-CRT group (17.78% (95% confidence interval (CI): 6.2-29.4)), the TRG0 was 30% (95% CI 16.8-43.2) in the NATRACE-CRT group (P = 0.231). The TRG0 + 1 rate was 60% (95% CI: 45.9-74.1) and 33.33% (95% CI: 19-47.7) in NATRACE-CRT group and NA-CRT group, respectively (P = 0.013). The ORR of the NATRACE-CRT group was 84% and that of the NA-CRT group was 66.67% (p = 0.058). Incidence of preoperative toxic side effects and surgical complications was similar between the two groups.Conclusion: TRACE with oxaliplatin plus concurrent S-1 chemoradiotherapy as a neoadjuvant therapy provided better pathological remission rate versus standard treatment with a similar safety profile.Trial Registration: NCT03601156. [ABSTRACT FROM AUTHOR]

Background: Preoperative chemoradiotherapy (PCRT) followed by surgery and adjuvant chemotherapy is the current standard treatment for stage II/III rectal cancer. However, radiotherapy in the pelvic area is commonly associated with complications such as anastomotic leakage, sexual dysfunction, and fecal incontinence. Recently, the MERCURY study showed that preoperative high-resolution magnetic resonance imaging (MRI) helped to selectively avoid PCRT. It remains unclear whether PCRT is necessary in patients who can achieve a negative circumferential resection margin (CRM) with surgery alone and in patients with cT1-2N1 or cT3N0 without CRM involvement and lateral lymph node metastasis. This study aims to evaluate the efficacy of upfront radical surgery with total mesorectal excision (TME) followed by adjuvant chemotherapy with folinic acid (or leucovorin), fluorouracil, and oxaliplatin (FOLFOX) versus the current standard treatment in patients with surgically resectable, locally advanced rectal cancer.Methods: This study, named TME-FOLFOX, is a prospective, open-label, multicenter, phase II randomized trial. Patients with locally advanced rectal cancer will be randomized to receive PCRT followed by TME and adjuvant chemotherapy (arm A) or upfront radical surgery with TME followed by adjuvant FOLFOX chemotherapy (arm B). Clinical stage II/III rectal cancer without CRM involvement and lateral lymph node metastasis will be defined using preoperative MRI. The primary endpoint is 3-year disease-free survival (DFS). Secondary endpoints include 5-year DFS, local recurrence rate, systemic recurrence rate, cost-effectiveness, and overall survival. We hypothesized that our experimental group (arm B) will have a 3-year DFS of 75% and a non-inferiority margin of 15%.Discussion: Identifying whether patients require PCRT is one of the critical issues in locally advanced rectal cancer. This study aims to elucidate whether PCRT may not be required for all patients with stage II/III rectal cancer, especially for the MRI-based intermediate-risk group (with cT1-2N1 or cT3N0) without CRM involvement and lateral lymph node metastasis. If the findings indicate that our proposed treatment, which omits PCRT, is non-inferior to the standard treatment, then patients may avoid unnecessary radiation-related toxicity, have a shorter treatment duration, and save on medical costs.Trial Registration: ClinicalTrials.gov, NCT02167321. Registered on 19 June 2014. [ABSTRACT FROM AUTHOR]

Introduction: The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. Methods: The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers (n = 48, 21–84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40–69 yrs.; blood: n = 13; TIL: n = 17) and elderly cancer patients (70–90 yrs.; blood: n = 20; TIL: n = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4+ and CD8+ T cells as well as regulatory T cells (Treg) were assessed by flow cytometry. Results: We observed lower frequencies of CD8+ cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. Conclusion: Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients. [ABSTRACT FROM AUTHOR]

Background: Salivary gland hypofunction and xerostomia are major complications following radiotherapy for head and neck cancer and may lead to debilitating oral disorders and impaired quality of life. Currently, only symptomatic treatment is available. However, mesenchymal stem cell (MSC) therapy has shown promising results in preclinical studies. Objectives are to assess safety and efficacy in a first-in-man trial on adipose-derived MSC therapy (ASC) for radiation-induced xerostomia.Methods: This is a single-center, phase I/II, randomized, placebo-controlled, double-blinded clinical trial. A total of 30 patients are randomized in a 1:1 ratio to receive ultrasound-guided, administered ASC or placebo to the submandibular glands. The primary outcome is change in unstimulated whole salivary flow rate. The secondary outcomes are safety, efficacy, change in quality of life, qualitative and quantitative measurements of saliva, as well as submandibular gland size, vascularization, fibrosis, and secretory tissue evaluation based on contrast-induced magnetic resonance imaging (MRI) and core-needle samples. The assessments are performed at baseline (1 month prior to treatment) and 1 and 4 months following investigational intervention.Discussion: The trial is the first attempt to evaluate the safety and efficacy of adipose-derived MSCs (ASCs) in patients with radiation-induced xerostomia. The results may provide evidence for the effectiveness of ASC in patients with salivary gland hypofunction and xerostomia and deliver valuable information for the design of subsequent trials.Trial Registration: EudraCT, Identifier: 2014-004349-29. Registered on 1 April 2015. ClinicalTrials.gov, Identifier: NCT02513238 . First received on 2 July 2015. The trial is prospectively registered. [ABSTRACT FROM AUTHOR]

