Development and validation of a clinical prediction-score model for distant metastases in major salivary gland carcinoma.

BACKGROUND: The most common pattern of failure in major salivary gland carcinoma (SGC) is development of distant metastases (DMs). The objective of this study was to develop and validate a prediction score for DM in SGC. PATIENTS AND METHODS: Patients with SGC treated curatively at four tertiary cancer centers were divided into discovery (n = 619) and validation cohorts (n = 416). Multivariable analysis using competing risk regression was used to identify predictors of DM in the discovery cohort and create a prediction score of DM; the optimal score cut-off was determined using a minimal P value approach. The prediction score was subsequently evaluated in the validation cohort. The cumulative incidence and Kaplan-Meier methods were used to analyze DM and overall survival (OS), respectively. RESULTS: In the discovery cohort, DM predictors (risk coefficient) were: positive margin (0.6), pT3-4 (0.7), pN+ (0.7), lymphovascular invasion (0.8), and high-risk histology (1.2). High DM-risk SGC was defined by sum of coefficients greater than two. In the discovery cohort, the 5-year incidence of DM for high- versus low-risk SGC was 50% versus 8% (P < 0.01); this was similar in the validation cohort (44% versus 4%; P < 0.01). In the pooled cohorts, this model performed similarly in predicting distant-only failure (40% versus 6%, P < 0.01) and late (>2 years post surgery) DM (22% versus 4%; P < 0.01). Patients with high-risk SGC had an increased incidence of DM in the subgroup receiving postoperative radiation therapy (46% versus 8%; P < 0.01). The 5-year OS for high- versus low-risk SGC was 48% versus 92% (P < 0.01). CONCLUSION: This validated prediction-score model may be used to identify SGC patients at increased risk for DM and select those who may benefit from prospective evaluation of treatment intensification and/or surveillance strategies.

HPV Status Improves Classification of Head and Neck Gray Zone Cancers.

In epidemiologic studies, patients with head and neck squamous cell carcinoma (HNSCC) are classified mainly by the International Classification of Diseases (ICD) codes. However, some patients are of an unclear subsite, the "gray zone" cases, which could reflect ICD coding error, absence of primary subsite, or extensive primary tumors that cross over multiple subsites of the oral cavity and oropharynx. Patients with gray zone squamous cell carcinomas were compared with patients with oral cavity squamous cell carcinoma (OSCC) or oropharyngeal squamous cell carcinoma (OPSCC) and stratified by human papillomavirus (HPV) status that was determined by p16 immunostaining or HPV serology. Comparisons consisted of clinicodemographic features and prognostic outcomes presented by Kaplan-Meier curves and Cox proportional hazards regression models, reported as hazard ratios. There were 158 consecutive patients with gray zone HNSCC diagnosed at the Princess Margaret Cancer Center between 2006 and 2017: 66 had subsite coding discrepancies against the clinician's documentation ("discrepant" cases; e.g., the diagnosis by the clinician was OSCC, while the classification by ICD coding was OPSCC), while 92 were squamous cell carcinoma of unknown primary of the head and neck (SCCUPHN) after complete diagnostic workup. Comparators included 721 consecutive OSCC and 938 OPSCC adult cases. All HPV-positive cohorts (OPSCC, discrepant, and SCCUPHN) had similar clinicodemographic characteristics and better 3- and 5-y overall survival and disease-free survival than their HPV-negative counterparts. In contrast, HPV-negative discrepant cases had prognostic outcomes most similar to HPV-negative OPSCC cases, while HPV-negative SCCUPHN had survival outcomes most similar to those of patients with OSCC in this study. HPV-positive status can improve the classification of patients with unclear or discrepant oral/oropharyngeal subsite, an improvement over classification systems that are solely clinician defined or conducted through ICD coding. However, due to clinical practice, we could not make definitive reclassification for patients with HPV-negative gray zone HNSCC.

