Delayed DNA double-strand break repair following platin-based chemotherapy predicts treatment response in head and neck squamous cell carcinoma.

INTRODUCTION: The aim of this study was to investigate if defective repair of DNA double-strand break (DSB) in head and neck squamous cell carcinoma (HNSCC) could be used as an early predictor of treatment response. METHODS: Tumour biopsy 24-36 h following induction chemotherapy (IC) and pre-treatment biopsies were stained for RAD51 and geminin (S-phase marker) for immunofluorescence in patients with HNSCC. The difference between RAD51 score (percentage of geminin-positive cells that were also positive for RAD51) was calculated for the two specimens. Tumours with a percentage difference of⩽10% were deemed to have repaired IC-induced DSBs, and were classified as 'RAD51 negative'. Response at 3 months post treatment and human papilloma virus (HPV) status were assessed. RESULTS: Thirteen pairs of samples were available for analyses. Three samples were classified as RAD51 negative and 10 as RAD51 positive at 24 h post IC. All of the three patients with tumours classified as RAD51 negative had partial response or progressive disease and the 10 patients with tumours deemed RAD51 positive had a complete response. 100% of the HPV-positive tumours were RAD51 positive and had a complete response. CONCLUSIONS: We have demonstrated that impaired DSB DNA repair may underlie enhanced treatment sensitivity of HPV-positive HNSCC and repair capacity following platinum-induced DNA damage predicts response in HNSCC. This has potential as a biomarker for patient selection in trials of DNA damage response pathway modulation.

Evaluation of radiotherapy techniques for radical treatment of lateralised oropharyngeal cancers : Dosimetry and NTCP.

AIM: The aim of this study was to investigate potential advantages and disadvantages of three-dimensional conformal radiotherapy (3DCRT), multiple fixed-field intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) in terms of dose to the planning target volume (PTV), organs at risk (OARs) and normal tissue complication probability (NTCP) for delivering ipsilateral radiotherapy. MATERIALS AND METHODS: 3DCRT, IMRT and VMAT were compared in patients with well-lateralised primary tonsillar cancers who underwent primary radical ipsilateral radiotherapy. The following parameters were compared: conformity index (CI); homogeneity index (HI); dose-volume histograms (DVHs) of PTVs and OARs; NTCP, risk of radiation-induced cancer and dose accumulation during treatment. RESULTS: IMRT and VMAT were superior to 3DCRT in terms of CI, HI and dose to the target volumes, as well as mandible and dose accumulation robustness. The techniques were equivalent in terms of dose and NTCP for the contralateral oral cavity, contralateral submandibular gland and mandible, when specific dose constraint objectives were used on the oral cavity volume. Although the volume of normal tissue exposed to low-dose radiation was significantly higher with IMRT and VMAT, the risk of radiation-induced secondary malignancy was dependant on the mathematical model used. CONCLUSION: This study demonstrates the superiority of IMRT/VMAT techniques over 3DCRT in terms of dose homogeneity, conformity and consistent dose delivery to the PTV throughout the course of treatment in patients with lateralised oropharyngeal cancers. Dosimetry and NTCP calculations show that these techniques are equivalent to 3DCRT with regard to the risk of acute mucositis when specific dose constraint objectives were used on the contralateral oral cavity OAR.

A phase II trial of induction chemotherapy and chemo-IMRT for head and neck squamous cell cancers at risk of bilateral nodal spread: the application of a bilateral superficial lobe parotid-sparing IMRT technique and treatment outcomes.