Background: Prognostic value of immune cells is not clear in testicular germ cell tumors (TGCTs). We aimed to investigate the prognostic value of tumor-infiltrating neutrophils in TGCTs. Methods: A total of 102 patients who underwent orchiectomy for TGCT were investigated for CD66b positive tumor-infiltrating neutrophils (CD66b + TINs). Immmunostaining for CD66b was performed in 102 sections as described. Clinicopathological parameters as well as cancer specific survival and overall survival were assessed for correlation with CD66b + TIN density. Results: High density group was significantly correlated with tumor diameter ≥ 10 cm, presence of nodal/distant metastasis, S stage, diagnosis of nonseminomatous germ cell tumor (NGCT), and presence of venous invasion (p = 0.0198, p < 0.0001, p = 0.0275, p = 0.0004, and p = 0.0287, respectively). It was also significantly associated with cancer-specific and overall survival (logrank p = 0.0036, and p = 0.0002, respectively). Multivariate analysis showed that increased CD66b + TIN was an independent prognostic factor for overall survival (p = 0.0095). Conclusions: Increased CD66b + TIN was significantly associated with presence of metastasis, S stage, and nonseminomatous germ cell tumor diagnosis. It was also an independent prognostic factor of overall survival in patients with TGCT. [ABSTRACT FROM AUTHOR]

Background: Carbonic anhydrase IX (CA IX) is a tumor-associated, highly active, transmembrane carbonic anhydrase isoform regulated by hypoxia and implicated in pH control and adhesion-migration-invasion. CA IX ectodomain (ECD) is shed from the tumor cell surface to serum/plasma of patients, where it can signify cancer prognosis. We previously showed that the CA IX ECD release is mediated by disintegrin and metalloproteinase ADAM17. Here we investigated the CA IX ECD shedding in tumor cells undergoing apoptosis in response to cytotoxic drugs, including cycloheximide and doxorubicin.Methods: Presence of cell surface CA IX was correlated to the extent of apoptosis by flow cytometry in cell lines with natural or ectopic CA IX expression. CA IX ECD level was assessed by ELISA using CA IX-specific monoclonal antibodies. Effect of recombinant CA IX ECD on the activation of molecular pathways was evaluated using the cell-based dual-luciferase reporter assay.Results: We found a significantly lower occurrence of apoptosis in the CA IX-positive cell subpopulation than in the CA IX-negative one. We also demonstrated that the cell-surface CA IX level dropped during the death progress due to an increased ECD shedding, which required a functional ADAM17. Inhibitors of metalloproteinases reduced CA IX ECD shedding, but not apoptosis. The CA IX ECD release induced by cytotoxic drugs was connected to elevated expression of CA IX in the surviving fraction of cells. Moreover, an externally added recombinant CA IX ECD activated a pathway driven by the Nanog transcription factor implicated in epithelial-mesenchymal transition and stemness.Conclusions: These findings imply that the increased level of the circulating CA IX ECD might be useful as an indicator of an effective antitumor chemotherapy. Conversely, elevated CA IX ECD might generate unwanted effects through autocrine/paracrine signaling potentially contributing to resistance and tumor progression. [ABSTRACT FROM AUTHOR]

Background: We compared the outcome of patients who received non-image-guided intensity-modulated radiotherapy (IMRT) with those who received helical tomotherapy (HT), a daily image-guided radiotherapy (IGRT), after surgery for oral cavity cancer (OCC).Methods: During the period November 2006 to December 2013, a total of 152 postoperative OCC patients underwent either IMRT (n = 79) or daily IGRT (n = 73) 4 to 6 weeks after surgery. Patients in the IMRT group received 6 MV photon beams to 7 fields and those in the IGRT group received daily fractions of 1.8 or 2 Gy on five consecutive days.Results: Patients who received daily IGRT had higher 5-year overall survival than those who received IMRT (87% versus 48%, p = 0.015). The local progression-free survival rate was also higher in patients who received IGRT (85% versus 58%, p = 0.006). More patients in the IGRT group completed the package of overall treatment time in ≤ 13 weeks and completed their course of radiation therapy in ≤ 8 weeks than patients in the IMRT group (89% versus 68%, p = 0.002; 84% versus 58%, p = 0.001), respectively. The rate of local failure in the primary tumor area was 24.0 % in the IMRT group and 6.8% in the IGRT group. Among patients with primary local failure, the marginal failure rate was 52.6% in the IMRT group and 0 % in the IGRT group.Conclusions: For patients with locally advanced OCC, postoperative IGRT results in better overall survival, better local progression-free survival, less marginal failure and shorter overall treatment time than postoperative non-image-guided IMRT. [ABSTRACT FROM AUTHOR]

