Timing of development of osteoradionecrosis post head and neck radiotherapy: does a safe time interval exist for dental extraction?

INTRODUCTION: Risk factors for developing osteoradionecrosis (ORN) are well known, but less is known about factors influencing the interval between radiotherapy and the onset of ORN. Also, it is unknown whether there is any specific period post-radiotherapy with a reduced probability of ORN when irradiated teeth require extraction. PURPOSE: The primary aim of this study was to identify factors influencing the interval in developing ORN in the following subgroups of patients: (1) patients who spontaneously developed ORN, (2) surgical-intervention-related ORN with a particular focus on patients after mandibulectomy. The secondary aim was to attempt to identify a possible time for safer dental intervention after primary treatment. MATERIALS AND METHODS: The authors retrospectively analysed 1608 head and neck cancer (HNC) patients treated in a single centre. Time intervals were measured from the end of radiotherapy to the development of ORN and further analysed in the subgroups listed above. RESULTS: In all, 141 patients (8.8%) developed intra-oral ORN. Median time from radiotherapy to ORN development in the whole cohort was 9 months. Median interval for spontaneous ORN was 8 months, 6.5 months for intervention-related ORN, and 15 months for patients post-mandibulectomy. In patients who required dental extraction preradiotherapy, median interval of ORN onset was 5 months. CONCLUSION: In our study, a slightly higher proportion of patients with intervention developed ORN earlier in comparison with spontaneous ORN. The period from 12-18 months after radiotherapy was identified as having the highest probability of developing ORN in patients after mandibulectomy. A time for safer dental intervention after primary treatment was not identified.

Shrinkage of the non-malignant prostate gland volume after receiving incidental radiotherapy for rectal cancer.

Background: The purpose of this study was to assess the impact of coincidental radiotherapy on the volume of the non-malignant prostate gland in rectal cancer patients treated with neo-adjuvant radiotherapy. Materials and methods: In this retrospective analysis, thirty male patients with rectal cancer who had neoadjuvant radiotherapy met the inclusion criteria. These patients had pre-treatment magnetic resonance imaging (MRI) and at least one post-treatment MRI of the pelvis and the whole of their prostate volume received the full prescribed radiotherapy dose; 45 Gy in 25 fractions (n = 22), 45 Gy in 20 fractions (n = 4) and 25 Gy in 5 fractions (n = 4). Results: The median age of this patient cohort was 66 years (range: 30-87). With a median interval between pre-treatment MRI and first MRI post-treatment of 2 months (range: 1-11), the mean prostate volume reduced from 36.1 cm3 [standard deviation (SD) 14.2] pre-radiotherapy to 31.3 cm3 (SD 13.0) post radiotherapy and this difference was significant (p = 0.0004). Conclusion: Radiotherapy may cause shrinkage in volume of normal (non-malignant) prostate. Further research is required in this field, since these results may be of some comfort to men contemplating the consequences of radiotherapy on their quality of life. The authors suggest recording flow-rate and international prostate symptom score (IPSS) during rectal radiotherapy as a next step.

Survival outcomes for patients with nasopharyngeal carcinoma in non-endemic region in the UK treated with intensity modulated based radiotherapy 65 Gy in 30 fractions ± weekly cisplatin chemotherapy.

Background: Nasopharyngeal carcinoma (NPC) is rare in the UK. The aim of the current study was to investigate survival outcomes for patients with NPC treated with (chemo)radiotherapy using 65 Gy in 30 fractions in a non-endemic region. Materials and methods: All consecutive 62 patients with histology proven non-metastatic nasopharyngeal carcinoma diagnosed between January 2009 to June 2019 were included in this retrospective analysis. Results: Median age was 59 years (range:19-81). The majority of patients had stage III disease (66.1%). Induction chemotherapy was given in 21% of patients and 82.3% of patients received concomitant systemic therapy. All patients were treated with 65 Gy in 30 fractions. There was disease recurrence in 17.4% patients. The 5-year disease-free, disease-specific and overall survival were 81.9%, 79.2% and 76.4%, respectively. On univariate analysis, disease recurrence was associated with N-stage (p = 0.047) and overall stage group (p = 0.023). Conclusion: To the best of authors' knowledge, this is the first report of the use of 65 Gy in 30 fractions of radiotherapy ± weekly cisplatin chemotherapy in NPC in a real-world setting. Our results are comparable to that from other non-endemic regions of the world using different dose fractionation of (chemo)radiotherapy. Future randomised control trials are warranted to compare various dose fractionations in these settings.

Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions.

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy.

Comparing morbidity and cancer control after 3D-conformal (70/74 Gy) and intensity modulated radiotherapy (78/82 Gy) for prostate cancer.

PURPOSE: The purpose of this work was to compare toxicity and cancer control between patients with prostate cancer treated using three-dimensional conformal radiotherapy (3D-CRT) and those treated using intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: A total of 553 patients with prostate cancer were treated with 3D-CRT 70-74 Gy (3D-CRT 70, 3D-CRT 74) or IMRT 78-82 Gy (IMRT 78, IMRT/SIB 82). Late toxicity was scored according to FC-RTOG/LENT criteria. Biochemical failure was defined using the Phoenix and ASTRO definitions. RESULTS: The 5-year risk of grade 2-4 genitourinary toxicity was 26.3 % (3D-CRT 70), 27.2 % (3D-CRT 74), 17.3 % (IMRT 78), and 25.1 % (IMRT/SIB 82) without statistical differences. The 5-year risk of grade 2-4 gastrointestinal toxicity was 19.4 % (3D-CRT 70), 42.1 % (3D-CRT 74), 20.5 % (IMRT 78), and 26.6 % (IMRT/SIB 82). The differences between 3D-CRT 74 and 3D-CRT 70 and between 3D-CRT 74 and IMRT 78 were statistically significant (log rank p = 0.03). The 5-year Phoenix PSA relapse-free survival (PSA-RFS) in low-risk, intermediate-risk, and high-risk patients treated using 3D-CRT were 89.4, 65.5, and 57.8 %, respectively. Patients treated with IMRT achieved the following results: 90.9, 89.4, and 83.9 %. Clinical relapse-free survival (C-RFS) in patients treated using 3D-CRT vs. IMRT for the aforementioned groups were 94.7 vs. 100 %, 86.8 vs. 98.6 %, and 84.4 vs. 94.5 %. Disease-free survival (DFS) for patients treated using 3D-CRT were 83.1, 70.9, and 71.5 %. The IMRT group reached 95.8, 89.1, and 87.6 %. The PSA-RFS for intermediate- and high-risk patients were statistically significant, while C-RFS and DFS were marginally better. CONCLUSION: Dose escalation with IMRT was associated with improved cancer control in intermediate- and high-risk patients in comparison with 3D-CRT, without compromising toxicity.

Paricalcitol treatment of secondary hyperparathyroidism in hemodialysis patients: a German-Austrian, single-arm, open-label, prospective, noninterventional, observational study.

BACKGROUND: Safety and efficacy of paricalcitol in hemodialysis patients with secondary hyperparathyroidism (sHPT) was investigated under routine clinical practice in German and Austrian dialysis centers. METHODS: Hemodialysis patients with sHPT initiating intravenous paricalcitol were enrolled in this noninterventional study regardless of concomitant sHPT treatment. Prior active vitamin D therapy was discontinued. Clinical laboratory values, including intact parathyroid hormone (iPTH), total serum calcium (Ca), phosphorus (P), Ca × P product, and alkaline phosphatase (AP), were recorded for 6 months following initiation of paricalcitol treatment. RESULTS: 1,313 patients (Austria, n = 280; Germany, n = 1,033) from 169 dialysis centers were enrolled. Most patients (n = 932; 79.1%) had received dialysis for ≥1 year. Median iPTH fell from 518.9 pg/ml [55.0 pmol/l] at baseline to 264.0 pg/ml [28.0 pmol/l] after 6 months (p < 0.0001). After 6 months of treatment, ≥30 and ≥60% reductions in iPTH were observed in 63.0 and 35.9% of patients, respectively. At 6 months, 27.2% of patients achieved iPTH levels between 150 and <300 pg/ml [15.9 and <31.8 pmol/l] compared with 9.7% at baseline. Ca, P, and Ca × P levels remained stable in the majority of patients. AP levels declined from a median of 98 U/l at baseline to 83 U/l (p < 0.0001) at 6 months. Monitoring of adverse events and clinical laboratory assessments identified no unexpected safety signals for paricalcitol. CONCLUSIONS: Paricalcitol is an effective and well-tolerated treatment option for the control of iPTH levels in hemodialysis patients with sHPT. The results of this study support the results of previous trials under real-time clinical practice conditions in Austria and Germany.