PURPOSE: To determine the feasibility of induction chemotherapy and chemo-IMRT in head and neck squamous cell cancers at risk of bilateral nodal spread (midline tumours) and to evaluate whether bilateral superficial lobe parotid-sparing IMRT can reduce the incidence of ⩾G2 subjective xerostomia. METHODS: Patients with midline tumours were enrolled to a phase II trial to receive induction platinum/5-fluorouracil and concomitant platinum with combined superficial lobe parotid-sparing IMRT. The primary site and involved nodal levels received 65 Gy in 30 fractions (f) and at risk nodal levels, 54 Gy/30f. Incidence of ⩾G2 subjective xerostomia was defined as the primary endpoint. Secondary endpoints included incidences of acute and late toxicities and survival outcomes dependent on human papilloma virus (HPV) status. RESULTS: One hundred and twenty patients with midline cancers completed treatment between December 2005 and May 2010 with median follow-up of 50 months. Incidences of ⩾G2 acute toxicities were: dysphagia 75%; xerostomia 65%; mucositis 86%; pain 83%; and fatigue 64%. At 12 months, ⩾G2 subjective xerostomia was observed in 21% (17% in HPV +ve). Two-year loco-regional progression-free survival (PFS) was 90.7% (95% CI: 85.2-96.2). According to HPV status, there was a significant difference for 2-year loco-regional PFS, 76.8% (HPV-negative) vs 98.6% (HPV-positive), P=0.001. 2-year overall survival was 93% for HPV-positive compared with 52% for HPV-negative cases, P<0.001. CONCLUSIONS: Sequential chemotherapy/chemo-IMRT for midline tumours is feasible, with excellent survival outcomes. At 1 year, 21% experience ⩾G2 subjective xerostomia. Two-year survival outcomes differ significantly between HPV-positive and HPV-negative disease, suggesting development of different treatment schedules for the different disease entities.

Accuracy of ringless casting and accelerated wax-elimination technique: a comparative in vitro study.

PURPOSE: The purpose of this study was to determine whether the ringless casting and accelerated wax-elimination techniques can be combined to offer a cost-effective, clinically acceptable, and time-saving alternative for fabricating single unit castings in fixed prosthodontics. MATERIALS AND METHODS: Sixty standardized wax copings were fabricated on a type IV stone replica of a stainless steel die. The wax patterns were divided into four groups. The first group was cast using the ringless investment technique and conventional wax-elimination method; the second group was cast using the ringless investment technique and accelerated wax-elimination method; the third group was cast using the conventional metal ring investment technique and conventional wax-elimination method; the fourth group was cast using the metal ring investment technique and accelerated wax-elimination method. The vertical marginal gap was measured at four sites per specimen, using a digital optical microscope at 100× magnification. The results were analyzed using two-way ANOVA to determine statistical significance. RESULTS: The vertical marginal gaps of castings fabricated using the ringless technique (76.98 ± 7.59 µm) were significantly less (p < 0.05) than those castings fabricated using the conventional metal ring technique (138.44 ± 28.59 µm); however, the vertical marginal gaps of the conventional (102.63 ± 36.12 µm) and accelerated wax-elimination (112.79 ± 38.34 µm) castings were not statistically significant (p > 0.05). CONCLUSIONS: The ringless investment technique can produce castings with higher accuracy and can be favorably combined with the accelerated wax-elimination method as a vital alternative to the time-consuming conventional technique of casting restorations in fixed prosthodontics.

Understanding the Benefit of Magnetic Resonance-guided Adaptive Radiotherapy in Rectal Cancer Patients: a Single-centre Study.