Background: Several randomized trials and meta-analyses confirmed a wide benefit of radiotherapy (RT), both after breast conserving surgery (BCS) and mastectomy. However, many elderly women don't receive RT. Hypofractionated (HF) RT allows « simplified » and more accessible treatments with equivalent results to classic RT in three large randomized trials. However, there are few available data on HF-RT for nodal irradiation, as well as for the boost. Methods: We evaluated patients treated for IBC by HF-RT between 2004 and 2012 in two regional cancer centres. We used an original scheme delivering 45 Gy in 15 fractions three times a week, both after BCS or mastectomy, with or without nodal irradiation. After BCS, a 9 Gy boost in 3 fractions was delivered. Local, regional and distant recurrences were assessed, as well as acute and late cutaneous, cardiac or pulmonary toxicities. Results: 205 patients were analysed, 116 after BCS (57 %) and 89 after mastectomy (43 %). Median age was 81 years (range: 52-91); 44 % had axillary nodal involvement (pN+). The Nottingham Prognostic Index (NPI) scored 0, 1, 2 and 3 in 10 %, 27 %, 44 % and 19 % of the cases. A nodal HF-RT was delivered in 65 patients (32 %) and boost in 98 patients (84 % of BCS) by 9 Gy/3 fr scheme. Fifty (24 %) patients underwent chemotherapy and 156 (75 %) hormonal treatment. With a 49-month median follow-up, 3/116 (2.6 %) patients and 4/89 (4.5 %) had local recurrence (LR) after BCS and mastectomy, respectively. The overall 5-year LR rate was 4.4 %. In univariate and multivariate analysis, LR risk factors were: high NPI (HR 5.46; p = 0.028), and triple negative tumour (HR 9.78; p = 0.006). Only 8 (4.5 %) patients had grade III skin toxicity; 29 (14 %) late fibrosis and 16 (8 %) telangiectasia. No pulmonary or cardiac toxicity was observed. Conclusion: Our HF-RT scheme (with or without nodal irradiation) confirms in elderly patients the data from randomized trials, both after BCS or mastectomy. Toxicity seems very acceptable but requires a longer follow-up. A larger evaluation is still ongoing in several other centres in France. [ABSTRACT FROM AUTHOR]

Since it was first described, the imprinted cluster 11p15.5 has been reported to be deregulated in a variety of pediatric and adult cancers including that of the lung. Both protein coding and non-coding genes functioning as oncogenes or as tumor suppressor genes reside within this cluster. Oncomirs that can function as oncogenes or as tumor suppressors have also been reported. While a complete account of the role played by the 11p15.5 imprinted cluster in lung cancer is beyond the scope of this review, we will focus on the role of the non-coding RNAs processed from the H19-IGF2 loci. A special emphasis will be given to the H19/miR-675 gene locus. Their potential diagnostic and therapeutic use in lung cancer will be described. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the differences between three methods of classification of recurrences in patients with head and neck tumours treated with Radiation Therapy (RT). Materials and methods: 367 patients with head and neck tumours were included in the study. Tumour recurrences were delineated in the CT images taken during patient follow-up and deformable registration was used to transfer this volume into the planning CT. The methods used to classify recurrences were: method CTV quantified the intersection volume between the recurrence and the Clinical Target Volume (CTV); method TV quantified the intersection between the Treated Volume and the recurrence (for method CTV and TV, recurrences were classified in-field if more than 95% of their volume were inside the volume of interest, marginal if the intersection was between 20-95% and outfield otherwise); and method COM was based on the position of the Centre Of Mass of the recurrence. A dose assessment in the recurrence volume was also made. Results: The 2-year Kaplan-Meier locoregional recurrence incidence was 10%. Tumour recurrences occurred in 22 patients in a mean time of 16.5 ± 9.4 months resulting in 28 recurrence volumes. The percentage of in-field recurrences for methods CTV, TV and COM was 7%, 43% and 50%, respectively. Agreement between the three methods in characterizing individually in-field and marginal recurrences was found only in six cases. Methods CTV and COM agreed in 14. The percentage of outfield recurrences was 29% using all methods. For local recurrences (in-field or marginal to gross disease) the average difference between the prescribed dose and D98% in the recurrence volume was -5.2 ± 3.5% (range: -10.1%-0.9%). Conclusions: The classification of in-field and marginal recurrences is very dependent on the method used to characterize recurrences. Using methods TV and COM the largest percentage of tumour recurrences occurred in-field in tissues irradiated with high doses. [ABSTRACT FROM AUTHOR]