In Response to "Acute Oral Mucositis During Hypo-Fractionated Radiation in Squamous Cell Carcinoma of Oral Cavity".

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Hypofractionated (2.75 Gy per fraction) versus Conventionally Fractionated Primary Radiotherapy for T2N0M0 Carcinoma of the Glottis.

Introduction Radiotherapy provides excellent outcome in early stage glottic cancer; however, the optimal radiotherapy dose fractionation remains unknown. Objective To investigate the outcome of patients with T2N0M0 treated with either hypofractionated (HypoFxn) or conventionally fractionated radical (ConFxn) radiotherapy. Methods According to our institutional protocol, patients with T2N0M0 glottic cancer can be treated either with ConfFxn or HypoFxn radiotherapy, as per clinician's and patient's choice, following shared decision making discussing the advantages and disadvantages of both modalities. A total of 77 patients with T2N0M0 squamous cell carcinoma of glottis treated with either HypoFxn 55Gy in 20 fractions ( n = 19) or ConFxn 63 to 65Gy in 30 fractions ( n = 58) were included. Results With median follow-up of 3.4 years, there was no significant difference in disease-free survival (median: HypoFxn = 65.2 months, and ConFxn = 75.3 months; p = 0.874), local recurrence free survival rates (median: HypoFxn = 78.8 months vs. ConFxn = 81.2 months; p = 0.274), and overall survival (median: HypoFxn = 65.9 months vs. ConFxn = 67.7 months; p = 0.532). Elective neck irradiation was given to 43 patients, all in the ConFxn group, and this was associated with poorer local control ( p = 0.027). The use of radiotherapy modality, three-dimensional conformal radiotherapy (3DRT) versus intensity modulated radiotherapy (IMRT), was not a prognostic factor ( p = 0.36). In the HypoFxn group, grade III acute dysphagia requiring nasogastric tube was 16%, compared with 25% in the ConFxn group ( p = 0.446). Conclusion HypoFxn radiotherapy provides a comparable treatment outcome with acceptable toxicity. The addition of prophylactic irradiation of the neck lymph nodes has no impact on regional control.

The role of combining immunotherapy with primary (Chemo)radiotherapy in curative treatment settings of the head and neck cancer.

The introduction of immunotherapy into the radical management of head and neck cancer (HNC) is a fast moving phenomenon, which is constantly developing. Although now established in the management of recurrent and metastatic disease in HNC, its use in radical treatment is being investigated in a whole spectrum of clinical trials looking at which immune altering agents give the best results, which can be added safely to radiotherapy, chemotherapy, and chemoradiotherapy for greatest efficiency and when the most appropriate time to add these agents is in the neoadjuvant, concurrent on adjuvant settings. These multiple questions produce a complex matrix for HNC investigators and this article brings together the existing evidence and contemporary trials going on with immunotherapy in HNC, giving an up to date snapshot of present investigations and near future directions for further research.

The Short-Term Antibacterial Activity of Three Selected Endodontic Sealers against Enterococcus faecalis Bacterial Culture.