AIMS: Neoadjuvant chemoradiotherapy followed by surgery is the mainstay of treatment for patients with rectal cancer. Standard clinical target volume (CTV) to planning target volume (PTV) margins of 10 mm are used to accommodate inter- and intrafraction motion of target. Treating on magnetic resonance-integrated linear accelerators (MR-linacs) allows for online manual recontouring and adaptation (MRgART) enabling the reduction of PTV margins. The aim of this study was to investigate motion of the primary CTV (CTVA; gross tumour volume and macroscopic nodes with 10 mm expansion to cover microscopic disease) in order to develop a simultaneous integrated boost protocol for use on MR-linacs. MATERIALS AND METHODS: Patients suitable for neoadjuvant chemoradiotherapy were recruited for treatment on MR-linac using a two-phase technique; only the five phase 1 fractions on MR-linac were used for analysis. Intrafraction motion of CTVA was measured between pre-treatment and post-treatment MRI scans. In MRgART, isotropically expanded pre-treatment PTV margins from 1 to 10 mm were rigidly propagated to post-treatment MRI to determine overlap with 95% of CTVA. The PTV margin was considered acceptable if overlap was >95% in 90% of fractions. To understand the benefit of MRgART, the same methodology was repeated using a reference computed tomography planning scan for pre-treatment imaging. RESULTS: In total, nine patients were recruited between January 2018 and December 2020 with T3a-T4, N0-N2, M0 disease. Forty-five fractions were analysed in total. The median motion across all planes was 0 mm, demonstrating minimal intrafraction motion. A PTV margin of 3 and 5mm was found to be acceptable in 96 and 98% of fractions, respectively. When comparing to the computed tomography reference scan, the analysis found that PTV margins to 5 and 10 mm only acceptably covered 51 and 76% of fractions, respectively. CONCLUSION: PTV margins can be reduced to 3-5 mm in MRgART for rectal cancer treatment on MR-linac within an simultaneous integrated boost protocol.

Marginal discrepancy as affected by selective placement of die-spacer: an in vitro study.

An increase in the marginal discrepancy is seen after cementation with a luting agent and provision of cement space with a die-spacer is the most preferred method to avoid it. Recommended thickness of die-spacer is 25-40 µm. Smaller die-spacer thickness was consistently found at the axio-occlusal line angles as compared to the other surfaces which has been postulated to that the spacer paint tends to flow away from the sharp line angles and cusp tips as a result of increased surface tension. The absence of adequate relief spaces in these areas impedes the flow of cement beyond the occlusal portion of the casting, which would result in incomplete seating because of hydraulic pressure. Fifty stone dies were duplicated from a steel die and were divided into five groups of sample size 10, where the die-spacer was selectively placed. Measurements were taken at four points, 90° apart from each other with the help of optical microscope. Later all the castings were cemented using Glass Inomer cement as a luting agent, under a 10 kg static load and measurements were recorded. Statistical analysis showed samples with no spacer had the maximum pre and post cementation gap while the least discrepancy was seen in group with additional layer of die-spacer painted over the axio-occlusal line angle. The results were highly significant which clearly indicated the superiority of this group over others. Within limitations of the study, it can be said that application of additional layer of die-spacer at the axio-occlusal line angle will help in decreasing the post cementation marginal discrepancy in full cast metal crowns.

Recent advances in radiotherapy.

Radiation therapy has come a long way from treatment planning based on orthogonal radiographs with large margins around tumours. Advances in imaging and radiation planning software have led to three-dimensional conformal radiotherapy and, further, to intensity modulated radiotherapy (IMRT). IMRT permits sparing of normal tissues and hence dose-escalation to tumours. IMRT is the current standard in treatment of head and prostate cancer and is being investigated in other tumour sites. Exquisitely sculpted dose distributions (increased geographical miss) with IMRT, plus tumour motion and anatomical changes during radiotherapy make image guided radiotherapy an essential part of modern radiation delivery. Various hardware and software tools are under investigation for optimal IGRT.

Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Treatment options for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are limited with response rates to cytotoxic chemotherapy of approximately 30% and median survival of 6 months. PATIENTS AND METHODS: In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m2, daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of >3 months; one prior chemotherapy regimen was allowed. RESULTS: Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36-79) and median ECOG PS was one (range 0-2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1-8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months. CONCLUSIONS: 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo.

Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC(50)=0.35 muM) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR-CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiation-induced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4',6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gammaH2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.

Sequential induction chemotherapy followed by radical chemo-radiation in the treatment of locoregionally advanced head-and-neck cancer.