Background: Although neoadjuvant chemoradiotherapy (CRT) has become a standard procedure to downstage locally advanced rectal cancer prior to surgery, markers to predict the response to CRT have not been fully identified. The aim of this study was to identify predictive factors of response to CRT, especially focusing on peripheral blood leukocyte subsets. Methods: A total of 45 consecutive patients diagnosed with primary rectal cancer were prospectively enrolled and received CRT followed by curative resection. The numbers of each lymphocyte subset in peripheral blood pre- and post-CRT were analyzed using flow cytometry. According to the pathological response to CRT, patients were classified into high (Hi-R) and low (Lo-R) response groups. Results: Hi-R cases had significantly higher numbers of pre-CRT lymphocytes (p = 0.018), T lymphocytes (p = 0.009) and helper T lymphocytes (Th lymphocytes, p = 0.015) compared to the Lo-R cases. With the receiver-operating characteristic curve for numbers of pre-CRT T lymphocytes, the area under the curve (AUC) was 0.733, and the optimal cutoff value was 1196/μl, with 76.5% sensitivity, 67.8% specificity, 59.1% positive and 82.6% negative predictive values. The numbers of pre-CRT Th lymphocytes and cytotoxic lymphocytes were both independent predictors of the high CRT response in the multivariate analysis. Conclusions: In addition to the direct cytotoxicity of CRT, recent studies have demonstrated the induction of an immunological host response, which also contributed to the tumor regression induced by CRT. Our result suggested the potential role of circulating T lymphocytes in predicting the response to CRT in colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Purpose To assess the impact of mid-treatment parotid gland shrinkage on long term xerostomia during IMRT for oropharyngeal SCC. Methods and materials All patients treated with IMRT at a single Institution from November 2007 to June 2010 and undergoing weekly CT scans were selected. Parotid glands were contoured retrospectively on the mid treatment CT scan. For each parotid gland, the percent change relative to the planning volume was calculated and combined as weighted average. Patients were considered to be xerostomic if developed GR2+ dry mouth according to CTCAE v3.0. Predictors of the time to xerostomia resolution or downgrade to 1 were investigated at both uni- and multivariate analysis. Results 85 patients were selected. With a median follow up of 35.8 months (range: 2.4-62.6 months), the actuarial rate of xerostomia is 26.2% (SD: 5.3%) and 15.9% (SD: 5.3%) at 2 and 3 yrs, respectively. At multivariate analysis, mid-treatment shrink along with weighted average mean parotid dose at planning and body mass index are independent predictors of the time to xerostomia resolution. Patients were pooled in 4 groups based on median values of both mid-reatment shrink (cut-off: 19.6%) and mean WA parotid pl-D (cut-off: 35.7 Gy). Patients with a higher than median parotid dose at planning and who showed poor shrinkage at mid treatment are the ones with the outcome significantly worse (3-yr rate of xerostomia ≈ 50%) than the other three subgroups (3-yr rate of xerostomia ≈ 10%). Conclusion For a given planned dose, patients whose parotids significantly shrink during IMRT are less likely to be long-term supplemental fluids dependent. [ABSTRACT FROM AUTHOR]

Background Large anatomical variations occur during the course of intensity-modulated radiation therapy (IMRT) for locally advanced head and neck cancer (LAHNC). The risks are therefore a parotid glands (PG) overdose and a xerostomia increase. The purposes of the study were to estimate: - the PG overdose and the xerostomia risk increase during a "standard" IMRT (IMRTstd); - the benefits of an adaptive IMRT (ART) with weekly replanning to spare the PGs and limit the risk of xerostomia. Material and methods Fifteen patients received radical IMRT (70Gy) for LAHNC. Weekly CTs were used to estimate the dose distributions delivered during the treatment, corresponding either to the initial planning (IMRTstd) or to weekly replanning (ART). PGs dose were recalculated at the fraction, from the weekly CTs. PG cumulated doses were then estimated using deformable image registration. The following PG doses were compared: pre-treatment planned dose, per-reatment IMRTstd and ART. The corresponding estimated risks of xerostomia were also compared. Correlations between anatomical markers and dose differences were searched. Results Compared to the initial planning, a PG overdose was observed during IMRTstd for 59% of the PGs, with an average increase of 3.7Gy (10.0Gy maximum) for the mean dose, and of 8.2% (23.9% maximum) for the risk of xerostomia. Compared to the initial planning, weekly replanning reduced the PG mean dose for all the patients (p < 0.05). In the overirradiated PG group, weekly replanning reduced the mean dose by 5.1Gy (12.2Gy maximum) and the absolute risk of xerostomia by 11% (p < 0.01) (30% maximum). The PG overdose and the dosimetric benefit of replanning increased with the tumor shrinkage and the neck thickness reduction (p < 0.001). Conclusion During the course of LAHNC IMRT, around 60% of the PGs are overdosed of 4Gy. Weekly replanning decreased the PG mean dose by 5Gy, and therefore by 11% the xerostomia risk. [ABSTRACT FROM AUTHOR]

Background We investigated whether routine elective irradiation of a clinically negative inguinal node (IGN) is necessary for patients with locally advanced distal rectal cancer and anal canal invasion (ACI). Methods We reviewed retrospectively 1,246 patients with locally advanced rectal adenocarcinoma managed using preoperative or postoperative chemoradiotherapy and radical surgery between 2001 and 2011. The patients' IGN was clinically negative at presentation and IGN irradiation was not performed. ACI was defined as the lower edge of the tumor being within 3 cm of the anal verge. Patients were divided into two groups, those with ACI (n = 189, 15.2%) and without ACI (n = 1,057, 84.8%). Results The follow-up period was a median of 66 months (range, 3-142 months). Among the 1,246 patients, 10 developed IGN recurrence; 7 with ACI and 3 without ACI. The actuarial IGN recurrence rate at 5 years was 0.7%; 3.5% and 0.2% in patients with and without ACI, respectively (p < 0.001). Isolated IGN recurrence occurred in three patients, all of whom had ACI tumors. These three patients received curative intent local treatments, and one was alive with no evidence of disease 10 years after IGN recurrence. Salvage treatments in the other two patients controlled successfully the IGN recurrence for >5 years, but they developed second malignancy or pelvic and distant recurrences. Seven patients with non-isolated IGN recurrence died of disease at 5-22 months after IGN recurrence. Conclusion The low IGN recurrence rate even with ACI and the feasibility of salvage of isolated IGN recurrence indicated that routine elective IGN irradiation is not necessary for rectal cancer with ACI. [ABSTRACT FROM AUTHOR]

