30-day morbidity and mortality after transoral robotic surgery for human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma: A retrospective analysis of two prospective adjuvant de-escalation trials (MC1273 & MC1675).

OBJECTIVE: Dose de-escalation of adjuvant therapy (DART) in patients with HPV(+)OPSCC was investigated in two prospective Phase II and III clinical trials (MC1273 and MC1675). We report the 30-day morbidity and mortality associated with primary TORS resection in patients enrolled in these trials. MATERIALS AND METHODS: Patients with HPV(+)OPSCC, who underwent TORS resection between 2013 and 2020 were considered in this analysis. The severity of postoperative transoral bleeding was graded using both the Hinni Grade (HG) transoral surgery bleeding scale and the Common Terminology for Adverse Events (CTCAE) v5.0. Post-surgical complications within 30 days of surgery, as well as rates of tracheostomy, PEG and nasogastric tube placement. RESULTS: 219 patients were included. A total of 7 (3.2 %) patients had a tracheostomy placed at the time of surgery, and all were decannulated within 26 days (median: 5, range: 2-26). There were 33 (15.1 %) returns to the emergency department (ED) with 10 (4.6 %) patients requiring readmission. Using the HG scale, 10 (4.6 %) patients experienced ≥ Grade 3 bleeding with no Grade 5 or 6 bleeds. In contrast, using the CTCAE scale, 15 patients (6.8 %) experienced ≥ Grade 3 bleeding with no Grade 5 bleeds. There was one post-operative death in a patient withdrawn from the trial, and no deaths related to hemorrhage. CONCLUSION AND RELEVANCE: TORS for HPV(+)OPSCC in carefully selected patients at a high volume center was associated with low morbidity and mortality.

Non-opioid analgesics and post-operative pain following transoral robotic surgery for oropharyngeal cancer.

OBJECTIVE: To investigate associations between multimodal analgesia and post-operative pain among patients undergoing transoral robotic surgery for oropharyngeal squamous cell carcinoma. METHODS: Records of patients who underwent surgery from 5 September 2012 to 30 November 2016 were abstracted. Associations were assessed using multivariable analysis. RESULTS: A total of 216 patients (mean age of 59.1 years, 89.4 per cent male) underwent transoral robotic surgery (92.6 per cent were human papilloma virus positive, 87.5 per cent had stage T1-T2 tumours, and 82.9 per cent had stage N0-N1 nodes). Gabapentin (n = 86) was not associated with a reduction in severe pain. Ibuprofen (n = 72) was administered less often in patients with severe pain. Gabapentin was not associated with increased post-operative sedation (p = 0.624) and ibuprofen was not associated with increased bleeding (p = 0.221). Post-operative opioid usage was not associated with surgical duration, pharyngotomy, bilateral neck dissections, tumour stage, tumour size, subsite or gabapentin. CONCLUSION: Scheduled low-dose gabapentin was not associated with improved pain control or increased respiratory depression. Ibuprofen was not associated with an increased risk of bleeding and may be under-utilised.

QTc interval in survivors of out of hospital cardiac arrest.

BACKGROUND: QTc interval (QTc) prolongation is seen on the post-arrest electrocardiogram (ECG) of many out of hospital cardiac arrest (OHCA) survivors. It remains unclear whether this is a transient phenomenon or a manifestation of an underlying arrhythmic substrate. This observational study assessed the trend of QTc in an unselected group of patients presenting with OHCA. We sought to identify any relationship between QTc, gender and aetiology of arrest. We observed whether targeted temperature management (TTM) is associated with malignant arrhythmia. METHOD: We analysed 60 patients presenting with OHCA to the Bristol Heart Institute during a 20-month period. We measured QTc on admission and assessed for persistence, development and resolution of prolongation at up to 5 time points post-OHCA. Aetiology of arrest was divided into coronary, non-coronary or primary arrhythmic to investigate for patterns in QTc behaviour. RESULTS: 81.7% (49/60) of arrests were attributed to an acute coronary event. 55% (33/60) had QTc prolongation on admission, of which 79% resolved. There were no significant differences in QTc behaviour by aetiology. One patient presenting with a normal QTc, developed prolongation during admission and received a genetic diagnosis of Long QT Syndrome. TTM was employed in 57/60, with no increased incidence of malignant arrhythmia. CONCLUSIONS: Prolonged QTc on admission does not imply a primary arrhythmic aetiology and resolves in the majority pre-discharge. However, an initial normal QTc post-OHCA does not preclude a diagnosis of Long QT syndrome, highlighting the importance of thorough investigations in these patients. TTM appears safe from a cardiac perspective.