(1) Background: Microorganisms originating from the microflora of the oral cavity are the main cause of the inflammatory diseases of the dental pulp and periapical periodontium, as well as the failure of endodontic treatment. The subsequent root canal treatment is not able to remove all the pathogens, and a small number of viable bacteria remain in the dentine tubules, which must be sealed by endodontic sealers. These sealers should have at least a bacteriostatic effect to prevent the remaining bacteria from reproducing. The aim of this study is to compare the short-term antibacterial activity of three endodontic sealers based on poly-epoxy resin, zinc oxide-eugenol and calcium silicate with a calcium hydroxide-based sealer. Calcium hydroxide is used as temporary intracanal medicament and, thus, should show significant antibacterial activity. (2) Methods: A total of 25 bovine dentine samples infected with Enterococcus faecalis were used in this study. After the sealer placement and a 24 h incubation period, the root canal walls were scraped, and the suspension of dentine fillings was used for a semi-quantitative evaluation of microbial growth. (3) Results: The poly-epoxide resin-based sealer ADSeal™ showed significant antibacterial properties. (4) Conclusions: The highest antibacterial activity was shown in poly-epoxide resin-based sealer group, followed by the zinc oxide-eugenol-based sealer and calcium silicate-based sealer.

Dental loss after radiotherapy for head and neck cancer.

Introduction In radiotherapy (RT) for head and neck cancer (HNC), dental morbidity is significant and it may result in loss of the dentition following treatment.Aims The aim of this clinical study is to identify the incidence of tooth loss over time and correlate this to the RT dose and various risk factors in patients with HNC treated with radical RT.Design A retrospective observational study.Materials and methods The records of 1,118 patients with HNC treated with radical or adjuvant RT from January 2010 to December 2019 were analysed. After applying strict inclusion criteria, 78 patients with 1,566 individual tooth data were selected. RT dose mapping was performed for each tooth.Results A total of 253 teeth (16.2%) were extracted. The following risk factors were significant: gender (p = 0.0001), xerostomia (p <0.0001), RT dose (p <0.0001) and smoking (p <0.0001). Non-significant factors were age, RT delivery technique and the addition of cisplatin.Conclusion Detailed RT dose mapping was used to identify RT dose as a risk factor for dental loss. Careful pre-RT dental treatment and minimisation of RT dose to teeth and salivary glands is required to prevent or reduce the loss of dentition.

Concomitant weekly cisplatin-based chemoradiotherapy in head and neck cancer: the value of a second measured glomerular filtration rate during treatment.

OBJECTIVES: To assess the efficacy of the second measured glomerular filtration rate (GFR) during the course of weekly cisplatin-based chemoradiotherapy in head and neck cancer. METHODS: Data was collected on consecutive 221 head and neck cancer patients who underwent cisplatin-based chemoradiotherapy. RESULTS: 68% patients managed to complete at least five out six proposed cycles of cisplatin, with a cumulative dose of ≥200 mg/m2. 181 patients underwent second measured GFR and it showed a mean fall in measured GFR by 12.0 ml/min/1.73 m2 (p < 0.0001). Out of these 181 patients, in 16 patients (9%), the decision to discontinue cisplatin was purely based on a low second measured GFR (below 50 ml/min/1.73 m2). CONCLUSION: Our study has shown that obtaining a second measured GFR is valuable in 9% of these patients. We propose that this should be considered as a standard procedure in these settings and also should be considered incorporating this additional safety measure, into future clinical trials as a mandatory procedure. ADVANCES IN KNOWLEDGE: To the best of author's knowledge, this is first study of its kind. The results of our study suggest that it should be a standard procedure of obtaining a second GFR in these settings.

A systematic review and practical considerations of stereotactic body radiotherapy in the treatment of head and neck cancer.

