Longitudinal functional outcomes and late effects of radiation following treatment of nasopharyngeal carcinoma: secondary analysis of a prospective cohort study.

BACKGROUND: The study objectives were: provide longitudinal data on upper aerodigestive tract function and late complications following IMRT for nasopharyngeal carcinoma, and elucidate factors that might predict a worse outcome. The hypotheses were: (1) Despite advances such as IMRT, radiation will cause significant functional decline and late complications that often progress or arise years after treatment. (2) Larger radiation volume will be associated with poorer outcomes. METHODS: Longitudinal, observational cohort study of nasopharyngeal carcinoma patients with retrospective analysis of prospectively collected, population-based data. Late sequelae and validated measures of overall performance, speech, and swallowing were documented pre-treatment and 3,6,12, 24, 36 and ≥ 60-months post-treatment. RESULTS: Forty-two patients treated curatively with radiation (N = 9) or chemoradiation (N = 33) were followed for a median 74 months. Functional outcomes showed an initial nadir at 3 months associated with acute effects of treatment, followed by initial recovery. There was subsequent functional decline years post-treatment with advancing dysphagia/aspiration, trismus, muscle spasm, and hypoglossal nerve palsy. Univariable regression analysis revealed that increasing high-dose radiation volumes (PTV 70 Gy) were associated with increased likelihood of less than solid diet (Performance Status Scale (PSS)-Normalcy of Diet score < 50; p = 0.04), and reduced PSS-Understandability of Speech (p = 0.005). The probability of poor outcome increased with time. Eleven percent of patients were tube feed dependent at ≥ 5 years. CONCLUSIONS: Despite improvements in radiation delivery, late effects of radiation remain common. Higher radiation volumes are associated with poorer outcomes that worsen over time.

PTH monitoring after total parathyroidectomy with forearm auto-transplantation: potential for spuriously high levels from grafted forearm.

BACKGROUND: We have identified a cause of falsely elevated parathyroid hormone (PTH) levels after total parathyroidectomy with forearm auto-transplantation (TPT-ATx). Our cases highlight the need to draw PTH samples remotely, away from forearm graft sites, to ensure accurate levels. CASE PRESENTATIONS: We report on four patients who were referred to our surgical team at an academic tertiary care center for what was perceived to be recurrent hyperparathyroidism 2-5 years following total parathyroidectomy with auto-transplantation. Further evaluation revealed highly discrepant results in these patients depending on where the blood was drawn, with spuriously high levels in blood drawn from the grafted arm (Range 337-3885 ng/l), and much lower levels when blood was drawn remotely away from the graft site (Range 9-242 ng/l). The difference in PTH level between the grafted forearm and remote site for these patients ranged between 328 and 3643 ng/l. Over the period these cases were accrued (2008-2012), 89 patients underwent TPT-ATx in our institution. Therefore, our case report series suggests that this phenomenon will be evident to a clinically important extent in at least 4% of patients. CONCLUSIONS: One can acquire spuriously high PTH levels from grafted forearms, leading to the false diagnosis of recurrent hyperparathyroidism. We recommend PTH levels be drawn remotely from graft sites to ensure accurate systemic levels are reflected.

Validation of 1-hour post-thyroidectomy parathyroid hormone level in predicting hypocalcemia.