The clinical effects of a low dose dexmedetomidine constant rate infusion in isoflurane anesthetized cats.

The aim of this study was to evaluate the effects of a low dose dexmedetomidine constant rate infusion (CRI) on cardiopulmonary function, inhalant anesthetic concentration and recovery in isoflurane anesthetized cats. In a prospective, randomized, blinded, controlled design, 12 cats undergoing anesthesia for ovariohysterectomy were administered hydromorphone (0.1mg/kg) intramuscularly, propofol (4.3-7.8mg/kg) intravenously and maintained with isoflurane. During isoflurane anesthesia, the cats were administered either a dexmedetomidine loading dose (0.5µg/kg) followed by a dexmedetomidine CRI (0.5µg/kg/h) (group LDD), or a saline loading dose followed by a saline CRI (group SAL). Heart rate (HR), respiratory rate, blood pressure, temperature, oxygen saturation (SpO2), end tidal carbon dioxide concentration (ETCO2), end tidal isoflurane concentration (ETISO) and anesthetic depth were recorded at nine time points (T0-T8). Overall effects (T1-8) and individual time point results were compared between groups. There were no significant differences in baseline variables (T0), age, weight, propofol dose, anesthesia and surgery time, time to extubation or recovery score between groups. Among the physiological variables measured, significant differences were observed in respiratory rate, ETCO2, and mean and diastolic blood pressure, between groups at individual time points. Systolic blood pressure, HR, SpO2, ETISO and temperature were not significantly different between groups at individual time points. Overall, ETCO2 and ETISO were significantly lower and respiratory rate was significantly higher for LDD compared to SAL. At the doses administered, a CRI of dexmedetomidine reduced isoflurane requirements in anesthetized cats undergoing ovariohysterectomy. The utility of a low dose dexmedetomidine CRI in the perioperative setting requires further investigation, since intraoperative cardiopulmonary values during dexmedetomidine infusion were not different from those receiving saline.

Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

OBJECTIVE: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC. METHODS: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases. RESULTS: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort. CONCLUSIONS: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

Differential loss of expression of common fragile site genes between oral tongue and oropharyngeal squamous cell carcinomas.

The common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. A number of the CFSs have been found to span genes that extend over large genomic regions (>700 kb). The expression of these genes is frequently abrogated in a number of different cancers and several of them have already been shown to function as tumor suppressor genes, both in vitro and in vivo. We analyzed the expression of 14 large CFS genes in two distinct groups of head and neck cancers using real-time RT-PCR. The first were oral tongue squamous cell carcinomas (SCCs) and the second were base of tongue/tonsillar (oropharyngeal) SCCs. These two groups were previously examined for the presence of human papillomavirus (HPV) and while 46% of the oropharyngeal cancers were positive for HPV16 only one of 52 oral cancers contained HPV16 sequences. We observed a distinct pattern of loss of expression of the large CFS genes in the two groups of head and neck cancers. In addition, there was no correlation between the relative instability in different CFS regions and which genes were inactivated. Thus, this report demonstrates another distinction between these two groups of head and neck cancer. In addition, it suggests that there is selection for loss of expression of specific CFS genes in these cancers.

Prospective analysis of the efficacy of continuous intraoperative nerve monitoring during thyroidectomy, parathyroidectomy, and parotidectomy.

OBJECTIVE: Continuous intraoperative electromyographic monitoring was prospectively performed in all parotidectomies, thyroidectomies, and parathyroidectomies over approximately 5 years to assess the efficacy of this technology. STUDY DESIGN AND SETTING: Continuous intraoperative nerve monitoring with perioperative nerve assessment was performed. The postresection minimal stimulation level of the nerves was determined to evaluate if this level would predict nerve function postoperatively. RESULTS: Forty-four parotidectomies and 70 thyroid/parathyroid operations were performed with 140 nerves at risk (44 facial, 96 recurrent laryngeal). The incidence of temporary facial paralysis was 15.9% (7 of 44) and the incidence of permanent paralysis was 0%. The incidence of temporary recurrent laryngeal nerve paralysis in terms of nerves at risk was 1.0% (1 of 96), and the incidence of permanent recurrent laryngeal nerve paralysis was 0%. All patients with normally functioning facial and recurrent laryngeal nerves postoperatively had minimal stimulation levels less than or equal to 0.4 mA. CONCLUSION: Continuous intraoperative nerve monitoring was associated with extremely low rates of temporary and permanent nerve paralysis in our series of 140 nerves at risk as compared to the rates documented in the literature.

