Introducing day case thyroid lobectomy at a tertiary head and neck centre.

BACKGROUND: Thyroid lobectomy is considered to be a safe day case procedure by the British Association of Day Surgery. However, currently only 5.5% of thyroid surgeries in the UK are undertaken as day cases. We determine if and how thyroid lobectomy with same-day discharge could safely be introduced in our centre. METHODS: We analysed all thyroid lobectomy surgeries performed between April 2015 and May 2019. Exclusion criteria included completion surgery, revision surgery, additional procedures and disseminated disease. Outcomes were benchmarked against surgeon-reported complications from the British Association of Endocrine and Thyroid Surgery's 5th National Audit. Additionally, we reviewed the number of patients who met day case criteria currently in use at our hospital to determine accessibility to the service. RESULTS: In total, 259 thyroid lobectomy surgeries were undertaken and of these 173 met the inclusion criteria. There was no mortality, return to theatre for evacuation of postoperative haematoma or readmission. There was one postoperative haematoma which was drained at the bedside. Some 47 of the 173 (27.2%) patients met day case criteria currently in use at our centre. CONCLUSIONS: Day case surgery provides a cost-effective solution to rising bed pressures and a coherent protocol can optimise patient safety and experience.

Tracheostomy in the coronavirus disease 2019 patient: evaluating feasibility, challenges and early outcomes of the 14-day guidance.

OBJECTIVES: To report feasibility, early outcomes and challenges of implementing a 14-day threshold for undertaking surgical tracheostomy in the critically ill coronavirus disease 2019 patient. METHODS: Twenty-eight coronavirus disease 2019 patients underwent tracheostomy. Demographics, risk factors, ventilatory assistance, organ support and logistics were assessed. RESULTS: The mean time from intubation to tracheostomy formation was 17.0 days (standard deviation = 4.4, range 8-26 days). Mean time to decannulation was 15.8 days (standard deviation = 9.4) and mean time to intensive care unit stepdown to a ward was 19.2 days (standard deviation = 6.8). The time from intubation to tracheostomy was strongly positively correlated with: duration of mechanical ventilation (r(23) = 0.66; p < 0.001), time from intubation to decannulation (r(23) = 0.66; p < 0.001) and time from intubation to intensive care unit discharge (r(23) = 0.71; p < 0.001). CONCLUSION: Performing a tracheostomy in coronavirus disease 2019 positive patients at 8-14 days following intubation is compatible with favourable outcomes. Multidisciplinary team input is crucial to patient selection.

Electrical generation of natural aerosols from vegetation.

It is suggested that an alternative, or additional, source of the blue haze above heavily forested areas may be the generation of submicrometer-sized wax particles by the action of strong electrical fields at the tips of pine needles and other wax-covered plant surfaces. Exposure of pine needles to high potential gradients results in the production of airborne wax particles with diameters less than 0.6 micrometer.

Effects of single-dose and fractionated cranial irradiation on rat brain accumulation of methotrexate.

The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same wether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation.

Tumour assessment and staging: United Kingdom National Multidisciplinary Guidelines.

In general, the first decision to be made in a patient with a confirmed head and neck cancer is whether or not to treat the patient before deciding what form of management strategy is appropriate. There is no more important an aspect of head and neck cancer care than the initial evaluation of the patient and the patient's tumour. The practice requires specific expertise and judgement. The current tumour-node-metastasis system relies on morphology of the tumour (anatomical site and extent of disease) but the final decision on treatment hinges on a full assessment of the patient including physiological age and general condition. The aim of this paper is primarily to describe why and how we appraise a patient and their tumour. It addresses the general principles applicable to the topic of evaluation, classification and staging. In addition, the limitations and pitfalls of this process are described. Recommendations • All patients with head and neck cancer (HNC) should undergo tumour classification and staging prior to treatment. (R) • Pre-therapeutic clinical staging of HNCs should be based on at least a C2 factor (evidence obtained by special diagnostic means, e.g. radiographic imaging (e.g. computed tomography, magnetic resonance imaging or ultrasound scan), endoscopy, biopsy and cytology). (R) • Imaging to evaluate the primary site should be performed prior to biopsy to avoid the effect of upstaging from the oedema caused by biopsy trauma. (G) • Panendoscopy is only recommended for symptomatic patients or patients with primary tumours known to have a significant risk of a second (synchronous) primary tumour. (G).

Neutrophil cathepsin G is specifically decreased under vitamin A deficiency.