We describe a retrospective series of patients with advanced head-and-neck cancer who were treated with induction chemotherapy followed by radical chemo-radiation. Patients treated with two cycles of induction chemotherapy followed by definitive chemo-radiation for squamous cell carcinoma of the head-and-neck region, from 2001 - 2006 at the Royal Marsden Hospital, formed the basis of this study. Cisplatin (75 mg m(-2)) on day 1 and 5-FU (1000 mg m(-2)) day 1 - 4 was the standard regimen used for induction treatment. Cisplatin (100 mg m(-2)) on day 1 and day 29 was used for concomitant treatment. The radiation was delivered using conformal technique. Tissues containing macroscopic and microscopic disease were treated to doses of 65 Gray (Gy) in 30 fractions and 50 Gy in 25 fractions, respectively. Data on patterns of relapse and acute toxicity (NCICTCv.3.0) were collected. A total of 129 patients were included, median age was 58 (range: 27 - 78). The site of tumour was: oropharynx 70 (54%), larynx 30 (23%), hypopharynx 24 (19%) and other 5 (4%). The median follow-up was 19 months (range: 4 - 58). Local control, disease-specific survival and overall survival at 2 years were 71%, 68% and 63%, respectively. The distant recurrence rate at 2 years was 9%. Ten patients required dose reduction during induction chemotherapy due to toxicity. The dose of 5-FU was reduced in six patients and that of cisplatin in four patients. The incidence of grade 3/4 toxicity was: neutropenia 5%, thrombocytopenia 1%, nausea and vomiting 3%. One cycle of concurrent cisplatin was omitted in 23 patients due to toxicity. Full-dose radiotherapy was administered to 98% of patients. The incidence of grade 3/4 toxicity was: skin 20%, dysphagia 65%, mucositis 60%, neutropenia 3%, anaemia 1%, nausea and vomiting 4%, nephrotoxicity 1%. Induction chemotherapy followed by radical chemo-radiation is a safe and tolerable regimen in the treatment of advanced head-and-neck cancer. Distant recurrence rates are lower with equivalent local control and survival compared to chemo-radiation alone (historical controls).

Intensity modulated radiotherapy in locally advanced thyroid cancer: Outcomes of a sequential phase I dose-escalation study.

BACKGROUND AND PURPOSE: To determine the safety and tolerability of dose-escalation using modestly accelerated IMRT in high-risk locally advanced thyroid cancer requiring post-operative radiotherapy, and to report preliminary data on efficacy. MATERIALS AND METHODS: A sequential Phase I dose-escalation design was used. Dose level one (DL1) received 58.8 Gy/28F to the post-operative bed and 50 Gy/28F to elective nodes. DL2 received 66.6 Gy/30F to the thyroid bed, 60 Gy/30F to post-operative nodal levels and 54 Gy/30F to elective nodal levels. Acute (NCICTCv.2.0) and late toxicities (RTOG and modified LENTSOM) were recorded. The primary endpoint was the number of patients with ≥Grade 3 (G3) toxicity at 12 months post-treatment. RESULTS: Fifteen patients were recruited to DL1 and twenty-nine to DL2. At 12 months ≥G3 toxicities were 8.3% in both DL1 and DL2. At 60 months, ≥G3 toxicity was reported in 3 (33%) patients in DL1 and 1 (7%) in DL2. One patient in DL2 died at 24 months from radiation-induced toxicity. Time to relapse and overall survival rates were higher in DL2, but this was not statistically significant. Dose-escalation using this accelerated regimen can be safely performed with a toxicity profile similar to reported series using conventional doses.

Circulating tumour DNA is a potential biomarker for disease progression and response to targeted therapy in advanced thyroid cancer.