BACKGROUND: Prior work by our group suggested that a single one hour post-thyroidectomy parathyroid hormone (1 hr PTH) level could accurately stratify patients into high and low risk groups for the development of hypocalcemia. This study looks to validate the safety and efficacy of a protocol based on a 1 hr PTH threshold of 12 pg/ml. STUDY DESIGN: Retrospective analysis of consecutive cohort treated with standardized protocol. METHODS: One hundred and twenty five consecutive patients underwent total or completion thyroidectomy and their PTH level was drawn 1-hour post operatively. Based on our previous work, patients were stratified into either a low risk group (PTH ≥12 pg/ml) or a high risk group (PTH < 12 pg/ml) [Corrected]. Patients in the high risk group were immediately started on prophylactic calcium carbonate (5-10 g/d) and calcitriol (0.5-1.0 mcg/d). The outcomes were then reviewed focusing mainly on how many low risk patients developed hypocalcemia (false negative rate), and how many high risk patients failed prophylactic therapy. RESULTS: Thirty one patients (25%) were stratified as high risk, and 94 (75%) as low risk. Five (16%) of the high risk patients became hypocalcemic despite prophylactic therapy. Two of the low risk group became hypocalcemic, (negative predictive value = 98%). None of the hypocalcemic patients had anything more than mild symptoms. CONCLUSIONS: A single 1-hour post-thyroidectomy PTH level is a very useful way to stratify thyroidectomy patients into high and low risk groups for development of hypocalcemia. Early implementation of oral prophylactic calcium and vitamin D in the high risk patients is a very effective way to prevent serious hypocalcemia. Complex protocols requiring multiple calcium and PTH measurements are not required to guide post-thyroidectomy management.

Prediction of hypocalcemia after using 1- to 6-hour postoperative parathyroid hormone and calcium levels: an analysis of pooled individual patient data from 3 observational studies.

BACKGROUND: Parathyroid hormone (PTH) levels up to 6 hours postthyroidectomy have been shown to have excellent predictive power in determining hypocalcemia. In this study, we investigate the usefulness of combining calcium and PTH to increase the predictive power. METHODS: Individual patient data were obtained from 3 studies (152 patients) that fulfilled our criteria (using PTH assay within hours postthyroidectomy to predict symptomatic hypocalcemia). RESULTS: Changes in combined PTH and calcium threshold levels checked 1 to 6 hours after thyroidectomy were excellent in predicting postoperative hypocalcemia. A decrease in PTH of 60%, coupled with a simultaneous decrease in calcium of 10%, 5 to 6 hours postoperatively resulted in a sensitivity and specificity of 100%. However, combined PTH and calcium threshold changes were not significantly better than using PTH threshold changes alone. CONCLUSIONS: Threshold changes in serum calcium and PTH, checked hours after surgery, can be used together to accurately predict whether a patient will become hypocalcemic after thyroidectomy.

Assessing flap perfusion: optical spectroscopy versus venous doppler ultrasonography.

OBJECTIVE: To use optical spectroscopy as a noninvasive method to monitor the viability of free flaps and to compare the near-infrared probe with the implantable venous Doppler ultrasound probe. DESIGN: Prospective, randomized series using an animal model. METHOD: Optical spectroscopy was used to measure variables that correlate with tissue perfusion and oxygenation. An epigastric artery island flap was raised in 20 rats. Vascular insults were simulated by clamping the vessels to the flap. Measurements were taken using near-infrared spectroscopy (NIRS) at the time of clamping and at 15, 30, 45, and 60 minutes of occlusion. The clamps were removed, and final NIRS measurements were taken. In the second experiment, a flap was raised in six rats, each of which underwent a series of short-lived occlusions. The occlusions were monitored with both NIRS and the implantable venous Doppler probe. RESULTS: In the first experiment, disruptions in flap perfusion resulted in significant changes in tissue hemoglobin oxygen saturation and total hemoglobin concentration as detected using NIRS. NIRS predicted vascular compromise with a sensitivity of 89.7% and a specificity of 97.9%. In the second experiment, NIRS predicted vascular compromise with a sensitivity of 63.3% and a specificity of 94.8%. The clinical assessment, based on recordings, yielded sensitivities and specificities of 70% and 94.8% (surgeon 1) and 71.7% and 94.8% (surgeon 2). CONCLUSION: Optical spectroscopy represents a reliable method of noninvasively monitoring free flaps. Further investigations as to the clinical utility of spectroscopy as an adjunctive monitoring device are currently being performed.

Impact of use of frozen section assessment of operative margins on survival in oral cancer.