Vitamin A deficiency leads to an increased susceptibility to infections, increased severity of infections and increased mortality. Because the neutrophil is the first cell to respond to infection, this study explores the effect of vitamin A deficiency on neutrophil proteinases. We found that neutrophils from vitamin A-deficient rats had lower levels of two cathepsin G-like enzymes (28 and 24 kDa) when compared to neutrophils from weight-matched pair-fed rats, vitamin A-deficient rats which were repleted with retinyl palmitate and nonrestricted vitamin A complete diet rats. The 28 kDa cathepsin G-like enzyme, which migrated with the same mobility as elastase on SDS-polyacrylamide gels, was quantified using Western blots. The 24 kDa cathepsin G-like enzyme was quantified using zymogram gels. This activity was inhibited by chymostatin. Other neutrophil proteinases, elastase, plasminogen activators and gelatinase, were not altered significantly by vitamin A deficiency. The low levels of cathepsin G may contribute to differences in the inflammatory process observed under vitamin A deficiency.

Neurobiologic antecedents of schizophrenia in children. Evidence for an inherited, congenital neurointegrative defect.

In chronic schizophrenics, disordered motor development in childhood is followed by more early cognitive and social impairment and poorer outcome; childhood schizophrenics represent the most extreme variants of this. Preschizophrenic infants show a fluctuating dysregulation of maturation--or "pandevelopmental retardation" (PDR)--that involves physical growth; gross motor, visual-motor, and cognitive development; proprioceptive and vestibular responses; muscle tone; and possibly arousal. Pandevelopmental retardation was significantly related to a genetic history for schizophrenia (less than .05), but not to obstetric complications. The severity of PDR was significantly related to the severity of later psychiatric and cognitive disorder (less than .01). Pandevelopmental retardation provides a "marker" in infancy for the inherited neurointegrative defect in schizophrenia. These disordered functions should be studied by anyone interested in the biology of the schizophrenic genotype or in specific early interventions for children at risk.

Vestibular hyporeactivity in infants at risk for schizophrenia. Association with critical developmental disorders.

Vestibular responses to caloric stimulation were measured from birth to age 2 years in ten infants born to schizophrenic mothers. This is part of a study of evolving neurointegrative disorders that may be associated with a genetic risk for schizophrenia. Transiently decreased vestibular responses coincided with several developmental disorders that were related to psychopathology at 10 years. Absent to decreased responses were associated with (1) a "pandevelopmental retardation" involving physical growth as well as postural-motor and visual-motor development, (2) an "abnormally quiet" state in the first month, and (3) failures of bimanual integration between 4 and 6 months. The transitory nature of the decreased nystagmus rules out the possibility of an organic lesion of the vestibular system. Rather, it suggests that some covert decrease in arousal accompanied those periods when central nervous system integration was disrupted.

Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. A review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study.

A 1975 report stated that a schizophrenic genotype may be manifested in infants by a neurointegrative defect called pandysmaturation. Recent evidence supports this: (1) 12 studies found delayed development in schizophrenics' infants and in preschizophrenics; (2) "blind" psychometric evaluations favored an adult schizotypal disorder in four to six of seven high-risk subjects with pandysmaturation in the New York study; and (3) finally, in a partial replication of this method using the Jerusalem data, blind diagnoses of "probable" and "possible" pandysmaturation were significantly related to a parental diagnosis of schizophrenia and to cognitive and motor neurointegrative deficits at 10 years. Obstetrical complications were unrelated to diagnosis, pandysmaturation, or outcome in the overall sample. However, we found a small subgroup of schizophrenic offspring in whom the most severe motor deficits at follow-up were related to obstetrical complications, pandysmaturation, and low birth weight.

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Influence of nephrotoxic drugs on the late renal toxicity associated with bone marrow transplant conditioning regimens.