Radiologic-Pathologic Correlation of Tumor Thickness and Its Prognostic Importance in Squamous Cell Carcinoma of the Oral Cavity: Implications for the Eighth Edition Tumor, Node, Metastasis Classification.

BACKGROUND AND PURPOSE: Addressing the performance of an imaging-based parameter compared to a "gold standard" pathologic measurement is essential to achieve accurate clinical T-classification. Our aim was to determine the radiologic-pathologic tumor thickness correlation and its prognostic value in oral squamous cell carcinoma. MATERIALS AND METHODS: All pathologic T1-T3 (seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer) oral squamous cell carcinomas diagnosed between 2010 and 2015 were reviewed. Radiologic tumor thickness was measured on preoperative CT or MR imaging blinded to pathology. The radiologic-pathologic tumor thickness correlation was calculated. The impact of the imaging-to-surgery time interval and imaging technique on the correlation was explored. Intra-/interrater reliability on radiologic tumor thickness was calculated. The correlation of radiologic-versus-pathologic tumor thickness and its performance as the seventh edition T-category modifier was evaluated. Multivariable analysis assessed the prognostic value of the radiologic tumor thickness for overall survival adjusted for age, seventh edition T-category, and performance status. RESULTS: For 354 consecutive patients, the radiologic-pathologic tumor thickness correlation was similar for the image-to-surgery interval of ≤4.0 weeks (ρ = 0.76) versus 4-8 weeks (ρ = 0.80) but lower in those with more than an 8-week interval (ρ = 0.62). CT and MR imaging had similar correlations (0.76 and 0.80). Intrarater and interrater reliability was excellent (0.88 and 0.84). Excluding 19 cases with an imaging-to-surgery interval of >8 weeks, 335 patients were eligible for further analysis. The radiologic-pathologic tumor thickness correlation was 0.78. The accuracy for upstaging the T-classification based on radiologic tumor thickness was 83% for pathologic T1 and 74% for pathologic T2 tumors. Multivariable analysis confirmed the prognostic value of radiologic tumor thickness (hazard ratio = 1.5, P = .02) for overall survival. CONCLUSIONS: This study demonstrates a good radiologic-pathologic tumor thickness correlation. Intrarater and interrater reliability for radiologic tumor thickness was excellent. Radiologically thicker tumor was predictive of inferior survival.

Correlation between clinical and MRI assessment of depth of invasion in oral tongue squamous cell carcinoma.

BACKGROUND: Neck metastasis is the most important prognostic factor in oral cavity squamous cell carcinomas (SCC). Apart from the T- stage, depth of invasion has been used as a highly predictable factor for microscopic neck metastasis, despite the controversy on the exact depth cut off point. Depth of invasion can be determined clinically and radio logically. However, there is no standard tool to determine depth of invasion preoperatively. Although MRI is used widely to stage the head and neck disease, its utility in depth evaluation has not formally been assessed. OBJECTIVE: To compare preoperative clinical and radiological depth evaluation in oral tongue SCC using the standard pathological depth. To compare clinical and radiological accuracy between superficial (<5 mm) vs. deep invaded tumor (≥5 mm) METHODS: This prospective study used consecutive biopsy-proven oral tongue invasive SCC that presented to the University health network (UHN), Toronto. Clinical examination, radiological scan and appropriate staging were determined preoperatively. Standard pathology reports postoperatively were reviewed to determine the depth of invasion from the tumor specimen. RESULTS: 72 tumour samples were available for analysis and 53 patients were included. For all tumors, both clinical depth (r = 0.779; p < 0.001) and radiographic depth (r =0.907; p <0.001) correlated well with pathological depth, with radiographic depth correlating slightly better. Clinical depth also correlated well with radiographic depth (r = 0.731; p < 0.001). By contrast, for superficial tumors (less than 5 mm on pathological measurement) neither clinical (r = 0.333, p = 0.34) nor radiographic examination (r = - 0.211; p = 0.56) correlated with pathological depth of invasion. CONCLUSION: This is the first study evaluating the clinical assessment of tumor thickness in comparison to radiographic interpretation in oral cavity cancer. There are strong correlations between pathological, radiological, and clinical measurements in deep tumors (≥5 mm). In superficial tumors (<5 mm), clinical and radiological examination had low correlation with pathological thickness.

