HPV ctDNA detection of high-risk HPV types during chemoradiotherapy for locally advanced cervical cancer.

BACKGROUND: Chemoradiotherapy (CRT) is the standard of care for patients diagnosed with locally advanced cervical cancer (LACC), a human papillomavirus (HPV)-related cancer that relapses in 30%-60% of patients. This study aimed to (i) design HPV droplet digital PCR (ddPCR) assays for blood detection (including rare genotypes) and (ii) monitor blood HPV circulating tumor DNA (HPV ctDNA) levels during CRT in patients with LACC. METHODS: We analyzed blood and tumor samples from 55 patients with HPV-positive LACC treated by CRT in a retrospective cohort (n = 41) and a prospective cohort (n = 14). HPV-ctDNA detection was carried out by genotype-specific ddPCR. RESULTS: HPV ctDNA was successfully detected in 69% of patients (n = 38/55) before CRT for LACC, including nine patients with a rare genotype. HPV-ctDNA level was correlated with HPV copy number in the tumor (r = 0.41, P < 0.001). HPV-ctDNA positivity for HPV18 (20%, n = 2/10) was significantly lower than for HPV16 (77%, n = 27/35) or other types (90%, n = 9/10, P = 0.002). HPV-ctDNA detection (positive versus negative) before CRT was associated with tumor stage (P = 0.037) and lymph node status (P = 0.02). Taking into account all samples from the end of CRT and during follow-up in the prospective cohort, positive HPV-ctDNA detection was associated with lower disease-free survival (DFS) (P = 0.048) and overall survival (OS) (P = 0.0013). CONCLUSION: This is one of the largest studies to report HPV-ctDNA detection before CRT and showed clearance of HPV ctDNA at the end of treatment in most patients. Residual HPV ctDNA at the end of CRT or during follow-up could help to identify patients more likely to experience subsequent relapse.

Review of clinical applications of radiation-enhancing nanoparticles.

PURPOSE: Clinical evidence of the radiation-enhancing effects of nanoparticles has emerged. MATERIALS AND METHODS: We searched the literature in English and French on PubMed up to October 2019. The search term was "nanoparticle" AND "radiotherapy", yielding 1270 results. RESULTS: The two main NP used in clinical trials were hafnium oxide and gadolinium involving a total of 229 patients. Hafnium oxide NP were used in three phase 1/2 trials on sarcoma, head and neck squamous cell carcinoma or liver cancer and one phase 2/3 trial. There are six ongoing phase 1/2 clinical trials to evaluate the combination of gadolinium-based NP and RT for the treatment of brain metastases and cervical cancer. CONCLUSION: So far, intratumoral hafnium oxide nanoparticles were safe and improved efficacy in locally advanced sarcoma.

Exploiting the full potential of proton therapy: An update on the specifics and innovations towards spatial or temporal optimisation of dose delivery.

Prescription and delivery of protons are somewhat different compared to photons and may influence outcomes (tumour control and toxicity). These differences should be taken into account to fully exploit the clinical potential of proton therapy. Innovations in proton therapy treatment are also required to widen the therapeutic window and determine appropriate populations of patients that would benefit from new treatments. Therefore, strategies are now being developed to reduce side effects to critical normal tissues using alternative treatment configurations and new spatial or temporal-driven optimisation approaches. Indeed, spatiotemporal optimisation (based on flash, proton minibeam radiation therapy or hypofractionated delivery methods) has been gaining some attention in proton therapy as a mean of improving (biological and physical) dose distribution. In this short review, the main differences in planning and delivery between protons and photons, as well as some of the latest developments and methodological issues (in silico modelling) related to providing scientific evidence for these new techniques will be discussed.

Isodose 20 Gy found as a threshold dose for radiation recall dermatitis.

Radiation recall is a rare phenomenon that can be observed in the field of radiotherapy, months or years after irradiation when a patient is exposed to certain pharmaceutical agents. In this report, we relate a case of radiation recall dermatitis induced after the application of a topical natural cream, 2 years after the initial radiotherapy treatment. Skin reactions were severe and limited to the irradiated volume, whereas a large part of the skin where the cream was applied outside the radiation field was strictly normal. More precisely, the radiation recall dermatitis matched with the isodose 20 Gy, whereas no recall reaction was observed in the lower dose areas (5, 10 or 15 Gy) despite these areas were also largely exposed to the cream. In conclusion, this is the first report that could provide a threshold dose for the occurrence of a radiation recall dermatitis, which was not observed below 20 Gy, in the context of this topical reagent.