Background The interaction between tumor cells and inflammatory cells has not been systematically investigated in esophageal squamous cell carcinoma (ESCC). The main aims of the study were to investigate the clinical significance of tumor-infiltrating neutrophils and neturophilto- CD8+ lymphocyte ratio (NLR), and to analyze the distribution of tumor-infiltrating neutrophils and CD8+ lymphocytes in ESCC treated by curative resection. Methods The expressions of CD66b and CD8 were assessed with double staining immunohistochemistry in the surgical specimens from 90 patients with ESCC treated by curative surgery. Results We showed that increased intratumoral neutrophils were significantly associated with lymph node metastasis (P = 0.016), and advanced pathological stages (P = 0.013). Decreased peritumoral CD8+ lymphocyte density was more frequently observed in patients with single positive lymph node (p = 0.045). Peritumoral NLR was significantly associated with advanced T stages (p < 0.001), lymph node metastasis (p = 0.041) and a trend towards advanced pathological stages (p = 0.053). Increased intratumoral neutrophils were significantly associated with decreased disease-free survival (p < 0.001) and overall survival (p < 0.001) in univariate analysis and were identified as an independent prognostic factor for disease-free survival (p = 0.006) and overall survival (p = 0.037) in multivariate analysis. Neither the density nor the distribution of tumor-infiltrating neutrophils was significantly correlated with that of CD8+ lymphocytes. The density of intratumoral CD8+ lymphocytes was significantly lower than (P < 0.001) and moderately correlated with (r = 0.434, p < 0.001) that in peritumoral area. Conclusions Increased intratumoral neutrophils were an independent poor prognostic factor and peritumoral NLR was significantly associated with disease progression in ESCC treated by curative surgery, suggesting the possible effect of immune misbalance of tumor microenvironment in facilitating ESCC progression. Immunotherapy targeted to the above predictors should be considered in the future. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis represents a highly multi-factorial and multi-cellular complex (patho-) physiologic event involving endothelial cells, tumor cells in malignant conditions, as well as bone marrow derived cells and stromal cells. One main driver is vascular endothelial growth factor (VEGFA), which is known to interact with endothelial cells as a survival and mitogenic signal. The role of VEGFA on tumor cells and /or tumor stromal cell interaction is less clear. Condition specific (e.g. hypoxia) or tumor specific expression of VEGFA, VEGF receptors and co-receptors on tumor cells has been reported, in addition to the expression on the endothelium. This suggests a potential paracrine/autocrine loop that could affect changes specific to tumor cells. Methods: We used the monoclonal antibody against VEGFA, bevacizumab, in various in vitro experiments using cell lines derived from different tumor entities (non small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC) and renal cell carcinoma (RCC)) in order to determine if potential VEGFA signaling could be blocked in tumor cells. The experiments were done under hypoxia, a major inducer of VEGFA and angiogenesis, in an attempt to mimic the physiological tumor condition. Known VEGFA induced endothelial biological responses such as proliferation, migration, survival and gene expression changes were evaluated. Results: Our study was able to demonstrate expression of VEGF receptors on tumor cells as well as hypoxia regulated angiogenic gene expression. In addition, there was a cell line specific effect in tumor cells by VEGFA blockade with bevacizumab in terms of proliferation; however overall, there was a limited measurable consequence of bevacizumab therapy detected by migration and survival. Conclusion: The present study showed in a variety of in vitro experiments with several tumor cell lines from different tumor origins, that by blocking VEGFA with bevacizumab, there was a limited autocrine or cellautonomous function of VEGFA signaling in tumor cells, when evaluating VEGFA induced downstream outputs known in endothelial cells. [ABSTRACT FROM AUTHOR]

Background: Increased risk of ischemic stroke has been validated for several cancers, but limited study evaluated this risk in cervical cancer patients. Our study aimed to evaluate the risk of ischemic stroke in cervical cancer patients. Methods: The study analyzed data from the 2003 to 2008 National Health Insurance Research Database (NHIRD) provided by the National Health Research Institutes in Taiwan. Totally, 893 cervical cancer patients after radiotherapy and 1786 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the risk of ischemic stroke. Results: The 5-year cumulative risk of ischemic stroke was significantly higher for the cervical cancer group than for the control group (7.8% vs 5.1%; p <0.005). The risk of stroke was higher in younger (age <51 years) than in older (age =51 years) cervical cancer patients (HR = 2.73, p = 0.04; HR = 1.37, p = 0.07) and in patients with more than two comorbid risk factors (5 years cumulative stroke rate of two comorbidities: 15% compared to no comorbidities: 4%). Conclusions: These study demonstrated cervical cancer patients had a higher risk of ischemic stroke than the general population, especially in younger patients. Strategies to reduce this risk should be assessed. [ABSTRACT FROM AUTHOR]