Healthy individuals treated with clomipramine: an fMRI study of brain activity during autobiographical recall of emotions.

Various functional magnetic resonance imaging studies addressed the effects of antidepressant drugs on brain functioning in healthy subjects; however, none specifically investigated positive mood changes to antidepressant drug. Sixteen subjects with no personal or family history of psychiatric disorders were selected from an ongoing 4-week open trial of small doses of clomipramine. Follow-up interviews documented clear positive treatment effects in six subjects, with reduced irritability and tension in social interactions, improved decision making, higher self-confidence and brighter mood. These subjects were then included in a placebo-controlled confirmatory trial and were scanned immediately after 4 weeks of clomipramine use and again 4 weeks after the last dose of clomipramine. The functional magnetic resonance imaging (fMRI) scans were run during emotion-eliciting stimuli. Repeated-measures analysis of variance of brain activity patterns showed significant interactions between group and treatment status during induced irritability (P<0.005 cluster-based) but not during happiness. Individuals displaying a positive subjective response do clomipramine had higher frontoparietal cortex activity during irritability than during happiness and neutral emotion, and higher temporo-parieto-occipital cortex activity during irritability than during happiness. We conclude that antidepressants not only induce positive mood responses but also act upon autobiographical recall of negative emotions.

Neural activity changes to emotional stimuli in healthy individuals under chronic use of clomipramine.

Previous functional magnetic resonance imaging (fMRI) studies examined neural activity responses to emotive stimuli in healthy individuals after acute/subacute administration of antidepressants. We now report the effects of repeated use of the antidepressant clomipramine on fMRI data acquired during presentation of emotion-provoking and neutral stimuli on healthy volunteers. A total of 12 volunteers were evaluated with fMRI after receiving low doses of clomipramine for 4 weeks and again after 4 weeks of washout. Fear-, happiness-, anger-provoking and neutral pictures from the International Affective Picture System (IAPS) were used. Data analysis was performed with statistical parametric mapping (P < 0.05). Paired t-test comparisons for each condition between medicated and unmedicated states showed, to negative valence paradigms, decrease in brain activity in the amygdala when participants were medicated. We also demonstrated, across both positive and negative valence paradigms, consistent decreases in brain activity in the medicated state in the anterior cingulate gyrus and insula. This is the first report of modulatory effects of repeated antidepressant use on the central representation of somatic states in response to emotions of both negative and positive valences in healthy individuals. Also, our results corroborate findings of antidepressant-induced temporolimbic activity changes to emotion-provoking stimuli obtained in studies of subjects treated acutely with such agents.

Application of deterministic model of isothermals for population dynamics of Synthesiomyia nudiseta (Diptera, Muscidae).

The isothermal deterministic model adherence was studied to evaluate the population dynamic of Synthesiomyia nudiseta (Diptera, Muscidae). The linear form of equation obtained for the experiments in the several phases, were for Egg: 1/D = -0.18 + 0.02. T; Larva: 1/D = -0.028 + 0.01. T; Pupa: 1/D = -0.069 + 0.01. T; and Adult: 1/D = -0.4178 + 0.02. T. In function of temperature, S. nudiseta can present from 4.18 to 8.95 and from 4.91 to 8.99 generations per year, when calculated through the equations of development and through the simulations, respectively. And the higher the temperature the larger the generation number. Through variance analysis it was verified the significance for the regression equations in relation to the annual generation number (Ng/year) of S. nudiseta in function of the isothermals, for two studied situations. It was obtained a significance of 0,1%. The regression equations obtained for these situations were: Ng/year = 5.4 + 0.5. T and Ng/year = 5.1 + 0.52. T. The number of generations of S. nudiseta varies linearly with the isothermal. Besides that, the number of annual generations for each isothermal does not differ statistically when calculated through the development equations or through the simulations. Such conditions suggest the adaptation of the deterministic model adopted.