OBJECTIVES: Stereotactic radiotherapy (SBRT) is gaining popularity although its use in head and neck cancer (HNC) is not well defined. The primary objective was to review the published evidence regarding the use of stereotactic radiotherapy in HNC. METHODS: A literature search was performed by using MEDLINE and EMBASE databases for eligible studies from 2000 to 2019 and 26 relevant studies were identified. RESULTS: Literature demonstrates a heterogeneous use of this technique with regards to patient population, primary or salvage treatment, dose fractionation regimens, outcomes and follow-up protocols. Carotid blow out syndrome is a risk as with other forms of reirradiation but alternative treatment regimens may reduce this risk. CONCLUSION: At present there is a lack of evidence regarding SBRT as a primary treatment option for HNC and definitive answers regarding efficacy and tolerability cannot be provided but there is growing evidence that SBRT reirradiation regimens are safe and effective. In lieu of evidence from large Phase III trials, we define appropriate organ at risk constraints and prescription doses, with accurate plan summation approaches. Prospective randomised trials are warranted to validate improved treatment outcomes and acceptable treatment morbidity. ADVANCES IN KNOWLEDGE: This article provides a comprehensive review of evidence of use of stereotactic radiotherapy in HNC site (either as a primary treatment or as reirradiation). We also provide an evidence-based approach to the implementation and practical consideration of stereotactic radiotherapy in HNC.

Sequential chemotherapy followed by radical thoracic radiotherapy (50 Gy in 25 fractions) in limited stage small cell lung cancer.

INTRODUCTION: For limited stage small cell lung cancer (LS-SCLC) where concurrent chemoradiotherapy is inappropriate due to tumour bulk, co-morbidities or performance status, sequential treatment using chemotherapy followed by radiotherapy is the standard of care. The outcomes are not well established; we assessed in a single institution, the survival of these patients, prognostic factors and compared to the limited existing literature. MATERIALS AND METHOD: Retrospective data was collected on all 59 patients diagnosed with LS-SCLC from 2011 to 2016 who received chemotherapy consisting of Carboplatin or Cisplatin + Etoposide followed by thoracic radiotherapy (50 Gy in 25 fractions) +/- prophylactic cranial irradiation (PCI). RESULTS: Median age at diagnosis was 66 years (range 46-90). Patients received a median of four cycles of chemotherapy (range: 1-6) and all the patients completed a full course of radiotherapy with only one patient experiencing grade >2 radiation induced toxicity. With a median follow up of 20.6 months, 45 patients had died with a median survival of 20.6 months. 2-year overall survival (OS) rates were 42%. Age using a cut-off of 65 was prognostic (median OS 25.6 months ≤65 years versus 14.1 months >65 years, p = 0.013) but gender, stage and receipt of PCI were not. CONCLUSIONS: Most of the literature reporting outcome from sequential treatment in LS-SCLC is old and used a variety of radiotherapy regimens. Our data shows inferior outcomes to the gold standard concurrent chemoradiotherapy but support its usage in less fit patients with reasonable outcome observed.

Successful treatment of familial Mediterranean fever with Anakinra and outcome after renal transplantation.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent episodes of fever and inflammation. The most severe complication of FMF is the development of AA amyloidosis, which can be life threatening. The only current effective treatment for FMF is colchicine. Regular prophylactic treatment with colchicine at a dose of 1-2 mg daily prevents or substantially reduces the clinical manifestations of FMF in at least 90% of cases. However, approximately 10% of patients are reported to be resistant or non-responsive to colchicine and in these cases there is no consensus as to which second line agents should be used. We describe the first case, to our knowledge, of a patient with FMF and end-stage renal failure due to AA amyloidosis, successfully treated with IL-1 receptor blockade. Our data suggest that the IL-1 receptor antagonist Anakinra (Kineret; r-metHuIL-1 ra) may represent a safe and effective therapy for the treatment of colchicine-resistant FMF, in patients requiring renal replacement therapy, with dialysis or transplantation.

Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil.

