A CT-based radiomics classification model for the prediction of histological type and tumour grade in retroperitoneal sarcoma (RADSARC-R): a retrospective multicohort analysis.

BACKGROUND: Retroperitoneal sarcomas are tumours with a poor prognosis. Upfront characterisation of the tumour is difficult, and under-grading is common. Radiomics has the potential to non-invasively characterise the so-called radiological phenotype of tumours. We aimed to develop and independently validate a CT-based radiomics classification model for the prediction of histological type and grade in retroperitoneal leiomyosarcoma and liposarcoma. METHODS: A retrospective discovery cohort was collated at our centre (Royal Marsden Hospital, London, UK) and an independent validation cohort comprising patients recruited in the phase 3 STRASS study of neoadjuvant radiotherapy in retroperitoneal sarcoma. Patients aged older than 18 years with confirmed primary leiomyosarcoma or liposarcoma proceeding to surgical resection with available contrast-enhanced CT scans were included. Using the discovery dataset, a CT-based radiomics workflow was developed, including manual delineation, sub-segmentation, feature extraction, and predictive model building. Separate probabilistic classifiers for the prediction of histological type and low versus intermediate or high grade tumour types were built and tested. Independent validation was then performed. The primary objective of the study was to develop radiomic classification models for the prediction of retroperitoneal leiomyosarcoma and liposarcoma type and histological grade. FINDINGS: 170 patients recruited between Oct 30, 2016, and Dec 23, 2020, were eligible in the discovery cohort and 89 patients recruited between Jan 18, 2012, and April 10, 2017, were eligible in the validation cohort. In the discovery cohort, the median age was 63 years (range 27-89), with 83 (49%) female and 87 (51%) male patients. In the validation cohort, median age was 59 years (range 33-77), with 46 (52%) female and 43 (48%) male patients. The highest performing model for the prediction of histological type had an area under the receiver operator curve (AUROC) of 0·928 on validation, based on a feature set of radiomics and approximate radiomic volume fraction. The highest performing model for the prediction of histological grade had an AUROC of 0·882 on validation, based on a radiomics feature set. INTERPRETATION: Our validated radiomics model can predict the histological type and grade of retroperitoneal sarcomas with excellent performance. This could have important implications for improving diagnosis and risk stratification in retroperitoneal sarcomas. FUNDING: Wellcome Trust, European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group, the National Institutes for Health, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.

Acoustic Analysis of Voluntary Coughs, Throat Clearings, and Induced Reflexive Coughs in a Healthy Population.

Cough efficacy is considered a reliable predictor of the aspiration risk in head and neck cancer patients with radiation-associated dysphagia. Currently, coughing is assessed perceptually or aerodynamically. The goal of our research is to develop methods of acoustic cough analysis. In this study, we examined in a healthy population the acoustical differences between three protective maneuvers: voluntary cough, voluntary throat clearing, and induced reflexive cough. Forty healthy participants were included in this study. Voluntary cough, voluntary throat clearing, and reflexive cough samples were recorded and analyzed acoustically. Temporal acoustic features were the following: the slope and curvature of the amplitude contour, as well as the average, slope, and curvature of the sample entropy and kurtosis contours of the recorded signal. Spectral features were the relative energy in the frequency bands (0-400 Hz, 400-800 Hz, 800-1600 Hz, 1600 Hz-3200 Hz, > 3200 Hz) as well as the weighted spectral energy. Results showed that, compared to a voluntary cough, a throat clearing starts with a weaker onset pulse and involves oscillations from the onset to the offset (concave curvature of the amplitude contour, p < 0.05), lower average (p < 0.05), and slope (p < 0.05) as well as lower convex curvature (p < 0.05) of the kurtosis contour. An induced reflexive cough starts with a higher and briefer onset burst and includes higher frication noise (larger convexity of the curvature of the amplitude and kurtosis contours (p < 0.05)) compared to a voluntary cough. The conclusion is that voluntary coughs are acoustically significantly different from voluntary throat clearings and induced reflexive coughs.

Intraoperative electron radiotherapy in early invasive ductal breast cancer: 6-year median follow-up results of a prospective monocentric registry.