[Stereotactic body radiation therapy for hepatocellular carcinoma: Results from a retrospective multicentre study]. / Radiothérapie en conditions stéréotaxiques du carcinome hépatocellulaire : résultats d'une étude rétrospective multicentrique.

PURPOSE: The purpose of this paper was to describe local control, overall survival, progression-free survival and toxicity of CyberKnife®-based stereotactic body radiation therapy of hepatocellular carcinoma. MATERIAL AND METHODS: Records of all the patients treated for hepatocellular carcinoma at the Eugene-Marquis cancer centre, Rennes and the Bretonneau hospital, Tours (France), between November 2010 and December 2016, were reviewed. Radiation therapy was performed as a salvage treatment, while awaiting liver transplantation or if no other treatment was possible. RESULTS: One hundred and thirty-six patients were consecutively included in the study. The median follow-up was 13months. Median total dose prescribed, fractionation and overall treatment time were respectively 45Gy, three fractions and 5 days. Overall survival, progression-free survival and local control rates at 1year and 2years were 79.8 % and 63.5 %, 61.3 % and 39.4 %; 94.5 % and 91 %. Two grade 3 acute toxicity events and two grade 4 late toxicity events corresponding to a duodenal ulcer have been reported. Seven patients underwent classic radiation-induced hepatitis and 13 patients showed non-classical radiation-induced hepatitis. Barcelona Clinic Liver Cancer stage, World Health Organisation grade and planning target volume were correlated with overall survival in univariate Cox analysis. CONCLUSION: Stereotactic body radiation therapy is effective and well-tolerated for inoperable hepatocellular carcinoma or as a bridge to liver transplantation. Toxicity is mainly related to cirrhotic background and requires a selection of patients and strict dose constraints.

(18F)-FDG PET/CT parameters to predict survival and recurrence in patients with locally advanced cervical cancer treated with chemoradiotherapy.

PURPOSE: To identify predictive (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based parameters for locoregional control, disease-free survival and overall survival, by testing different thresholds of metabolic tumor volume and total lesion glycolysis in patients with locally-advanced cervical cancer. PATIENTS AND METHODS: Thirty-seven patients treated with standard chemoirradiation underwent a pretreatment (18F)-FDG-PET/CT. Using different thresholds of maximum standardized uptake value, the following PET parameters were computed: maximum standardized uptake value, mean standardized uptake value, metabolic tumor volume and total lesion glycolysis for primary tumor and lymph nodes and a new parameter combining the metabolic tumor volume and the distance between lymph nodes and the primary tumor, namely metabolic node distance. Correlation between PET and clinical parameters with clinical outcome (overall survival, disease-free survival, and locoregional control) was assessed using univariate and multivariate analyses (Cox model). RESULTS: In univariate analyses, PET/CT parameters associated with overall survival and disease-free survival were: metabolic tumor volume and total lesion glycolysis of the primary tumor, total lesion glycolysis of lymph nodes and metabolic node distance. The most predictive threshold segmentation for metabolic tumor volume and total lesion glycolysis was 48% of maximum standardized uptake value for the primary tumor and 30% for the lymph nodes. In multivariate Cox analysis, the total lesion glycolysis of primary tumor 48% and metabolic node distance were the two independent risk factors for overall survival (P<0.01), disease-free survival (P<0.01) and locoregional control (P=0.046). CONCLUSION: Total lesion glycolysis of primary tumor and distance between the invaded positive lymph node and the primary tumor seem to have the highest predictive value when compared to classical clinical prognostic parameters and may be useful to identify high risk groups at time of diagnosis and to tailor the therapeutic approach in locally-advanced cervical cancer.

Reirradiation of gliomas under stereotactic conditions: Prognostic factors for survival without relapse or side effects, a retrospective study at Tours regional university hospital (France).

PURPOSE: To search for factors correlated with relapse-free survival following stereotactic reirradiation in patients with recurrent glioma following radiochemotherapy and evaluate tolerance to this treatment. PATIENTS AND METHODS: Initial radiotherapy was given according to the protocol of Stupp and al. Reirradiation was performed using the CyberKnife® system. Patients could have had surgical resection initially and at the time of recurrence. We analysed 13 patients treated between July 2010 and September 2014. The median age was 55 years. The doses delivered ranged from 20 to 36Gy, in one to ten fractions. RESULTS: Median survival after stereotactic radiotherapy was 14 months. Survival without relapse was 3.7 months. Factors significantly influencing duration of relapse-free survival were: age (P=0.04), total dose (P=0.02), dose per fraction (P=0.04) and number of fractions (P=0.01). We found no correlation between gross tumour volume, clinical target volume, grade of tumour or prescription isodose and relapse-free survival following radiochemotherapy. Three patients developed radionecrosis. CONCLUSION: Reirradiation under stereotactic conditions is well tolerated. A dose of more than 30Gy delivered in 5 or more fractions seems to prolong relapse-free survival.