BACKGROUND: Triggered by heightened interest in mycophenolate mofetil (MMF) for the treatment of autoimmune diseases (AID) and encouraged by the results from a previous study, we hypothesized that therapeutic drug monitoring of mycophenolic acid (MPA) based on troughs may be useful for effective MMF dosing in patients with AID. METHODS: A two-step approach was pursued. First, we confirmed in 38 AID patients (26 with antineutrophil cytoplasmic antibody-associated vasculitis; 12 with systemic lupus erythematosus) a significant correlation (r = 0.545, P < 0.001) between MPA C(12 h) and MPA exposure (AUC). Second, we performed an analysis of 294 MPA 12-h trough levels serially collected from 39 patients (same indications) receiving MMF for remission maintenance therapy to elucidate possible associations with disease activity and MMF toxicity. RESULTS: Higher MPA trough levels were associated with better protection from recurrence of active disease. While at levels <3 mg/L 29% of collected samples (43/147) were from patients with active disease, this was only the case in 2% of samples (3/147) with an MPA concentration of >or=3 mg/L. Remission persisted in all patients with MPA troughs >or=3.5 mg/L. Upon combined analysis of efficacy and safety data, most favourable results were obtained with MPA troughs between 3.5 and 4.5 mg/L. There was no discernable relationship between MMF dose and clinical endpoints. CONCLUSION: The target range proposed by this explorative study may serve as an initial guidance for MPA monitoring in the context of further prospective controlled trials in patients with AID.

Hypofractionated (2.75 Gy per fraction) versus Conventionally Fractionated Primary Radiotherapy for T2N0M0 Carcinoma of the Glottis

Abstract Introduction Radiotherapy provides excellent outcome in early stage glottic cancer; however, the optimal radiotherapy dose fractionation remains unknown. Objective To investigate the outcome of patients with T2N0M0 treated with either hypofractionated (HypoFxn) or conventionally fractionated radical (ConFxn) radiotherapy. Methods According to our institutional protocol, patients with T2N0M0 glottic cancer can be treated either with ConfFxn or HypoFxn radiotherapy, as per clinician's and patient's choice, following shared decision making discussing the advantages and disadvantages of both modalities. A total of 77 patients with T2N0M0 squamous cell carcinoma of glottis treated with either HypoFxn 55Gy in 20 fractions (n = 19) or ConFxn 63 to 65Gy in 30 fractions (n = 58) were included. Results With median follow-up of 3.4 years, there was no significant difference in disease-free survival (median: HypoFxn = 65.2 months, and ConFxn = 75.3 months; p = 0.874), local recurrence free survival rates (median: HypoFxn = 78.8 months vs. ConFxn = 81.2 months; p = 0.274), and overall survival (median: HypoFxn = 65.9 months vs. ConFxn = 67.7 months; p = 0.532). Elective neck irradiation was given to 43 patients, all in the ConFxn group, and this was associated with poorer local control (p = 0.027). The use of radiotherapy modality, three-dimensional conformal radiotherapy (3DRT) versus intensity modulated radiotherapy (IMRT), was not a prognostic factor (p = 0.36). In the HypoFxn group, grade III acute dysphagia requiring nasogastric tube was 16%, compared with 25% in the ConFxn group (p = 0.446). Conclusion HypoFxn radiotherapy provides a comparable treatment outcome with acceptable toxicity. The addition of prophylactic irradiation of the neck lymph nodes has no impact on regional control.

Palliative radiotherapy for locally advanced non-metastatic head and neck cancer: A systematic review.

OBJECTIVES: The objective of this systematic review was to identify and appraise the existing evidence of role of palliative radiotherapy for locally advanced non-metastatic head and neck cancer. METHODS: A systematic search of the literature was conducted using Medline, Embase and Cochrane databases and relevant references were included. RESULTS: Literature search revealed a wide variation in dose fractionation regimens. Reported outcomes showed high efficacy and low rate of significant side effects, except in studies utilising higher doses of radiotherapy where higher grade toxicities were seen. Reported median overall survival was in the range of 3.3-17 months, but most studies reported median survival of around 6 months. CONCLUSIONS: The choice of palliative radiotherapy varies significantly. This is in contrast to regimens of curative radiotherapy for locally advanced head and neck cancer, which are well standardised. Given the reported relatively short overall survival of this patient group, an ideal treatment should be of the shortest possible duration whilst ensuring effective palliation and minimal side effects. Future well designed trials are needed to evaluate quality of life and duration of side effects in addition to survival and severity of toxicities in this group of patients.