BACKGROUND: Intraoperative electron radiotherapy (IOERT) can be used to treat early breast cancer during the conservative surgery thus enabling shorter overall treatment times and reduced irradiation of organs at risk. We report on our first 996 patients enrolled prospectively in a registry trial. METHODS: At Jules Bordet Institute, from February 2010 onwards, patients underwent partial IOERT of the breast. Women with unifocal invasive ductal carcinoma, aged 40 years or older, with a clinical tumour size ≤ 20 mm and tumour-free sentinel lymph node (on frozen section and immunohistochemical analysis). A 21 Gy dose was prescribed on the 90% isodose line in the tumour bed with the energy of 6 to 12 MeV (Mobetron®-IntraOp Medical). RESULTS: Thirty-seven ipsilateral tumour relapses occurred. Sixteen of those were in the same breast quadrant. Sixty patients died, and among those, 12 deaths were due to breast cancer. With 71.9 months of median follow-up, the 5-year Kaplan-Meier estimate of local recurrence was 2.7%. CONCLUSIONS: The rate of breast cancer local recurrence after IOERT is low and comparable to published results for IORT and APBI. IOERT is highly operator-dependent, and appropriate applicator sizing according to tumour size is critical. When used in a selected patient population, IOERT achieves a good balance between tumour control and late radiotherapy-mediated toxicity morbidity and mortality thanks to insignificant irradiation of organs at risk.

Recent advances in radiosensitivity determinants in melanoma.

PURPOSE OF REVIEW: Radiotherapy has been proven to be useful but insufficient in melanoma management due to the intrinsic radioresistance of melanoma cells. Elucidation of the molecular mechanisms and pathways related to resistance/sensitivity to radiotherapy in melanoma is of paramount importance. In this review, we will summarize and discuss the recent 'discoveries' and advances in radiosensitivity determinants in melanoma. RECENT FINDINGS: The different levels of radiosensitivity among the various melanoma tumors could be attributed to the DNA damage signaling and repair proteins, tumor microenvironment, hypoxia, cell metabolism, glutathione and redox balance, protein kinase signaling pathways as well as pigmentation and melanin content. SUMMARY: It is therapeutically important to elucidate the factors involved in radiation resistance/sensitivity of melanoma. More importantly, improving radiosensitivity may 'widen the clinical utility' in melanoma of this important therapeutic modality.

Meta-Analysis on Induction Chemotherapy in Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: Concurrent chemo radiotherapy (CCRT) has been the standard of care in locally advanced nasopharyngeal carcinoma (LA-NPC) for many years. The role of induction chemotherapy (ICT) has always been controversial. This systematic review and meta-analysis investigates the value of adding ICT to CCRT in LA-NPC. MATERIALS AND METHODS: Two reviewers independently assessed the eligibility of randomized controlled trials (RCTs) comparing ICT followed by CCRT versus CCRT alone, including treatment-naive adult patients with histologically proven nonmetastatic LA-NPC. RESULTS: Eight RCTs with in total 2,384 randomized patients, of whom 69% had N2-N3 disease, were selected. ICT was the allocated treatment in 1,200 patients, of whom 1,161 actually received this. Treatment compliance varied, with a median rate of 92% (range, 86%-100%) of patients receiving all cycles of ICT. The percentage of patients completing radiotherapy was 96% and 95% [(Combined Risk difference(CRD)= 0.004; 95% Confidence Interval (CI) -0.001-0.01; p = 0.14)] in the ICT group and CCRT group, respectively, whereas chemotherapy during radiotherapy could be completed in only 28% of the ICT group versus 61% in the CCRT group (CRD, -0.243; 95% CI, -0.403 to -0.083; p = .003). Grade 3-4 acute toxicity was mostly hematologic during the ICT phase (496 events vs. 191 nonhematologic) and was predominant in the ICT group (1,596 events vs. 1,073 in the CCRT alone group) during the CCRT. Adding ICT to CCRT provided a significant benefit in overall survival (hazard ratio [HR], 0.680; 95% CI, 0.511-0.905; p = .001) and progression-free survival (HR, 0.657; 95% CI, 0.568-0.760; p < .001). CONCLUSION: Although ICT followed by CCRT is associated with more acute toxicity and a lower compliance of the chemotherapy during the CCRT phase, this association resulted in a clinically meaningful survival benefit. ICT should be considered as a standard option in patients with LA-NPC, but further study on optimal patient selection for this treatment is warranted. IMPLICATIONS FOR PRACTICE: Locally advanced nasopharyngeal carcinoma (LA-NPC) is a relatively common disease in some parts of the world, with a rather poor prognosis due to its high metastatic potential. The role of induction chemotherapy (ICT) has always been controversial. This meta-analysis found that ICT followed by concurrent chemoradiotherapy (CCRT) in LA-NPC is associated with a significant clinical improvement in both overall survival and progression-free survival compared with CCRT alone. ICT should be considered as a standard option in patients with LA-NPC.