BACKGROUND: Conventional biomarkers in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful biomarker in other solid tumours. This is a multimutational study of ctDNA over multiple timepoints, designed to test the hypothesis that ctDNA is a potential biomarker in patients with advanced thyroid cancer. METHODS: Mutational analysis of archival tumour tissue was performed using NGS with a targeted gene panel. Custom TaqMan assays were designed for plasma ctDNA testing using digital droplet polymerase chain reaction. Concentrations of detected ctDNA were correlated with the conventional biomarker concentration and axial imaging status defined by the Response Evaluation Criteria in Solid Tumours criteria. RESULTS: Tumour tissue from 51 patients was obtained, with the following histologies: 32 differentiated (differentiated thyroid cancer [DTC]), 15 medullary (medullary thyroid cancer [MTC]), three poorly differentiated and one anaplastic. NGS analysis detected variants in 42 (82%) of cases. Plasma was assayed for these patients in 190 samples, and ctDNA was detected in 67% of patients. Earlier detection of disease progression was noted in three patients with MTC. In two cases (PTC and ATC), where conventional biomarkers were not detectable, ctDNA was detected before disease progression. Changes in ctDNA concentration occurred earlier than conventional markers in response to disease progression in multiple patients with DTC receiving targeted therapies. CONCLUSION: The majority of patients with advanced thyroid cancer had detectable ctDNA. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in MTC; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer.

Otological toxicity after postoperative radiotherapy for parotid tumours.

Radiotherapy is commonly used in the management of malignant parotid gland tumours that have adverse pathological risk factors after surgery. Radiation to the parotid bed is associated with predictable complications. In particular, the close proximity of the auditory apparatus, which receives a significant radiation dose, results in significant toxicity in a proportion of patients. Here we review auditory toxicity after radiation to the parotid bed.

Pneumococcal hemolytic uremic syndrome.

We report Hemolytic Uremic Syndrome (HUS) induced by Streptococcus pneumoniae in a 20 month-old girl. She responded well to hemodialysis.

Dysphagia-optimised Intensity-modulated Radiotherapy Techniques in Pharyngeal Cancers: Is Anyone Going to Swallow it?

Dysphagia after primary chemoradiotherapy or radiation alone in pharyngeal cancers can have a devastating impact on a patient's physical, social and emotional state. Establishing and validating efficient dysphagia-optimised radiotherapy techniques is, therefore, of paramount importance in an era where health-related quality of life measures are increasingly influential determinants of curative management strategies, particularly as the incidence of good prognosis, human papillomavirus-driven pharyngeal cancer in younger patients continues to rise. The preferential sparing achievable with intensity-modulated radiotherapy (IMRT) of key swallowing structures implicated in post-radiation dysfunction, such as the pharyngeal constrictor muscles (PCM), has generated significant research into toxicity-mitigating strategies. The lack of randomised evidence, however, means that there remains uncertainty about the true clinical benefits of the dosimetric gains offered by technological advances in radiotherapy. As a result, we feel that IMRT techniques that spare PCM cannot be incorporated into routine practice. In this review, we discuss the swallowing structures responsible for functional impairment, analyse the studies that have explored the dose-response relationship between these critical structures and late dysphagia, and consider the merits of reported dysphagia-optimised IMRT (Do-IMRT) approaches, thus far. Finally, we discuss the dysphagia/aspiration-related structures (DARS) study (ISRCTN 25458988), which is the first phase III randomised controlled trial designed to investigate the impact of swallow-sparing strategies on improving long-term function. To maximise patient benefits, improvements in radiation delivery will need to integrate with novel treatment paradigms and comprehensive rehabilitation strategies to eventually provide a patient-centric, personalised treatment plan.

A Four-Biomarker Blood Signature Discriminates Systemic Inflammation Due to Viral Infection Versus Other Etiologies.

The innate immune system of humans and other mammals responds to pathogen-associated molecular patterns (PAMPs) that are conserved across broad classes of infectious agents such as bacteria and viruses. We hypothesized that a blood-based transcriptional signature could be discovered indicating a host systemic response to viral infection. Previous work identified host transcriptional signatures to individual viruses including influenza, respiratory syncytial virus and dengue, but the generality of these signatures across all viral infection types has not been established. Based on 44 publicly available datasets and two clinical studies of our own design, we discovered and validated a four-gene expression signature in whole blood, indicative of a general host systemic response to many types of viral infection. The signature's genes are: Interferon Stimulated Gene 15 (ISG15), Interleukin 16 (IL16), 2',5'-Oligoadenylate Synthetase Like (OASL), and Adhesion G Protein Coupled Receptor E5 (ADGRE5). In each of 13 validation datasets encompassing human, macaque, chimpanzee, pig, mouse, rat and all seven Baltimore virus classification groups, the signature provides statistically significant (p < 0.05) discrimination between viral and non-viral conditions. The signature may have clinical utility for differentiating host systemic inflammation (SI) due to viral versus bacterial or non-infectious causes.