Cancer research has devoted most of its energy over the past decades on unraveling the control mechanisms within tumor cells that govern its behavior. From this we know that the onset of cancer is the result of cumulative genetic mutations and epigenetic alterations in tumor cells leading to an unregulated cell cycle, unlimited replicative potential and the possibility for tissue invasion and metastasis. Until recently it was often thought that tumors are more or less undetected or tolerated by the patient’s immune system causing the neoplastic cells to divide and spread without resistance. However, it is without any doubt that the tumor environment contains a wide variety of recruited host immune cells. These tumor infiltrating immune cells influence anti-tumor responses in opposing ways and emerges as a critical regulator of tumor growth. Here we provide a summary of the relevantimmunological cell types and their complex and dynamic roles within an established tumor microenvironment. For this, we focus on both the systemic compartment as well as the local presence within the tumormicroenvironment of late-stage non-small cell lung cancer (NSCLC), admitting that this multifaceted cellular composition will be different from earlier stages of the disease, between NSCLC patients. Understanding the paradoxical role that the immune system plays in cancer and increasing options for their modulation may alter the odds in favor of a more effective anti-tumor immune response. We predict that the future standard of care of lung cancer will involve patient-tailor-made combination therapies that associate (traditional) chemotherapeutic drugs and biologicals with immune modulating agents and in this way complement the therapeutic armamentarium for this disease. [ABSTRACT FROM AUTHOR]

Background: To evaluate the feasibility of image-guided radiotherapy based on helical Tomotherapy to spare the contralateral parotid gland in head and neck cancer patients with unilateral or no neck node metastases. Methods: A retrospective review of 52 patients undergoing radiotherapy for head and neck cancers with image guidance based on daily megavoltage CT imaging with helical tomotherapy was performed. Results: Mean contralateral parotid dose and the volume of the contralateral parotid receiving 40 Gy or more were compared between radiotherapy plans with significant constraint (SC) of less than 20 Gy on parotid dose (23 patients) and the conventional constraint (CC) of 26 Gy (29 patients). All patients had PTV coverage of at least 95% to the contralateral elective neck nodes. Mean contralateral parotid dose was, respectively, 14.1 Gy and 24.7 Gy for the SC and CC plans (p<0.0001). The volume of contralateral parotid receiving 40 Gy or more was respectively 5.3% and 18.2% (p<0.0001) Conclusion: Tomotherapy for head and neck cancer minimized radiotherapy dose to the contralateral parotid gland in patients undergoing elective node irradiation without sacrificing target coverage. [ABSTRACT FROM AUTHOR]

Background: Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. Radiosensitivity has recently been shown to be greatly affected by immune function of the host. Methods: In 48 cases of advanced RC, we retrospectively examined the density of tumor infiltrating CD4(+) and CD8(+) T cells using immunohistochemical staining of biopsy samples before CRT, and examined the correlation with tumor response. Results: The numbers of both CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL) in pre-CRT biopsy samples were strongly correlated with tumor reduction ratio evaluated by barium enema. Moreover, the densities of CD4(+) and CD8(+) TIL were significantly associated with histological grade after CRT. The density of CD8(+) TIL was an independent prognostic factor for achieving complete response after CRT. Conclusions: In RC patients, T lymphocyte-mediated immune reactions play an important role in tumor response to CRT, and the quantitative measurement of TIL in biopsy samples before CRT can be used as a predictor of the clinical effectiveness of CRT for advanced RC. [ABSTRACT FROM AUTHOR]

Background: Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. In order to find other factors possibly related with radiosensitivity, we evaluated the relationships between circulating blood cell counts and RT effects. Methods: In 179 cases with advanced RC, we retrospectively examined hemoglobin (Hb) levels and counts of white blood cells (WBC), platelets and WBC subsets before and after RT and investigated their associations with the complete response (CR) rate together with other clinicopathological factors. Results: The ratio of lymphocytes in WBC taken before RT was significantly greater in 15 CR cases as compared with those in non-CR cases. Patients with high lymphocyte percentages (25.7%) showed better outcome than the counterparts. Conversely, the ratio of neutrophiles was reduced in CR cases. The lymphocyte ratio showed an independent association with CR with multivariate analysis, and tended to be maintained at relatively high levels in CR cases. Conclusions: In RC patients, peripheral blood lymphocytes have a significant impact on the CR rate in response to RT. Lymphocyte-mediated immune reactions are supposed to have positive roles on clinical response in radiotherapy for RC. [ABSTRACT FROM AUTHOR]

Although neoadjuvant chemoradiotherapy (CRT) is the standard treatment for advanced rectal cancer (RC), markers to predict the treatment response have not been fully established. In 73 patients with advanced RC who underwent CRT in a neoadjuvant setting, we retrospectively examined the associations between the clinical effects of CRT and blood cell counts before and after CRT. Clinical or pathological complete response (CR) was observed in 10 (14%) cases. The CR rate correlated significantly with the size and the circumferential extent of the tumor. Hemoglobin level, white blood cell (WBC) count and platelet count before CRT did not show a significant difference between CR and non-CR cases. Interestingly, however, lymphocyte ratio in WBC was significantly higher (p = 0.020), while neutrophil ratio tended to be lower (p = 0.099), in CR cases, which was shown to be an independent association by multivariate analysis. When all the blood data obtained in the entire treatment period were evaluated, circulating lymphocyte count was most markedly decreased in the CRT period and gradually recovered by the time of surgery, while the numbers of neutrophils and monocytes were comparatively stable. Moreover, the lymphocyte percentage in samples obtained from CR patients was maintained at a relatively higher level than that from non-CR patients. Since tumor shrinkage is known to be dependent not only on the characteristics of tumor cells but also on various host conditions, our data raise the possibility that a lymphocyte-mediated immune reaction may have a positive role in achieving complete eradication of tumor cells. Maintenance of circulating lymphocyte number may improve the response to CRT in rectal cancer. [ABSTRACT FROM AUTHOR]