The total body irradiation that is given as part of bone marrow transplant conditioning regimens is a factor in the renal toxicity that is observed after bone marrow transplant, but it may not be the only factor. We hypothesize that nephrotoxic drugs used in prior chemotherapy can precipitate renal radiation damage. Studies were designed to determine if nephrotoxic antineoplastic drugs could shorten the latent period for the development of radiation nephritis. Rats were given bilateral renal irradiation using a radiation schedule that produced moderate nephritis. Cisplatinum, BCNU, or mitomycin were given before, during, or after irradiation at doses that produced only mild nephrotoxicity. All cisplatinum-radiation sequences resulted in decreased renal function, with radiation prior to cisplatinum producing the greatest dysfunction. BCNU increased renal dysfunction equally in all schedules, but mitomycin had only minimal effects. Most drug schedules, including those with mitomycin, produced earlier development of morbidity after fractionated renal irradiation. In a second set of studies, rats were given single doses of the same nephrotoxic drugs, followed 3 months later by total body irradiation plus bone marrow transplant. The drugs had no effect on the marrow ablation dose, but BCNU and cisplatinum decreased gastrointestinal tolerance. Four months after total body irradiation, rats which received drugs alone or total body irradiation alone have essentially normal renal function, but rats which received cisplatinum plus total body irradiation or BCNU plus total body irradiation show a dose-dependent decrease in renal function. These studies show that radiation nephritis can be precipitated by low doses of nephrotoxic drugs, and may help to explain the incidence of early radiation nephritis in bone marrow transplant patients conditioned with total body irradiation.

Intermittent use of a perfluorochemical emulsion (Fluosol-DA 20%) and carbogen breathing with fractionated irradiation.

Oxygen carrying perfluorochemical emulsions have been shown to enhance the response of animal tumors to large single doses of radiation. Clinically, however, perfluorochemical emulsions are being used with only some fractions in multiple fraction radiation courses. To test the efficacy of a perfluorochemical emulsion under conditions that are closer to those used in current clinical trials, BA1112 rat sarcomas were treated with three fractions per week of 6 Gy per fraction. Once a week, animals were infused i.v. with a perfluorochemical emulsion at 15 ml/kg, and allowed to breathe carbogen (95% O2:5% CO2) for 30 minutes prior to and during irradiation. The 50% tumor control dose was 93.1 (87.9-103.1) Gy in the control arm compared to 74.3 (64.9-83.9) Gy for the animals given the perfluorochemical infusion plus carbogen breathing. The dose modification factor for intermittent perfluorochemical infusion and carbogen breathing was 1.26 (1.15-1.40). In a similar fractionated schedule, the hypoxic cell radiosensitizer, misonidazole, given once per week at 600 mg/kg, gave a dose modification factor of 1.22 (1.14-1.32).

Late toxicity of total body irradiation with bone marrow transplantation in a rat model.

In defined-flora, barrier-maintained rats, radiation nephritis is the principle late toxicity seen after high dose-rate total body irradiation (TBI), when hematologic toxicity is prevented by bone marrow transplantation (BMT). Pneumonitis develops only if rats are placed in a conventional microbiological environment during and after BMT. Low dose-rate TBI gives qualitatively similar late toxicity, but at radiation doses twice as large. Fractionation of the TBI has little effect on the bone marrow ablation doses, but results in increased gastrointestinal and renal tolerance. The addition of immunosuppressive or cytotoxic drugs (cyclosporine-A, methotrexate, cis-platinum) after TBI and BMT greatly decreases the dose of TBI that can be tolerated. The use of a cyclophosphamide plus cytosine arabinoside conditioning regimen prior to TBI and BMT increases the bone marrow ablation dose, but has no effect on acute gastrointestinal toxicity or on renal toxicity. These results indicate that substantial late toxicity may be associated with the TBI conditioning regimens used for BMT even in the absence of cytotoxic and antibiotic drugs, immunosuppressive agents, infection and graft-versus-host disease; and that radiation may be a contributing factor in the nephritis sometimes observed after TBI and BMT.

Treatment of radiation nephropathy with ACE inhibitors.

PURPOSE: A previous study showed that radiation nephritis could be treated with captopril, an angiotensin-converting-enzyme inhibitor. These studies were designed to determine whether other angiotensin-converting-enzyme inhibitors would be effective, whether captopril would inhibit the development of the histopathologic lesions typical of radiation nephritis, and whether captopril could be used to treat the nephropathy observed in bone marrow transplant recipients conditioned with total body irradiation. METHODS AND MATERIALS: In radiation nephritis studies, rats were given 17-27 Gy bilateral renal irradiation in 5 fractions. Six months after irradiation animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l) or enalapril (50 mg/l) in the drinking water. A subset of animals was sacrificed for histopathology after 3 months; the remaining animals continued on drugs for 7 months. In the bone marrow transplant nephropathy study, rats received 14-17 Gy total body irradiation in 6 fractions over 3 days followed by syngeneic bone marrow transplant. Six months after irradiation, animals were stratified by blood urea nitrogen and assigned to no treatment, or treatment with captopril (500 mg/l). Animals remained on drugs for 6 months. In all studies animals were followed with periodic renal function tests. RESULTS: In the radiation nephritis study, survival and renal function were significantly enhanced by both captopril and enalapril, but there were no significant differences between the drugs. The histopathologic severity of the lesions of radiation nephritis correlated with the degree of renal dysfunction; and in irradiated animals with equal initial azotemia, captopril-treated rats developed less severe renal lesions. Finally, captopril also prolonged survival and preserved renal function in this rat bone marrow transplant nephropathy model. CONCLUSION: Angiotensin-converting-enzyme inhibitors are an effective treatment for both radiation nephritis and bone marrow transplant nephropathy.