OBJECTIVE: This study looked at the independent impact of intraoperative frozen section assessment of the adequacy of margins of excision on disease control and survival. STUDY DESIGN: The design was a review of outcome of historical cohort of 416 surgically treated oral cancer patients at a comprehensive cancer center. Status of the margins at permanent sections, disease failure at the primary site, and survival data of 229 patients who had frozen sections were compared by univariate and multivariate analysis with 197 patients who did not have frozen sections. RESULTS: Failure at the primary site was independently influenced by age at diagnosis (P < .001), T stage (P = .016), N stage (P = .042), and status of margins on paraffin sections (P = .005). Chance of achieving clear margins on paraffin sections was, however, not significantly improved by the use of frozen sections. On multivariate analysis, the use of frozen sections did not independently have an impact on local failure or survival. CONCLUSIONS: Frozen section assessment of mucosal margins has not improved the disease outcome.

Early prediction of hypocalcemia after thyroidectomy using parathyroid hormone: an analysis of pooled individual patient data from nine observational studies.

BACKGROUND: Monitoring for hypocalcemia after thyroidectomy, using only symptoms and serum calcium levels, can delay the discharge of patients who will remain normocalcemic and can delay the treatment of hypocalcemic patients. STUDY DESIGN: We conducted a systematic search for articles describing use of parathyroid hormone (PTH) assay, checked within hours of completing thyroidectomy, to predict postoperative symptomatic hypocalcemia. Studies were excluded if all patients were treated with postoperative calcium, or if early PTH values were used to alter management of the patient. Individual patient data (perioperative PTH and calcium levels, development of hypocalcemia) were obtained for 457 patients from the corresponding authors of 9 studies and pooled to yield the following results. RESULTS: PTH, checked at three time periods after removal of the thyroid gland (0 to 20 minutes, 1 to 2 hours, and 6 hours), was substantially lower in patients who became hypocalcemic compared with those who remained normocalcemic. The accuracy of PTH in determining hypocalcemia increased with time and was excellent when checked 1 to 6 hours postoperatively. A single PTH threshold (65% decrease compared with preoperative level), checked 6 hours after completing thyroidectomy, had a sensitivity of 96.4% and specificity of 91.4% in detecting postoperative hypocalcemia. CONCLUSIONS: PTH assay, when checked 1 to 6 hours after thyroidectomy, has excellent accuracy in determining which patients will become symptomatically hypocalcemic. Routine use of this assay should be considered because it may allow earlier discharge of the normocalcemic patient and earlier identification of patients requiring treatment of postthyroidectomy hypocalcemia.

Structure-activity studies with cytotoxic anthrapyrazoles.

Anthrapyrazoles have been investigated as cancer chemotherapeutic agents. The mechanism of action of these compounds is thought to involve inhibition of DNA topoisomerase II. A structure-activity study was carried out to determine the in vitro cytotoxic activity of nine novel anthrapyrazoles against human breast carcinoma, head and neck squamous cell carcinoma and leukemia cells, and against Chinese hamster ovary cells. The activity of these anthrapyrazole analogues was compared with that of two clinically tested anthrapyrazoles, losoxantrone and piroxantrone. Inhibition of topoisomerase II as a mechanism of action for the analogues was also investigated. The cytotoxic activity of the analogues was determined in vitro by MTT cell growth inhibition assay and inhibition of catalytic topoisomerase II activity by each compound was measured using a fluorometric DNA decatenation assay. All of the anthrapyrazole analogues inhibited the growth of the four cell lines with IC50 values that ranged from 0.1 to 45.2 microM. Losoxantrone was the most potent of the anthrapyrazole analogues studied. A tertiary amine in the basic side chain at N-2 increased the cytotoxic activity compared with a secondary amine in this side chain for many of the analogues, but not if there was a basic side chain at the C-5 position. A chlorine substituent on the basic side chain at N-2 did not have a consistent effect on activity. Moving the position of a chlorine substituent from C-5 to C-7 or introducing a basic side chain at C-5 did not have a consistent effect on cytotoxic activity. Anthrapyrazole analogues showed a broad range of activity for inhibiting topoisomerase II decatenation activity. Losoxantrone and piroxantrone were the most potent inhibitors of topoisomerase II activity. There was no significant correlation between the cytotoxic activity of the anthrapyrazole analogues and their ability to inhibit decatenation by topoisomerase II.