Prophylactic gastrostomy in locally advanced head and neck cancer: results of a national survey among radiation oncologists.

BACKGROUND: Nutritional complications in patients with locally advanced head and neck cancer (LA-HNC) treated by concurrent chemoradiotherapy (CCRT) often lead to placement of a prophylactic gastrostomy (PG) tube, while indication lacks harmonization. Our aim was to explore the current PG tube utilization among Belgian radiation oncology centers. METHODS: A survey was distributed to all 24 Belgian Radiation oncology departments, with questions about the number of patient treated per year, whether the PG indication is discussed at the multidisciplinary board, placement technique, time of starting nutrition and removal, its impact on swallowing function and importance of clinical factors. For the latter Relative Importance and Discordance Indexes were calculated to describe the ranking and agreement. RESULTS: All 24 centers submitted the questionnaire. Twenty three treat more than 20 head and neck (HNC) patients per year, while four (1 in 21-50; 3 in 51-100) are not discussing the gastrostomy tube indication at the multidisciplinary board. For the latter, endoscopic placement (68%) is the dominant technique, followed by the radiologic (16%) and laparoscopic (16%) methods. Seventy-five percent start the enteral nutrition when clinically indicated, 17% immediately and 8% from the start of radiotherapy. Majority of specialists (19/24) keep the gastrostomy tube until the patient assume an adequate oral feeding. Fifteen centres are considering PG decrease swallowing function. Regarding factors and their importance in the decision for the PG, foreseen irradiated volume reached highest importance, followed by 'anatomical site', 'patients' choice' and 'postoperative versus definitive' and 'local expertise', with decreasing importance respectively. Disagreement indexes showed moderate variation. CONCLUSIONS: The use of a PG tube for LAHNC patients treated by CCRT shows disparity at national level. Prospective studies are needed to ensure proper indication of this supportive measure.

Neo-CheckRay: radiation therapy and adenosine pathway blockade to increase benefit of immuno-chemotherapy in early stage luminal B breast cancer, a randomized phase II trial.

BACKGROUND: Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC. METHODS: The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/- durvalumab +/- oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk. DISCUSSION: combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates. TRIAL REGISTRATION: trial registered on ClinicalTrials.gov ( NCT03875573 ) on March 14th, 2019.

Checkpoint inhibition in combination with an immunoboost of external beam radiotherapy in solid tumors (CHEERS): study protocol for a phase 2, open-label, randomized controlled trial.

BACKGROUND: While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors. METHODS/DESIGN: Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study's primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples. DISCUSSION: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018.

Immune checkpoint blockade for organ transplant patients with advanced cancer: how far can we go?

PURPOSE OF REVIEW: Checkpoint inhibitors (CPIs) provide impressive response rates among immunocompetent patients with various solid tumors. So far, organ transplant recipients have been excluded from clinical studies due to the putative risk of allograft rejection however 48 cases of liver and renal transplant patients treated with CPI were already described in literature. RECENT FINDINGS: Here we discuss 19 cases of liver and 29 cases of renal transplant patients who received CPI for advanced cancer. Disease control rate [stable disease, complete response (CR) and partial response (PR) together] was 35% (21% for liver and 45% for kidney transplant patients). Graft rejection was seen in 37% of liver and 45% and kidney transplant patients. Significantly, our analysis shows that an 'ideal' response occurs in 21% of all patients (antitumor response accompanied with durable graft tolerance). SUMMARY: We believe that transplant patients can be treated with CPI in a controlled setting and for well informed patients. To obtain a durable antitumor immune response while avoiding rejection, to be able to adjust immunosuppression and to have the opportunity to develop biomarkers for tumor response and transplant rejection, these patients should be treated according to a clinical care path or a prospective clinical trial.