Background: Heterogeneous nuclear ribonucleoproteins (hnRNPs) of the A/B type (hnRNP A1, A2/B1, A3) are highly related multifunctional proteins participating in alternative splicing by antagonising other splicing factors, notably ASF/SF2. The altered expression pattern of hnRNP A2/B1 and/or splicing variant B1 alone in human lung cancer and their potential to serve as molecular markers for early diagnosis remain issues of intense investigation. The main objective of the present study was to use paired tumour/non-tumour biopsies from patients with nonsmall cell lung cancer (NSCLC) to investigate the expression profiles of hnRNP A1, A2/B1 and A3 in conjunction with ASF/SF2. Methods: We combined western blotting of tissue homogenates with immunohistochemical examination of fixed tissue sections and quantification of mRNA expression levels in tumour versus adjacent normal-looking areas of the lung in the same patient. Results: Our study, in addition to clear evidence of mostly uncoupled deregulation of hnRNPs A/B, has revealed hnRNP A1 to be the most deregulated protein with a high frequency of over-expression (76%), followed by A3 (52%) and A2/B1 (43%). Moreover, direct comparison of protein/mRNA levels showed a lack of correlation in the case of hnRNP A1 (as well as of ASF/SF2), but not of A2/B1, suggesting that different mechanisms underlie their deregulation. Conclusion: Our results provide strong evidence for the up-regulation of hnRNP A/B in NSCLC, and they support the existence of distinct mechanisms responsible for their deregulated expression. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown that microRNAs (miRNAs) play roles in tumorigenesis and are reliable classifiers of certain cancer types and subtypes. However, the role of miRNAs in the pathogenesis and diagnosis of small cell carcinoma (SCLC), the majority of which represent the most aggressive lung tumors, has not been investigated. Methods: In order to explore miRNA involvement in the pathogenesis of small cell lung carcinoma (SCLC) and the potential role of miRNAs in SCLC diagnosis, we compared the miRNA expression profile of a set of SCLC cell lines to that of a set of non-small cell lung cancer (NSCLC) cell lines and normal immortalized human bronchial epithelial cells (HBECs) using microarray analysis. Results: Our results show that miRNA profiles reliably distinguish SCLC cell lines from NSCLC and HBEC cell lines. Further analysis of the miRNA expression profile of the two subtypes of lung cancer cell lines indicates that the expression levels of the majority of the miRNAs that are differentially expressed in SCLC cells relative to NSCLC cells and HBECs show a progressive trend from HBECs to NSCLC cells to SCLC cells. Conclusions: The distinctive miRNA expression signature of SCLCs relative to NSCLCs and HBECs suggests that miRNA profiles have the potential to serve as a diagnostic marker of SCLC lung tumors. The progressive trend of miRNA profile changes from HBECs to NSCLCs to SCLCs suggests a possible pathological relationship between SCLCs and NSCLCs, and suggests that the increasing dysregulation of miRNA expression may play a role in lung tumor progression. The specific role of these miRNAs in lung tumor pathogenesis and differentiation need to be investigated further in future studies. [ABSTRACT FROM AUTHOR]

Background: The extent of angiogenesis is an important prognostic factor for colorectal carcinoma, however, there are few studies concerning changes in angiogenesis with radiotherapy (RTX). Our aim was to investigate changes in tumor angiogenesis influenced by radiotherapy to assess the prognostic value of angiogenesis the microvessel density (MVD) in overall survival after radiotherapy. Methods: Tumor specimens were taken from 101 patients resected for rectal cancer. The patients were divided into three groups according to the treatment they received before surgery (not treated, a short course, or long course of RTX). Tumor specimens were paraffin-embedded and immunohistochemistry was performed with primary antibody against CD-34 to count MVD. Results: MVD was significantly lower in the group of patients treated with a long course of RTX (p <0.025). The mean MVD for the long RTX group was 134.8; for the short RTX group -- 192.5; and for those not treated with RTX -- 193.0. There were no significant statistical correlations between MVD and age, sex, grade of tumor differentiation (G) and tumor size (T) in those untreated with RTX. In long RTX group we found a significant prognostic rate for MVD when the density cut off was near 130 with 92.3% sensitivity and 64.7% specificity. When the MVD was lower than a cut off of 130, the survival period significantly increased (p = 0.001), the mortality rate is significantly higher if the MVD is higher than 130 (microvessel/mm²) (1953.047; p = 0.002), if the histological grade is moderate/poor (127.407; p = 0.013), if the tumor is T3/T4 (111.618; p = 0.014), and if the patient is male (17.92; p = 0.034) adjusted by other variable in model. Conclusion: Our results show that a long course of radiotherapy significantly decreased angiogenesis in rectal cancer tissue. MVD was found to be a favourable marker for tumor behaviour during RTX and a predictor of overall survival after long course of RTX. Further investigations are now needed to determine the changes in angiogenesis during a shorter course of RTX. [ABSTRACT FROM AUTHOR]