Monitoring the domiciliary and peridomiciliary invasion process of Triatoma rubrovaria in the State of Rio Grande do Sul, Brazil.

The presence of Triatoma rubrovaria in Brazil has only been confirmed in the States of Paraná and Rio Grande do Sul (RS), where it is found naturally infected with Trypanosoma cruzi. In the wild environment it occurs in rocky habitats and has an eclectic diet, feeding from cockroaches, reptiles and mammals. Data from the Chagas Disease Control Program obtained by the Fundação Nacional de Saúde, between 1975 and 1997, indicate a growing domiciliary and peridomiciliary invasion of T. rubrovaria in RS, where it has become the most frequently Triatominae species captured in this state since the control of Triatoma infestans. In order to monitor this process, we analyzed collection data derived from 22 years of control campaigns against T. infestans. Collection data for triatomines from domestic habitats show an inverse relationship, with high numbers of T. infestans and low numbers of T. rubrovaria during 1976-1987, compared to the following ten years, 1986-1997, when the number of T. infestans dropped drastically and that of T. rubrovaria increased. There are no consistent indications of intradomiciliary colonization by T. rubrovaria, since only low numbers of nymphs have been captured in the intradomiciliary ecotopes. Nevertheless, this species appears to have preadaptive characteristics for anthropic ecotopes, and should be kept under constant epidemiological surveillance.

Ecotopes, natural infection and trophic resources of Triatoma brasiliensis (Hemiptera, Reduviidae, Triatominae).

Triatoma brasiliensis is considered as one of the most important Chagas disease vectors in the northeastern Brazil. This species presents chromatic variations which led to descriptions of subspecies, synonymized by Lent and Wygodzinsky (1979). In order to broaden bionomic knowledge of these distinct colour patterns of T. brasiliensis, captures were performed at different sites, where the chromatic patterns were described: Caicó, Rio Grande do Norte (T. brasiliensis brasiliensis Neiva, 1911), it will be called the "brasiliensis population"; Espinosa, Minas Gerais (T. brasiliensis melanica Neiva & Lent 1941), the "melanica population" and Petrolina, Pernambuco (T. brasiliensis macromelasoma, Galvão 1956), the "macromelasoma population". A fourth chromatic pattern was collected in Juazeiro, Bahia the darker one in overall cuticle coloration, the "Juazeiro population". At the sites of Caicó, Petrolina and Juazeiro, specimens were captured in peridomiciliar ecotopes and in wilderness. In Espinosa the specimens were collected only in wilderness, even though several exhaustive captures have been performed in peridomicile at different sites of this municipality. A total of 298 specimens were captured. The average registered infection rate was 15% for "brasiliensis population" and of 6.6% for "melanica population". Specimens of "macromelasoma" and of "Juazeiro populations" did not present natural infection. Concerning trophic resources, evaluated by the precipitin test, feeding eclecticism for the different colour patterns studied was observed, with dominance of goat blood in household surroundings as well as in wilderness.

Behavior of triatomines (Hemiptera:Reduviidae) vectors of Chagas' disease. IV. Fecundity, fertility and longevity of Panstrongylus megistus (Burm., 1835) pairs and virgin females starved under laboratory conditions.

A laboratory study was conducted on the fecundity, fertility and life span of Panstrongylus megistus pairs and on the fecundity and life span of P. megistus virgin females submitted to starvation after the last moulting. Of the mated females, 22.2% laid eggs, 4.4% of which were fertile. Females resisted starvation more than males. Of the starved virgin females, only 10% laid eggs, with a low egg-laying rate (0.47) per female. Resistance to starvation was lower in virgin than in mated females.

Behavior of triatomines (Hemiptera: Reduviidae) vectors of Chagas' disease. III. Influence of the number of matings on the fecundity and fertility of Panstrongylus megistus (Burm., 1835) in the laboratory.