A feasibility study on adaptive 18F-FDG-PET-guided radiotherapy for recurrent and second primary head and neck cancer in the previously irradiated territory.

PURPOSE: To evaluate feasibility, disease control, survival, and toxicity after adaptive 18F-fluorodeoxyglucose (FDG) positron emisson tomography (PET) guided radiotherapy in patients with recurrent and second primary head and neck squamous cell carcinoma. METHODS: A prospective trial investigated the feasibility of adaptive intensity modulated radiotherapy (IMRT) ± concomitant cetuximab in 10 patients. The primary endpoint was achieving a 2-year survival free of grade >3 toxicity in ≥30% of patients. Three treatment plans based on 3 PET/CT scans were consecutively delivered in 6 weeks. The range of dose painting was 66.0-85.0 Gy in the dose-painted tumoral volumes in 30 fractions. RESULTS: Two-year locoregional and distant control rates were 38 and 76%, respectively. Overall and disease-free survival at 2 years was 20%. No grade 4 or 5 acute toxicity was observed in any of the patients, except for arterial mucosal hemorrhage in 1 patient. Three months after radiotherapy, grade 4 dysphagia and mucosal wound healing problems were observed in 1/7 and 1/6 of patients, respectively. Grade 5 toxicity (fatal bleeding) was seen in 2 patients, at 3.8 and 4.1 months of follow-up. Data on 2­year toxicity could only be assessed in 1 of the 2 surviving patients, in whom grade 4 mucosal wound healing problems were observed; no other grade >3 toxicity was observed. In this respect, a 30% 2­year survival free of grade >3 toxicity will not be achieved. CONCLUSIONS: Adaptive PET-guided reirradiation is feasible. However, due to slow accrual and treatment results that seemed inconsistent with achieving the primary endpoint, the trial was stopped early.

Unusual presentation of a hepatocellular carcinoma as a potential late side effect of radiotherapy in a patient treated for Wilms tumor in childhood.

BACKGROUND: The development of a second primary tumor is a potential late side effect of radiotherapy. Particularly, an increased risk of secondary cancers, mostly of digestive or breast origin, has been observed in patients treated with high-dose radiotherapy for Wilms tumor (WT) in childhood. However, hepatocellular carcinoma (HCC) has been very rarely described as a potentially radiotherapy-induced tumor. We describe the case of a patient with an aggressive HCC 50 years after the treatment of a WT. CASE PRESENTATION: A 49-year old man, treated at the age of 6 weeks for a right WT by a right nephrectomy and adjuvant radiotherapy, presented with a right abdominal mass. Imaging demonstrated a 100-mm tumor invading the inferior segment of the right liver, the right colon and the right psoas muscle. The patient had no previous history of liver disease, nor of alcohol consumption, and hepatitis serologies were negatives. Biopsy demonstrated a poorly differentiated tumor of unknown origin. A panel of tumor markers was negative. Explorative surgery has been performed allowing en bloc R0 tumor resection, including resection of segments VI and VII of the liver, right hemicolectomy and resection of the anterior sheet of the right psoas muscle. Pathological examination revealed a poorly differentiated HCC. No signs of cirrhosis or chronic liver disease were observed in the non-tumor liver. Twenty weeks after surgery, the patient developed a multifocal tumor recurrence that was treated with intra-arterial 90Yttrium radioembolization. CONCLUSION: In this case, the absence of risk factors for HCC, such as cirrhosis, viral hepatitis and chronic liver disease, highly suggests the development of HCC to be related to previous high-dose radiation therapy given for a right WT to a field involving the inferior part of the liver. This observation shows radiotherapy to/near the liver, particularly in childhood, to be a potential risk factor for HCC, stressing the need for a long-term specific follow-up in patients irradiated in childhood.