Tumor and normal tissue tolerance for fractionated low-dose-rate radiotherapy.

Radiobiological evidence suggests that an improved therapeutic ratio might be achieved through the use of smaller than conventional dose fractions. The ultimate in small dose fractions for external beam radiotherapy would be fractionated low-dose-rate (LDR) irradiation, and clinical trials of fractionated external beam LDR therapy are already in progress. Using the BA1112 rat sarcoma, we have determined the 50% tumor control dose for LDR and for conventional-dose-rate (CDR) fractionated radiotherapy. These tumor control doses were compared to normal tissue tolerance doses for hemi-body irradiation in similar CDR and LDR schedules. Animals were treated 3 times per week without anesthesia using 10-19 fractions. LDR radiotherapy was done with 60Co at dose rates of 0.028-0.033 Gy/min; CDR radiotherapy was done with 250 kVp X rays at dose rates of 0.54-2.1 Gy/min. The tumor control dose modification factor (DMF) for LDR compared to CDR irradiation was 1.3 (1.0-1.5). For LDR and CDR hemi-body irradiation, the dose modification factor for 7 day lethality (gastrointestinal damage) was 1.7 (1.5-1.9), for 100 day morbidity was 1.8 (1.6-2.2), and for radiation nephritis at 90 days was 1.9 (1.7-2.3). The therapeutic gain factor for fractionated low-dose-rate irradiation compared to conventional-dose-rate fractionated radiotherapy was therefore 1.8/1.3 = 1.4 (1.2-1.8). The study shows that there is an experimental as well as a theoretical basis for anticipating a therapeutic benefit from the use of external beam fractionated LDR radiotherapy, and implies that the recognized therapeutic efficacy of brachytherapy is not due solely to the high localized dose.

Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation.

PURPOSE: Chronic renal failure is a significant cause of late morbidity in bone marrow transplant patients whose conditioning regimen includes total body irradiation (TBI). Radiation is a major cause of this syndrome (bone marrow transplant nephropathy), but it may not be the only cause. These studies use a rat syngeneic bone marrow transplant model to determine whether nephrotoxic agents used in conjunction with bone marrow transplantation (BMT) could be enhancing or accelerating the development of radiation nephropathy. METHODS AND MATERIALS: Rats received 11-17 Gy TBI in six fractions over 3 days followed by syngeneic bone marrow transplant. In conjunction with the bone marrow transplants, animals received either no drugs, cyclosporine, amphotericin, gentamicin, or busulfan. Drugs were given in schedules analogous to their use in clinical bone marrow transplantation. Drug doses were chosen so that the drug regimen alone caused detectable acute nephrotoxicity. Animals were followed for 6 months with periodic renal function tests. RESULTS: Gentamicin had no apparent interactions with TBI. Amphotericin increased the incidence of engraftment failure, but did not enhance radiation nephropathy. Cyclosporin with TBI caused late morbidity that appeared to be due to neurological problems, but did not enhance radiation nephropathy. Busulfan resulted in a significant enhancement of radiation nephropathy. CONCLUSION: Of the nephrotoxins used in conjunction with bone marrow transplantation only radiation and busulfan were found to be risk factors for bone marrow transplant nephropathy.

Renal irradiation and the pharmacology and toxicity of methotrexate and cisplatinum.