A study of the effect of mating in the fecundity and fertility of females of P. megistus fed on pigeon blood every 14 days, was carried out in the laboratory. Two groups were constituted: I - females which mated only once; II - females which stayed always with the males. Only 56.7% of group I females laid fertile eggs, while as much as 90% of group II females laid fertile eggs. The duration of the fertile oviposition was greater in the females which stayed always with the males. Some females of this group were able to mate up to seven times throughout their life-span. This fact render useless sterile males in the control of these insects.

Behavior of triatomines (Hemiptera: Reduviidae) vectors of Chagas' disease. II. Influence of feeding, lighting and time of day on the number of matings, mating speed and duration of copulation of Panstrongylus megistus (Burm, 1835) under laboratory conditions.

To determine the influence of feeding, lighting and time of day on the copulating behavior of Panstrongylus megistus, 480 insect pairs were divided into four groups of 120 each and tested in the following respective situations: without food deprivation (F.D.), with five days of F.D., with ten days of F.D., and with 20 days of F.D. The tests were performed between 9:00 a.m. to 12:00 a.m. and 7:00 p.m. to 10:00 p.m., with light (700-1400 lux) and in the dark (1.4-2.8 lux) and behavior was recorded by the time sampling technique. Mating speed (MS) and duration of copulation (DC) were also calculated for each situation. The maximum frequency of copulation was observed after five days of F.D., at night, in the dark (n = 16), and the minimum was observed for recently-fed pairs, at night, with light (n = 4). Males approached females more often than females approached males. MS was lowest in pairs with twenty days of F.D., at night, with light (mean = 23.0 +/- 16.0 minutes), and highest in recently-fed pairs, during the day, with light (mean = 2.9 +/- 2.5 minutes). DC was shortest in recently-fed insects, during the day, in the dark (mean = 23.5 +/- 6.7 minutes), and longest in recently-fed animals, at night, in the dark (mean = 38.3 +/- 6.9 minutes).

Behavior of triatomines (Hemiptera: Reduviidae) vectors of Chagas' disease. I. Courtship and copulation of Panstrongylus megistus (Burm., 1835) in the laboratory.

A study of the courtship and copulation behavior of Panstrongylus megistus was carried out in the laboratory. Fifty-five newly-fed virgin couples were used. Experiments were performed during the day (9:00 to 12:00 a.m.) and at night (7:00 to 10:00 p.m.). Behavior was recorded by direct observation and was found to consist of the following sequence of behavioral patterns: the male approached the female and jumped on her or mounted her; he took on a dorsolateral position and immobilized the female dorsally and ventrally with his three pairs of legs; the male genital was placed below those of the female; the paramers of the male immobilized the female's genitals; copulation started. The couple joined by the iniciative of the male. The female could be receptive and accept copulation, or nonreceptive and reject the male. Copulation occurred more often on the occasion of the first attempt by the male. Duration of copulation was X = 29.3 +/- 9.3 min (CV = 83%). No behavioral differences were observed between couples tested during the day or at night.

[Cimetidine in the treatment of gastric ulcer]. / Cimetidine no tratamento da úlcera gástrica.

Fourteen gastric ulcer patients were submitted to treatment with Cimetidine. They were endoscopically controlled before the beginning of treatment and at the third and sixth week. In the first phase of the investigation, cimetidine was given in a dosage of 1.0 g/day. At the end of the 3rd week, those patients who showed a reduction of less than 50% on the size of the ulcer had the cimetidine doses increased to 1.6 g/day. The second phase started with nine patients which healed at the end of the six weeks. These patients were randomly allocated to two groups in a double blind trial involving cimetidine (600 mg/day) or placebo for 12 weeks. At the end of this period, the patients were submitted to an endoscopic control. Two patients in the placebo group had a recurrence of their ulcers. This did not happen to any of the patients taking cimetidine. Two and a half months after stopping their maintenance treatment, two patients of the cimetidine group had a recurrence of their lesions.