Feasibility of tongue strength measurements during (chemo)radiotherapy in head and neck cancer patients.

PURPOSE: The aim of this study was to investigate the feasibility of tongue strength measures (TSMs) and the influence of bulb location, sex, and self-perceived pain and mucositis in head and neck cancer (HNC) patients during chemoradiotherapy (CRT). METHODS: Twenty-six newly diagnosed HNC patients treated with CRT performed anterior and posterior maximal isometric tongue pressures by means of the Iowa Oral Performance Instrument (IOPI). The Oral Mucositis Weekly Questionnaire (OMWQ) and a Visual Analogue Scale (VAS) for pain during swallowing were completed weekly from baseline to 1 week post CRT. RESULTS: Feasibility of TSMs during CRT declines significantly from 96 to 100% at baseline to 46% after 6 weeks of CRT. But post-hoc analyses reveal only significant differences in feasibility between baseline and measurements after 4 weeks of treatment. No effect of gender or bulb location was established, but feasibility is influenced by pain and mucositis. CONCLUSIONS: Feasibility of TSMs declines during CRT and is influenced by mucositis and pain. For the majority of subjects, TSMs were feasible within the first 4 weeks, which provides a window of scientific and clinical opportunities in this patient population.

The Outcome of the First 100 Nasopharyngeal Cancer Patients in Thailand Treated by Helical Tomotherapy.

BACKGROUND: The aim of the study was to analyse of two-year loco-regional failure free survival (LRFFS), distant metastasis free survival (DMFS), overall survival (OS), and toxicity outcomes of the first 100 nasopharyngeal carcinoma patients in Thailand treated by helical tomotherapy. PATIENTS AND METHODS: Between March 2012 and December 2015, 100 patients with non-metastatic nasopharyngeal carcinoma were treated by helical tomotherapy. All patients were treated by platinum-based concurrent chemoradiotherapy and adjuvant or neo-adjuvant chemotherapy. RESULTS: The median age was 51 years (interquartile ranges [IQR]: 42.5-57.0). The mean ± SD of D95% of planning target volume (PTV) 70, 59.4 and 54 were 70.2 ± 0.5, 59.8 ± 0.6, and 54.3 ± 0.8 Gy, respectively. The mean ± SD of conformity index, and homogeneity index were 0.89 ± 0.13 and 0.06 ± 0.07. Mean ± SD of D2 % of spinal cord and brainstem were 34.1 ± 4.4 and 53.3 ±6.3 Gy. Mean ± SD of D50 of contralateral and ipsilateral parotid gland were 28.4 ± 6.7 and 38.5 ± 11.2 Gy. At a median follow-up of 33 months (IQR: 25-41), the 2-year LRFFS, DMFS, OS were 94% (95%CI: 87-98%), 96% (95% CI: 89-98%), and 99% (95% CI: 93-100%), respectively. Acute grade 3 dermatitis, pharyngoesophagitis, and mucositis occurred in 5%, 51%, and 37%, respectively. Late pharyngoesophagitis grade 0 and 1 were found in 98% and 2% of patients. Late xerostomia grade 0, 1 and 2 were found in 17%, 78% and 5%, respectively. CONCLUSIONS: Helical tomotherapy offers good dosimetric performance and achieves excellent treatment outcome in nasopharyngeal carcinoma patients.

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.

BACKGROUND: Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed. METHODS: We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate. RESULTS: A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce. CONCLUSION: This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated. IMPLICATIONS FOR PRACTICE: Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.

Helical tomotherapy in head and neck cancer: a European single-center experience.