[Doses to organs at risk in conformational and stereotactic body radiation therapy: Liver]. / Doses aux organes à risque en radiothérapie conformationnelle et en radiothérapie stéréotaxique : le foie.

The liver is an essential organ that ensures many vital functions such as metabolism of bilirubin, glucose, lipids, synthesis of coagulation factors, destruction of many toxins, etc. The hepatic parenchyma can be irradiated during the management of digestive tumors, right basithoracic, esophagus, abdomen in toto or TBI. In addition, radiotherapy of the hepatic area, which is mainly stereotactic, now occupies a central place in the management of primary or secondary hepatic tumors. Irradiation of the whole liver, or part of it, may be complicated by radiation-induced hepatitis. It is therefore necessary to respect strict dosimetric constraints both in stereotactic and in conformational irradiation in order to limit the undesired irradiation of the hepatic parenchyma which may vary according to the treatment techniques, the basic hepatic function or the lesion size. The liver is an organ with a parallel architecture, so the average tolerable dose in the whole liver should be considered rather than the maximum tolerable dose at one point. The purpose of this article is to propose a development of dose recommendations during conformation or stereotactic radiotherapy of the liver.

A PET-based nomogram for oropharyngeal cancers.

PURPOSE: In the context of locally advanced oropharyngeal cancer (LAOC) treated with definitive radiotherapy (RT) (combined with chemotherapy or cetuximab), the aims of this study were: (1) to identify PET-FDG parameters correlated with overall survival (OS) from a first cohort of patients; then (2) to compute a prognostic score; and (3) finally to validate this scoring system in a second independent cohort of patients. MATERIALS AND METHODS: A total of 76 consecutive patients (training cohort from Rennes) treated with chemoradiotherapy or RT with cetuximab for LAOC were used to build a predictive model of locoregional control (LRC) and OS based on PET-FDG parameters. After internal calibration and validation of this model, a nomogram and a scoring system were developed and tested in a validation cohort of 46 consecutive patients treated with definitive RT for LAOC in Lausanne. RESULTS: In multivariate analysis, the metabolic tumour volume (MTV) of the primary tumour and the lymph nodes were independent predictive factors for LRC and OS. Internal calibration showed a very good adjustment between the predicted OS and the observed OS at 24 months. Using the predictive score, two risk groups were identified (median OS 42 versus 14 months, p < 0.001) and confirmed in the validation cohort from Lausanne (median OS not reached versus 26 months, p=0.008). CONCLUSIONS: This is the first report of a PET-based nomogram in oropharyngeal cancer. Interestingly, it appeared stronger than the classical prognostic factors and was validated in independent cohorts markedly diverging in many aspects, which suggest that the observed signal was robust.

Surgical closure of persisting failed tracheoesophageal voice fistula.

Tracheoesophageal puncture (TEP) is a highly successful procedure for voice restoration. Occasionally, however, patients fail to achieve satisfactory voice or develop salivary leakage through the fistula into the trachea. Closure of the TEP is then necessary. In most cases, spontaneous closure occurs once the prosthesis has been removed. When the fistula does not close spontaneously, surgical closure is indicated to prevent aspiration and pulmonary complications. We describe a three-layer technique that employs interposition of dermal graft. The technique was used on 14 patients over a 7-year period. Most patients received irradiation to the neck. Complete closure was achieved in 13 of 14 cases; 1 patient developed partial breakdown of the closure. Our technique is relatively easy to perform and has a high success rate (92%). Irradiation did not adversely affect the closure rate.

Nonseptic lateral sinus thrombosis: the otolaryngologic perspective.

Nonseptic lateral sinus thrombosis (NSLST) differs from septic lateral thrombosis (SLST) in that it is not associated with ear or sinus infection, it usually occurs in the adult population, and it has an ambiguous clinical presentation. The otolaryngologist is often consulted about diagnostic findings associated with lateral sinus thrombosis. We report three cases of NSLST that required otolaryngologic assessment. The patients were women, ages 23 to 31 years. Presenting symptoms were headaches in all three patients; one also had concomitant ear pain. Two patients had negative head computed tomography scans; only magnetic resonance imaging was diagnostic. Treatment of NSLST consists of anticoagulation and elimination of predisposing factors. Familiarity with this condition is fundamental for early diagnosis and initiation of appropriate therapy. We discuss the origins and causes of NSLST, clinical presentation, preferred diagnostic strategy, and treatment alternatives.