Atrophic rhinitis: a review of 242 cases.

Atrophic rhinitis is a debilitating nasal mucosal disease of unknown etiology. It is characterized by progressive nasal mucosal atrophy, nasal crusting, fetor, and enlargement of the nasal space with paradoxical nasal congestion. Primary atrophic rhinitis has decreased markedly in incidence in the last century. This probably relates to the increased use of antibiotics for chronic nasal infection. Secondary atrophic rhinitis resulting from trauma, surgery granulomatous diseases, infection, and radiation exposure accounts for the majority of cases encountered by the rhinologist today. Excessive turbinate surgery has been both acquitted and accused in the literature as an etiology for secondary atrophic rhinitis. We saw 242 patients with the diagnosis of atrophic rhinitis between 1982 and 1999. The diagnosis was confirmed by physical examination, biopsy, and imaging studies. Patients were diagnosed with primary atrophic rhinitis if their condition developed in a previously healthy nose and secondary atrophic rhinitis if their condition developed after sinonasal surgery, trauma, or chronic granulomatous disease. Prevention and treatment of the disease is discussed.

Microcystins (cyanobacterial toxins) in drinking water enhance the growth of aberrant crypt foci in the mouse colon.

Microcystis aeruginosa produces toxic cyclic peptides called microcystins, potent hepatotoxins that have been implicated in tumor promotion in skin and liver. The model used in this investigation was the azoxymethane (AOM)-induced aberrant crypt focus (ACF) in the male C57Bl/6J mouse colon. Three intraperitoneal (i.p.) injections of 5 mg/kg AOM were administered at 7-d intervals to mice; 19 d after the last AOM injection, drinking water containing Microcystis extract was commenced and continued for a further 212 d. The content of microcystins in the drinking water was determined by mouse bioassay, high-performance liquid chromatography (HPLC), capillary eletrophoresis, and protein phosphatase inhibition. The doses employed were 0, 382, and 693 micrograms/kg bodyweight/d at the midpoint of the trial. Following postmortem examination blood cells, serum enzymes and organ pathology were investigated. A significant microcystin dose-dependent increase in the area of aberrant crypt foci was observed. There was no marked increase in the number of crypts/colon. Two overt colonic tumors (approximately 30 mm3) were seen in microcystin-treated mice, and one microscopic colonic tumor in an AOM-alone-treated mouse. This investigation provides the first evidence for the stimulation of preneoplastic colon tumor growth by microcystin.

Preoperative and postoperative topical tretinoin on high-tension excisional wounds and full-thickness skin grafts in a porcine model: A pilot study.

BACKGROUND: Tretinoin induces neovascularization and the formation of collagen when applied topically. OBJECTIVE: The goal was to determine whether preoperative and postoperative treatment with tretinoin enhances the healing of high-tension, full-thickness excisional wounds and the survival of full-thickness skin grafts. METHODS: A blinded, randomized, placebo-controlled pilot study involved high-tension excisional wounds and full-thickness skin grafts treated perioperatively with tretinoin in a porcine model. RESULTS: Perioperative treatment of high-tension excisional surgery sites with tretinoin appeared to have no consistent beneficial or adverse effects on wound healing or scar spreading. In the full-thickness skin graft model, a trend toward impaired wound healing was noted. CONCLUSION: The collagen-inducing effects of topical tretinoin do not appear to enhance the healing of high-tension excisional surgery wounds in a porcine model. Tretinoin does not appear to improve the survival of full-thickness skin grafts and, in fact, a detrimental effect was apparent in our model.

Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma.

BACKGROUND: The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. METHODS: Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. RESULTS: The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 +/- 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 +/- 3.7 weeks), with 1/18 alive at 1 year (> 6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. CONCLUSIONS: Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted.

Cone biopsy: a review of 112 cases.

A chart review of 112 patients who underwent cold knife conisation was performed. Records showed that 73.5% of the patients smoked cigarettes and 26.5% were using oral contraception. In 85.7% of cases pre-operative cytology/colposcopy findings were within one grade of the cone histology. The majority of lesions were CIN III (59.9%). Only 4.5% were normal. Human papilloma virus infection was detected histologically in 26.8% of patients. Pre-operative punch biopsy was undertaken in only five cases. Post-operative haemorrhage (9.0%) and genito-urinary infection (9.0%) were the main complications seen. The incidence of residual disease and post-cone hysterectomy was significantly higher if the margins of resection of the cone were unclear. Large-loop excision of the transformation zone (LLETZ) has now replaced cold knife conisation in both study centres due to its lower morbidity and reduced demand on hospital resources.