BACKGROUND: We report on a retrospective analysis of 147 patients with early and locoregionally advanced squamous cell head and neck cancer (SCCHN) treated with helical tomotherapy (HT). PATIENTS AND METHODS: Included were patients with SCCHN of the oral cavity (OC), oropharynx (OP), hypopharynx (HP), or larynx (L) consecutively treated in one radiotherapy center in 2008 and 2009. The prescribed HT dose was 60-66 Gy in the postoperative setting (group A) and 66-70 Gy when given as primary treatment (group B). HT was given alone, concurrent with systemic therapy (ST), that is, chemotherapy, biotherapy, or both, and with or without induction therapy (IT). Acute and late toxicities are reported using standard criteria; locoregional failure/progression (LRF), distant metastases (DM), and second primary tumors (SPT) were documented, and event-free survival (EFS) and overall survival (OS) were calculated from the start of HT. RESULTS: Group A patients received HT alone in 22 cases and HT + ST in 20 cases; group B patients received HT alone in 17 cases and HT + ST in 88 cases. Severe (grade ≥ 3) acute mucosal toxicity and swallowing problems increased with more additional ST. After a median follow-up of 44 months, grade ≥2 late toxicity after HT + ST was approximately twice that of HT alone for skin, subcutis, pharynx, and larynx. Forty percent had grade ≥2 late xerostomia, and 29% had mucosal toxicity. At 3 years, LRF/DM/SPT occurred in 7%/7%/17% and 25%/13%/5% in groups A and B, respectively, leading to a 3-year EFS/OS of 64%/74% and 56%/63% in groups A and B, respectively. CONCLUSION: The use of HT alone or in combination with ST is feasible and promising and has a low late fatality rate. However, late toxicity is nearly twice as high when ST is added to HT.

The radiosensitising effect of gemcitabine and its main metabolite dFdU under low oxygen conditions is in vitro not dependent on functional HIF-1 protein.

BACKGROUND: Regions within solid tumours often experience oxygen deprivation, which is associated with resistance to chemotherapy and irradiation. The aim of this study was to evaluate the radiosensitising effect of gemcitabine and its main metabolite dFdU under normoxia versus hypoxia and to determine whether hypoxia-inducible factor 1 (HIF-1) is involved in the radiosensitising mechanism. METHODS: Stable expression of dominant negative HIF-1α (dnHIF) in MDA-MB-231 breast cancer cells, that ablated endogenous HIF-1 transcriptional activity, was validated by western blot and functionality was assessed by HIF-1α activity assay. Cells were exposed to varying oxygen environments and treated with gemcitabine or dFdU for 24 h, followed by irradiation. Clonogenicity was then assessed. Using radiosensitising conditions, cells were collected for cell cycle analysis. RESULTS: HIF-1 activity was significantly inhibited in cells stably expressing dnHIF. A clear radiosensitising effect under normoxia and hypoxia was observed for both gemcitabine and dFdU. No significant difference in radiobiological parameters between HIF-1 proficient and HIF-1 deficient MDA-MB-231 cells was demonstrated. CONCLUSIONS: For the first time, radiosensitisation by dFdU, the main metabolite of gemcitabine, was demonstrated under low oxygen conditions. No major role for functional HIF-1 protein in radiosensitisation by gemcitabine or dFdU could be shown.

C. elegans: A potent model for high-throughput screening experiments investigating the FLASH effect.

This study explores the effects of UHDR irradiation on Caenorhabditis elegans embryos. UHDR proton and electron beams demonstrate a sparing effect, aligning with literature findings. This highlights C. elegans suitability as a screening model for studying the LET impact on the FLASH effect, reinforcing its potential in radiation research.

The potential of helical tomotherapy in the treatment of head and neck cancer.

A decade after its first introduction into the clinic, little is known about the clinical impact of helical tomotherapy (HT) on head and neck cancer (HNC) treatment. Therefore, we analyzed the basics of this technique and reviewed the literature regarding HT's potential benefit in HNC. The past two decades have been characterized by a huge technological evolution in photon beam radiotherapy (RT). In HNC, static beam intensity-modulated radiotherapy (IMRT) has shown superiority over three-dimensional conformal RT in terms of xerostomia and is considered the standard of care. However, the next-generation IMRT, the rotational IMRT, has been introduced into the clinic without any evidence of superiority over static beam IMRT other than being substantially faster. Of these rotational techniques, HT is the first system especially developed for IMRT in combination with image-guided RT. HT is particularly promising for the treatment of HNC because its sharp dose gradients maximally spare the many radiosensitive organs at risk nearby. In addition, HT's integrated computed tomography scan assures a very precise dose administration and allows for some adaptive RT. Because HT is specifically developed for IMRT in combination with (integrated) image-guidance, it allows for precise dose distribution ("dose painting"), patient setup, and dose delivery. As such, it is an excellent tool for difficult HNC irradiation. The literature on the clinical results of HT in HNC all show excellent short-term (≤2 years) results with acceptable toxicity profiles. However, properly designed trials are still warranted to further substantiate these results.