Locoregionally advanced paranasal sinus carcinoma. Favorable survival with multimodality therapy.

To determine the efficacy of multimodality treatment for stage III and IV, advanced paranasal carcinoma, we have retrospectively reviewed local control rate and disease-free survival in patients treated at the University of Chicago (Ill). Twelve consecutive patients with stage III or IV, newly diagnosed paranasal sinus carcinoma treated between 1984 and 1991 were included in this study. Multimodality therapy was composed of a sequence of fluorouracil-cisplatin-based neoadjuvant chemotherapy (in 12 of 12 patients) followed by standard surgical resection (11 of 12 patients) and radiotherapy (12 of 12 patients, 45 to 73 Gy) with or without concomitant chemotherapy. Eleven patients (92%) are currently alive and free of disease, with a median follow-up of 55 months (range, 13 to 105 months). One patient died of persistent disease. Failure was attributed to incomplete surgical resection. There was only one major irreversible treatment complication (cisplatin ototoxic reaction). Our preliminary data suggest improved local control and survival with multimodality therapy that includes systemic neoadjuvant chemotherapy and standard tumor resection in patients with advanced paranasal sinus carcinoma. These results are superior to the reported 40% survival with bimodal therapy and are better than those achieved in our institution for other head and neck primaries with the same treatment regimens.

Positron emission tomographic evaluation of patients with head and neck cancer undergoing occlusion and removal of the carotid artery.

We used positron emission tomography (PET) to evaluate cerebral metabolic changes in five patients who underwent resection of the internal carotid artery (ICA) for malignant tumors of the head and neck. These patients received a thorough clinical neurologic examination as well as neuroradiologic evaluation, including computed tomography (CT), magnetic resonance imaging (MRI), and PET of the head, before and after balloon occlusion of the ICA. All five were free of cerebral or peripheral vascular disease. In addition, each patient was evaluated with an electroencephalogram (EEG) before and during the balloon occlusion for signs of ischemic changes. No abnormalities were noted on clinical neurologic examination, CT, MRI, or EEG, either before or after occlusion, and excision of the ICA. The PET examination showed a mean preoperative metabolic rate of 7.52 mg of glucose/min/100 gm of brain tissue and a mean postoperative rate of 6.32 mg/min/100 gm of brain tissue; these values were within the normal range of 5.00 to 9.00 mg of glucose/min/100 gm of tissue observed at this center. Only one subject showed asymmetry of glucose metabolism; this subject had received radiation treatment to one side of the brain after the initial PET evaluation. The results of this study support our clinical experience with occlusion and resection of the ICA in patients with head and neck tumors that in the past have been considered inoperable.

New concepts in head and neck surgery.

New methods in head and neck cancer treatment have enabled the oncologic surgeon to pursue the goals of conservation of head and neck physiologic function, reduce the morbidity and mortality associated with advanced head and neck cancers, and increase the cure rates for cancers once considered inoperable. Advances in multimodality therapy may lead in the next decade to less surgical mutilation and higher cure rates.

Baseline motility of the free jejunal graft in a new canine model.

Reconstruction of pharyngoesophageal defects using free jejunal grafts has become an accepted technique of reconstruction. However, there are functional problems associated with the jejunal graft. We developed a canine model that allows us easy access to perform various studies on grafted jejunum, including videofluoroscopy and pressure manometry to determine baseline function. Using a microvascular technique, free jejunal grafts 10 to 30 cm in length were implanted in 11 mongrel dogs. The jejunal segments were implanted subcutaneously and exteriorized proximally and distally. The grafted dogs underwent videofluoroscopic studies. These studies revealed three different types of jejunal graft contractions of variable intensity: circumferential, longitudinal, and mixed. These contractions resulted in four patterns of barium movement: anterograde propulsion, retrograde propulsion, to-and-fro motion, and peristaltic propulsion. Videofluoroscopic studies were repeated on five dogs after an intravenous injection of metoclopramide (Reglan), which caused a significant short-term increase in the intensity of the basic jejunal contractions and barium propulsion. Pressure manometry studies using intraluminal pressure transducers were performed, revealing an inherent baseline contractility. Each dog has its own individual pattern of activity. The pressure generated by the contractions ranged from 5 to 350 mm Hg. Intravenous injection of Reglan produced a marked increase in pressure, but no change in the frequency of contractions. This study suggests that a free jejunal graft will maintain baseline motility. However, this graft may cause dysphagia by discoordination of contractions, retrograde propulsion of a bolus, or a sustained local contraction, demonstrating the clinical problems associated with free jejunal graft reconstruction of the cervical esophagus. Our results with Reglan suggest that it might be possible to improve the function of these grafts using pharmacologic agents.