Background: Hypofractionated radiotherapy is the current standard for adjuvant radiotherapy across many centres. Further hypofractionation may be possible but remains to be investigated in non-Caucasian populations with more advanced disease, with a higher proportion of patients requiring mastectomy as well as tumour bed boost. We are reporting the design of randomized controlled trial testing the hypothesis that a 1-week (5 fractions) regimen of radiotherapy will be non-inferior to a standard 3-week (15 fractions) schedule.Methods: We describe a multicentre, randomized controlled trial recruiting patients at large academic centres across India. Patients without distant metastases who merit adjuvant radiotherapy will be eligible for inclusion in the study. Patients in the control arm will receive adjuvant radiotherapy to the breast or chest wall (with/without regional nodes) to a dose of 40 Gy/15 fractions/3 weeks, while those in the experimental arm will receive a dose of 26 Gy/5 fractions/1 week (to the same volume). The use of a simultaneous integrated boost (dose of 8 Gy and 6 Gy, respectively) is allowed in patients who have undergone breast conservation. A sample size of 2100 patients provides an 80% power to detect a non-inferiority of 3% in the 5-year locoregional recurrence rate with a one-sided type I error of 2.5%, assuming that the locoregional recurrence rate in the control arm is 5% at 5 years (corresponding to a hazard ratio of 1.63). Patients will be recruited over a period of 5 years and followed up for a further 5 years thereafter.Discussion: If a five-fraction regimen of breast cancer is proven to be non-inferior, this will result in a significant improvement in the access to radiotherapy, as well as reduced costs of treatment. The trial gives an opportunity to standardize and quality-assure radiotherapy practices across the nation at the same time. Along with the results of the FAST-Forward trial, the safety of this intervention in advanced node-positive disease requiring regional nodal radiation will be established.Trial Registration: The trial has been registered at the Clinical Trial Registry of India (CTRI) vide registration number: CTRI/2018/12/016816 (December 31, 2018) as well as the ClinicalTrial.gov website at NCT03788213 (December 28, 2018). [ABSTRACT FROM AUTHOR]

Background: The definition of clinical target volume (CTV) in intensity modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) has not been addressed. We performed this study to assess the feasibility and efficacy of using IMRT with reduced-volume CTV for the treatment of nasopharyngeal carcinoma.Methods: We retrospectively reviewed 293 non-metastatic NPC patients treated with IMRT from 2002 to 2013. A total of 180 matched cases finally included with 90 received conventional-volume IMRT (CV-IMRT) and 90 received reduced-volume IMRT (RV-IMRT). Kaplan-Meier method and log-rank tests were used to compare NPC-specific survival. Multivariate analyses using the Cox proportional hazards model were conducted to detect independent predictors.Results: With a median follow-up of 70 months, the 3-year overall survival, progression-free survival, distant metastasis-free survival, local recurrence-free survival, regional recurrence-free survival, locoregional recurrence-free survival rates were 88.9, 84.4, 92.2, 91.1, 98.9, 91.1% for the CV-IMRT arm and 92.2, 85.6, 90.0, 93.3, 98.9, 93.3% for the RV-IMRT arm, respectively. None significant survival difference was observed. Additionally, RV-IMRT was associated with reduced risk of late xerostomia (P = 0.039) and hearing loss (P = 0.008), compared versus CV-IMRT.Conclusions: The use of RV-IMRT for the treatment of NPC led to comparable survival condition and truly reduced toxicity reactions compared versus CV-IMRT. [ABSTRACT FROM AUTHOR]

Introduction: The ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Currently, there are no recommendations for an inclusion of the 'true' AILD in the clinical target volume (CTV) of definitive chemoradiation for anal cancer patients. To estimate the relevance of inguinal recurrence, we compared the incidental dose to the AILD in anal cancer (AC) patients who were treated either with Volumetric Arc Therapy - Intensity Modulated Radiation Therapy (VMAT-IMRT) or conventional 3D-radiation technique.Methods: One VMAT-IMRT-plans and one 3D-plans were calculated on the same target volumes and identical dose prescription in ten patients. We defined the volume of the AILD on the planning CT-scans based on the information of new fluorescence methods. Furthermore, we defined several anatomical subvolumes of interest inside the AILD. We examined and compared absolute and relative dosimetric parameters of the AILD and different anatomical subunits.Results: The Dmean of the AILD was 40 Gy in the 3D-group and 38 Gy in the IMRT-group. Dmean and Dmedian as well as the V30Gy of the AILD and all subvolumes of the caudal AILD were significant higher using 3D-RT compared to IMRT. Even though the absolute differences were small, in the caudal aspect of the ano-inguinal lymphatic drainage the V30Gy could be more than 10% less with VMAT-IMRT.Conclusions: 3D-RT was slightly superior to IMRT in terms of dose coverage of the AILD. However, the absolute differences were very small. Some relevant caudal parts of the AILD received an insufficient dose for treating potential micrometastases. Particularly in high-risk situations, this may lead to inguinal recurrence and therefore the true deep AILD should be included into the target volume in high risk patients. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard treatment for patients with locally advanced non-metastatic rectal cancer is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU) followed by surgery, but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. Methods: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic rectal cancer patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-three patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. Results: We have highlighted 384 differentially abundant proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially abundant proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Data are available via ProteomeXchange with identifier PXD008440. Conclusions: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic rectal cancer. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment. [ABSTRACT FROM AUTHOR]