The current understanding of the immune landscape relative to radiotherapy across tumor types.

Radiotherapy is part of the standard of care treatment for a great majority of cancer patients. As a result of radiation, both tumor cells and the environment around them are affected directly by radiation, which mainly primes but also might limit the immune response. Multiple immune factors play a role in cancer progression and response to radiotherapy, including the immune tumor microenvironment and systemic immunity referred to as the immune landscape. A heterogeneous tumor microenvironment and the varying patient characteristics complicate the dynamic relationship between radiotherapy and this immune landscape. In this review, we will present the current overview of the immunological landscape in relation to radiotherapy in order to provide insight and encourage research to further improve cancer treatment. An investigation into the impact of radiation therapy on the immune landscape showed in several cancers a common pattern of immunological responses after radiation. Radiation leads to an upsurge in infiltrating T lymphocytes and the expression of programmed death ligand 1 (PD-L1) which can hint at a benefit for the patient when combined with immunotherapy. In spite of this, lymphopenia in the tumor microenvironment of 'cold' tumors or caused by radiation is considered to be an important obstacle to the patient's survival. In several cancers, a rise in the immunosuppressive populations is seen after radiation, mainly pro-tumoral M2 macrophages and myeloid-derived suppressor cells (MDSCs). As a final point, we will highlight how the radiation parameters themselves can influence the immune system and, therefore, be exploited to the advantage of the patient.

Assessment of radio(chemo)therapy-related dysphagia in head and neck cancer patients based on cough-related acoustic features: a prospective phase II national clinical trial (ACCOUGH-P/A trial).

BACKGROUND: Radiation-associated dysphagia is defined as impaired swallowing efficiency/safety following (chemo)radiotherapy in head and neck cancer patients. In a dysphagia framework, impaired coughing may lead to lung aspiration and fatal lung infection. Although cough efficacy is a predictor of the risk of aspiration, cough investigation is minimal in patients with radiation-associated dysphagia. Because cough is a transient signal, existing software for speech analysis are not appropriate. The goal of our project is to develop an assessment method using acoustic features related to voluntary and reflexive coughs as biomarkers of the risk of penetration/aspiration in patients with radiation-associated dysphagia. METHODS: Healthy subjects and head and neck cancer patients with and without dysphagia will produce voluntary coughs, throat clearings and reflexive coughs. Recordings will be made using an acoustic microphone and a throat microphone. The recorded signals will be manually segmented and subsequently analysed with a software under development. Automatic final segmentation enables to measure cough duration. The first method of analysis includes temporal features: the amplitude contour, the sample entropy and the kurtosis. These features report respectively the strength, the unpredictability (turbulence noise due to the air jet) and the impulsive quality (burst) of the signal. The second method of analysis consists of a spectral decomposition of the relative cough signal energy into several frequency bands (0-400 Hz, 400-800 Hz, 800-1600 Hz, 1600-3200 Hz, > 3200 Hz). The primary outcome of this exploratory research project is the identification of a set of descriptive acoustic cough features in healthy subjects as reference data (ACCOUGH). The secondary outcome of this research in head and neck cancer patients with radiation-associated dysphagia includes the identification of (1) a set of descriptive acoustic cough features as biomarkers of penetration-aspiration (ACCOUGH-P/A), (2) swallowing scores, (3) voice features and (4) aerodynamic cough features. DISCUSSION: This study is expected to develop methods of acoustic cough analysis to enhance the assessment of radiation-associated dysphagia in head and neck cancer patients following (chemo)radiation. TRIAL REGISTRATION: International Standard Randomized Controlled Trials Number (ISRCTN) registry ISRCTN16540497. Accepted on 23 June 2023.