Role of NQO1 polymorphisms as risk factors for squamous cell carcinoma of the head and neck.

A case: control study was carried out to determine if inactivating polymorphisms of the NQO1 gene at bases 609 and 465 are associated with altered risk of developing squamous cell carcinoma of the head and neck (SCCHN). Genotyping was carried out by PCR RFLP analysis on whole blood samples. The frequency of the inactive 609T and active 609C forms, and the inactive 465T and active 465C forms, of NQO1 were compared in patient and control groups by a logistic regression analysis and odds ratios (ORs) were calculated. Participants were stratified by tobacco and alcohol use, and genotype distributions in these sub-groups were compared. There were no significant differences in genotype distribution between SCCHN patients and the control population for the base 609 or 465 polymorphisms. There were also no significant differences in genotype distributions between patient and control groups for tobacco and/or alcohol users and non-users. Genotype distributions were similar for SCCHN patients at all disease sites with the exception of the nasopharynx where there was a higher incidence of the 609C:609T and 609T:609T genotypes. These results suggest that individuals having either 609T or 465T alleles generally do not have an altered risk of developing SCCHN.

Parathyroid hormone: an early predictor of postthyroidectomy hypocalcemia.

OBJECTIVE: To determine whether there is a correlation between the level of parathyroid hormone (PTH) soon after thyroidectomy and the development of hypocalcemia. STUDY DESIGN: Prospective series of 40 consecutive patients undergoing total thyroidectomy or completion thyroidectomy between January 2001 and October 2002. METHOD: Ionized calcium was measured before surgery and at 1, 6, 18, 30, and 42 hours after surgery. PTH was measured before surgery and at 1 and 6 hours after surgery using an assay that accurately measures low levels of PTH. Patients were followed up at 1 week and 3 months after surgery with respect to their symptoms and need for calcium supplementation. Clinically significant hypocalcemia was defined as an ionized calcium level of less than or equal to 0.9 mmol/L. RESULTS: The incidence of postoperative hypocalcemia was 30% (12/40). The mean PTH level 1 hour after surgery was much lower in patients who ultimately became hypocalcemic than in those who remained normocalcemic (3.8+/- 1.9 vs. 33 +/- 21 pg/mL, P =.001). All patients with a PTH level less than or equal to 8 pg/mL 1 hour after surgery developed hypocalcemia, whereas all those with greater than or equal to 9 pg/mL remained normocalcemic. CONCLUSIONS: A single PTH level of less than or equal to 8 pg/mL 1 hour postthyroidectomy is a strong predictor for the development of clinically significant hypocalcemia. Once validated, this test may serve to identify those who require more intensive monitoring, prompt early therapy in those deemed at risk, and enable confident early discharge in the majority of thyroidectomy patients.

Paranasal sinus teratocarcinosarcoma with intradural extension.

Teratocarcinosarcoma, although a rare neoplastic entity, should be considered as a differential diagnosis in any middle-aged adult presenting with a history of intermittent unilateral epistaxis and nasal obstruction. Tissue biopsy may fail to reveal a full spectrum of histologic heterogeneity in these tumours, and definitive diagnosis is usually made with tumour resection. Aggressive treatment including surgery followed by adjuvant radiation therapy is advocated and confers a better rate of survival than radiotherapy alone. Our current report is unique in two respects. First, disease recurrence is usually manifested very early on, leading some authors to conclude that a neoplastic-free interval of 3 years or longer probably indicates a good chance of being cured. Our patient, in contrast, experienced a disease-free interval of 4 years before evidence of recurrence emerged. Second, intracranial extension with brain parenchymal involvement has not been previously reported despite the tumour's proximity to the anterior cranial fossa and its locally aggressive behaviour with frequent bony invasion. Despite intracranial invasion, our patient experienced a long disease-free interval. As such, even advanced disease should be treated aggressively.