Evaluation of a multi-atlas CT synthesis approach for MRI-only radiotherapy treatment planning.

BACKGROUND AND PURPOSE: Computed tomography (CT) imaging is the current gold standard for radiotherapy treatment planning (RTP). The establishment of a magnetic resonance imaging (MRI) only RTP workflow requires the generation of a synthetic CT (sCT) for dose calculation. This study evaluates the feasibility of using a multi-atlas sCT synthesis approach (sCTa) for head and neck and prostate patients. MATERIAL AND METHODS: The multi-atlas method was based on pairs of non-rigidly aligned MR and CT images. The sCTa was obtained by registering the MRI atlases to the patient's MRI and by fusing the mapped atlases according to morphological similarity to the patient. For comparison, a bulk density assignment approach (sCTbda) was also evaluated. The sCTbda was obtained by assigning density values to MRI tissue classes (air, bone and soft-tissue). After evaluating the synthesis accuracy of the sCTs (mean absolute error), sCT-based delineations were geometrically compared to the CT-based delineations. Clinical plans were re-calculated on both sCTs and a dose-volume histogram and a gamma analysis was performed using the CT dose as ground truth. RESULTS: Results showed that both sCTs were suitable to perform clinical dose calculations with mean dose differences less than 1% for both the planning target volume and the organs at risk. However, only the sCTa provided an accurate and automatic delineation of bone. CONCLUSIONS: Combining MR delineations with our multi-atlas CT synthesis method could enable MRI-only treatment planning and thus improve the dosimetric and geometric accuracy of the treatment, and reduce the number of imaging procedures.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

AIMS: A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. RESULTS: Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. CONCLUSIONS: The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

Effect of partial hepatectomy on tumor incidence and metabolism of mice fed thioacetamide.

Six-week-old male Swiss mice were given 0.03% thioacetamide (TAA) in the diet 24, 72, and 168 hours after partial hepatectomy. TAA-treated mice from all three groups were killed when they were 4, 9, and 13 months old. Intact and partially hepatectomized animals on normal diets served as controls. None of the controls evidenced neoplasms at any age. All three experimental groups developed liver tumors earlier than did intact mice treated with the TAA diet. Progressive metabolic studies on the livers or tumor tissues of treated mice showed that the levels of glucose-6-phosphatase, fructose-1,6-diphosphatase, and glycogen decreased significantly in the 4-month-old treated group when there was no significant alteration in liver histology. These parameters were lowest in the tumor tissues of treated mice.

Induction of oral mucosal tumors in hamsters and rats treated with methyl(acetoxymethyl)nitrosamine.

An oral tumor model has been developed in inbred Syrian golden hamsters by continuous applications every 2 weeks of methyl(acetoxymethyl)nitrosamine [(DMN-OAC) CAS: 56856-83-8; methylnitrosaminomethyl ester acetic acid] at 2 mg/kg body weight alone or by a single application of DMN-OAC followed by continuous twice weekly applications of 12-O-tetradecanoylphorbol 13-acetate (TPA) (1 microgram/animal). Similar studies were done in the W rat buccal mucosa. In the hamsters treated continuously with DMN-OAC, 100% of the tumors were observed in the cheek pouch; none were observed at other sites. In contrast, in the rats treated similarly, only a 67% tumor incidence was observed, of which only 42% were oral tumors. A promoter effect of TPA was observed in hamster cheek pouch tumors induced by DMN-OAC, whereas rat oral mucosa did not respond to TPA treatment.