Endotracheal intubation as an alternative to tracheostomy after intraoral or oropharyngeal surgery.

Patients who undergo oral or oropharyngeal surgery usually require a tracheostomy for postoperative airway maintenance. However, the development in recent years of soft endotracheal tubes now provides the alternative of short-term endotracheal intubation, with minimal sequelae. Our favorable experience with the use of short-term intubation in children with epiglottitis prompted us to apply the technique to adults. Over a 2-year period at the University of Chicago Medical Center, we successfully used postoperative endotracheal intubation for 19 adult and pediatric patients who underwent major intraoral procedures, thus avoiding the possible complications, discomfort, and anxiety associated with tracheostomy. The patients were given intravenous steroids and antibiotics concomitantly, so that tissue edema and inflammation were minimized. No complications related to intubation and no postextubation airway compromise were noted in any of the patients.

Facial reanimation by XI-VII anastomosis without shoulder paralysis.

Transposition of the spinal accessory (XI) and facial (VII) nerves has been used successfully in reanimation of facial paralysis, but because of the severity of symptoms associated with denervation of the trapezius muscle, this technique has largely been abandoned. Hypoglossal-facial (XII-VII) nerve anastomosis has now become a more favored procedure; however, the resultant hemiglossal atrophy carries some morbidity. Transposition of the sternocleidomastoid (SCM) branch of the accessory nerve as a way to avoid shoulder paralysis was reported more than 20 years ago with initially excellent results, yet few follow-up studies have been done. Twenty-one fresh cadaver dissections of the accessory nerve-SCM branch and facial nerve were performed to determine if adequate numbers of fascicle groups and sufficient proximal nerve length are available for an adequate end-to-end anastomosis without nerve interposition grafting. This paper presents our anatomic and histologic findings to support the use of proximal SCM nerve anastomosis to distal facial nerve in facial reanimation. When feasible, the use of this technique to correct facial paralysis is encouraged rather than hypoglossal-to-facial nerve anastomotic repair.

Transoral carbon dioxide laser ablation for cancer, tumors, and other diseases.

A carbon dioxide laser was used on 71 patients for the removal of oral cavity or oropharyngeal cancers, premalignant lesions, benign tumors, or elongated soft palates. Evaluation of patient morbidity, speech, and swallowing, as well as survival data, suggests that the use of this modality for treatment of these conditions is highly successful, with excellent preservation of oral and pharyngeal function and minimal patient morbidity. Deep excisions of tumors that could lead to restricted motion of the tongue and/or jaw tended to have an adverse effect on both speech and swallowing. Immediate reconstruction should be considered, especially for defects created by excision of large tumors in the anterior oral cavity or in the lateral oropharyngeal wall cancers. Multimodality cancer therapy should be considered for large oral cavity and oropharyngeal cancers that have been treated by carbon dioxide laser excision.

The transfacial approach for combined anterior craniofacial tumor ablation.

The transfacial approach to the anterior cranial fossa for tumor removal provides for excellent surgical exposure, improved postoperative appearance, and a minimum of complications. The technique is different from previously reported combined craniofacial ablative procedures in that the head and neck surgeon and the neurosurgeon approach the anterior fossa mass through the same facial incision, thus avoiding the need for a separate craniotomy incision. The formation of a vascularized nasofrontal bone flap allows for better wound healing regardless of preoperative and postoperative radiotherapy and/or chemotherapy. This report presents 42 cases in which the transfacial approach was exclusively used in a combined manner to remove nasal, paranasal sinus, and nasopharyngeal neoplasms. The transfacial technique offers a significant advantage over previously described approaches to the anterior skull base.

New canine model for free jejunal graft studies.

The need to more fully understand the function and physiology of the free jejunal graft prompted us to develop a new canine model. Twelve dogs were used to transplant a free jejunal graft in the neck with proximal and distal stomas exteriorized to the skin. The techniques used, complications encountered, and the potential for acute and chronic studies with this animal model are presented.