We used a rat model to study the effects of renal irradiation on the pharmacology of methotrexate (MTX) and cisplatinum (cis-Pt). Unanesthetized rats were given bilateral kidney irradiation (20 Gy in 9 fractions). At 9 months after irradiation, 3% of the animals had died and survivors showed moderately impaired renal function. At 15 months, 30% of the animals had died and survivors showed severely impaired renal function. Some animals were given i.v. MTX 1 week to 15 months after irradiation. In irradiated rats, the area under the MTX plasma clearance curve equaled that of controls through 6 months, and was significantly above controls from 9 months on. Other animals were given i.p. cis-Pt 1 week to 9 months after irradiation. The acute toxicity of cis-Pt was the same in control and irradiated rats when cis-Pt was given immediately before or after irradiation. Beginning 3 months after irradiation there was a progressive increase in cis-Pt toxicity and a simultaneous decrease in urinary platinum excretion. Irradiated animals that survived cis-Pt treatment showed increased radiation nephritis; the greatest effect occurred when cis-Pt was given 3 months or more after irradiation. MTX and cis-Pt clearance decreased when renal dysfunction was first observed and changes in renal function preceded changes in drug clearance and toxicity.

Development of a rat lung cancer model.

A rat lung cancer model based on intrabronchial instillation of a tumor cell suspension has been developed for use in therapy and toxicity testing. Two tumors were used in this study, a sarcoma and an adenocarcinoma, both of which were of spontaneous origin in the strain of rats used. The inoculated tumor cells implant on the bronchiolar mucosa, forming a detectable single "primary" tumor resembling the spontaneous lung cancers arising in humans. The tumor growth is detectable by use of diagnostic radiographs, weight loss and other "clinical" signs. The tumors appear on chest radiographs 3 to 5 weeks after inoculation, and the implant rate is proportional to the number of tumor cells inoculated. Untreated animals have a median survival (after radiographic detection of the tumor) of 8 days, and die of local complications of tumor growth. When a slow growing transplantable tumor line of lung origin is developed, this model will be used to evaluate radiotherapy and chemotherapy schedules.

Hepatic function and drug pharmacokinetics after total body irradiation plus bone marrow transplant.

Radiation nephritis is the principle late toxicity seen after total body irradiation in barrier-maintained rats when hematologic toxicity is prevented by bone marrow transplantation. Renal dysfunction is observed for single doses as low as 7.5 Gy. Hepatic blood flow, as measured by indocyanine green clearance, is decreased after 8.5-9.5 Gy single-dose total body irradiation. Serum albumin levels are decreased after 9.5 Gy single-dose total body irradiation. Hypoalbuminemia is a symptom of hepatic damage, but can also be caused by renal damage or edema. No decrease in total serum protein is observed, indicating that proteinuria resulting from renal damage is not the cause of hypoalbuminemia. No edema and some dehydration are observed. These data indicate that hepatic damage as well as renal damage may be occurring after total body irradiation plus bone marrow transplantation. Animals given total body irradiation plus bone marrow transplantation show decreased tolerance to a wide variety of immunosuppressive and cytotoxic drugs, even when these drugs are given months after total body irradiation. Altered drug clearance after total body irradiation plus bone marrow transplantation is observed for cis-platinum, vincristine, and adriamycin. The increase in cis-platinum toxicity after total body irradiation plus bone marrow transplantation is caused by decreased renal drug clearance. The decrease in vincristine tolerance and the alterations in adriamycin and vincristine pharmacokinetics are caused by altered drug distribution after total body irradiation plus bone marrow transplantation. These results indicate that bone marrow transplant survivors may show altered clearance of, and decreased tolerance to, a wide variety of drugs that are used after bone marrow transplantation.

Chronic effects of fractionated renal irradiation on the pharmacokinetics of intravenous methotrexate.

the chronic effects of renal irradiation on the pharmacology of methotrexate was studied in a rat model. Unanesthetized rats received 2 doses of bilateral fractionated kidney irradiation (16.2 Gy or 19.8 Gy in 9 fractions). Alterations in renal function were first seen at 3 months in the 19.8 Gy group and 12 months in the 16.2 Gy groups. Life table analysis showed a shift in the survival curve of about 3 months between the 2 radiation doses. The pharmacokinetics of i.v. methotrexate showed an increase in the area under the plasma curve beginning at 9 months in the 19.8 Gy group and at 15 months in the 16.2 Gy group. The volume of distribution of methotrexate was smaller in the irradiated rats than in unirradiated controls. Multiple linear regression models showed significant correlations between parameters of methotrexate clearance and certain renal function tests. Nevertheless, no set of renal function tests consistently predicted alteration in methotrexate clearance in the 2 radiation groups. Furthermore, time after irradiation remained a highly significant variable indicating that renal irradiation causes time dependent change in methotrexate pharmacokinetics that can not be accounted for by the usual tests of renal function.