Trends in thyroid function testing, neck ultrasound, thyroid fine needle aspiration, and thyroidectomies in North-eastern Italy.

PURPOSE: Evidence of an increased diagnostic pressure on thyroid has emerged over the past decades. This study aimed to provide estimates of a wide spectrum of surveillance indicators for thyroid dysfunctions and diseases in Italy. METHODS: A population-based study was conducted in North-eastern Italy, including 11.7 million residents (20% of the total Italian population). Prescriptions for TSH testing, neck ultrasound or thyroid fine needle aspiration (FNA), surgical procedures, and drugs for hypo- or hyperthyroidism were extracted from regional health databases. Proportions and rates of selected examinations were calculated from 2010 to 2017, overall and by sex, calendar years, age, and region. RESULTS: Between 2010 and 2017 in North-eastern Italy, 24.5% of women and 9.8% of men received at least one TSH test yearly. In 2017, 7.1% of women and 1.5% of men were prescribed drugs for thyroid dysfunction, 94.6% of whom for hypothyroidism. Neck ultrasound examinations were performed yearly in 6.9% of women and 4.6% of men, with a nearly two-fold variation between areas. Thyroid FNA and thyroidectomies were three-fold more frequent in women (394 and 85 per 100,000) than in men (128 and 29 per 100,000) with a marked variation between areas. Both procedures decreased consistently after 2013. CONCLUSIONS: The results of this population-based study describe recent variations over time and between surrounding areas of indicators of 'diagnostic pressure' on thyroid in North-eastern Italy. These results emphasize the need to harmonize practices and to reduce some procedures (e.g., neck ultrasound and total thyroidectomies) in certain areas.

Predictive Value of CD8 Expression and FoxP3 Methylation in Nasopharyngeal Carcinoma Patients Treated with Chemoradiotherapy in a Non-endemic Area.

Undifferentiated Nasopharyngeal Carcinoma (UNPC) is associated with Epstein-Barr Virus (EBV) and characterized by an abundant immune infiltrate potentially influencing the prognosis. Thus, we retrospectively assessed the significance of immunosuppression in the UNPC microenvironment as prognostic biomarker of treatment failure in a non-endemic area, and monitored the variation of systemic EBV-specific immunity before and after chemoradiotherapy (CRT). DNA and RNA were extracted from diagnostic biopsies obtained by tumor and adjacent mucosa from 63 consecutive EBV+ UNPC patients who underwent radical CRT. Among these patients 11 relapsed within 2 years. The expression of the EBV-derived UNPC-specific BARF1 gene and several immune-related genes was monitored through quantitative RT-PCR and methylation-specific PCR analyses. Peripheral T cell responses against EBV and BARF1 were measured in 14 patients (7 relapses) through IFN-γ ELISPOT assay. We found significantly higher expression levels of BARF1, CD8, IFN-γ, IDO, PD-L1, and PD-1 in UNPC samples compared to healthy tissues. CD8 expression was significantly reduced in both tumor and healthy tissues in UNPC patients who relapsed within two years. We observed a hypomethylated FOXP3 intron 1 exclusively in relapsed UNPC patients. Finally, we noticed a significant decrease in EBV- and BARF1-specific T-cells after CRT only in relapsing patients. Our data suggest that a high level of immunosuppression (low CD8, hypomethylated FoxP3) in UNPC microenvironment may predict treatment failure and may allow an early identification of patients who could benefit from the addition of immune modulating strategies to improve first line CRT.

Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial.

Fluconazole is recommended in the prophylaxis of oropharyngeal candidiasis (OPC) in patients undergoing radiotherapy for head-neck tumours; however, the actual effectiveness of fluconazole in this setting remains unclear. Adult patients with cervico-cephalic carcinoma submitted to radical or adjuvant radiotherapy were randomized to 100 mg fluconazole (n = 138) or matched placebo (n = 132) oral suspension once daily from the sixth session of radiotherapy up to the end of treatment. The final analysis of the investigation showed a higher rate of the OPC outbreak-free survival in the fluconazole compared with placebo (P = 0.008 in the log-rank test). The mean time (95% CI) to OPC outbreak was 56 (53-59) days in the fluconazole group and 47 (43-51) days with placebo. The mean duration of radiotherapy was 43.5 and 39.9 days, respectively in the two groups (P = 0.027). Adverse effects were reported in 70.3% of patients in the fluconazole group and in 67.4% with placebo. The results showed prophylaxis with fluconazole given in irradiated patients with head-neck tumours significantly reduces the rate and the time to development of OPC compared with placebo.

Paclitaxel as a radiosensitiser: a proposed schedule of administration based on in vitro data and pharmacokinetic calculations.

Paclitaxel is efficacious against many human cancers. Because it blocks cells at the radiosensitive G2-M interface, paclitaxel has been investigated as a radiosensitiser. The results have been equivocal and somewhat contradictory. It is impossible to obtain proper pharmacokinetic calculations, aimed at obtaining maximum cytotoxicity and/or radiosensitisation, without knowing (i) how long the drug must be in contact with the cells, (ii) how long the effect lasts after the drug is removed from the cellular environment, (iii) whether the drug acts as a radiosensitiser even when, like cis-platinum, it is added after the radiation and (iv) what the minimum quantity of drug in the cellular environment is required for both chemotoxicity and radiosensitisation. The present work addresses the above questions. Two radioresistant cell lines of human origin were used, A375 melanoma and S549 lung carcinoma, in a clonogenic assay where only colonies with 50 or more cells were counted. For the irradiation, 6 MV X-rays were used. Any G2-M block was quantified by cell cycle kinetics analysis. From the results, a simulation of pharmacokinetics was conducted to calculate the schedule of administration of paclitaxel most likely to achieve and maintain significant chemotoxocity and radiosensitisation. The minimum concentration of paclitaxel for measurable cytotoxicity was 3 nM for both cell lines, but the drug was more toxic to the A549 cells. The minimum concentration for measurable radiosensitisation was 3 nM for A375 and approximately 0.1 nM for A549, but whereas above 3 nM the radiosensitivity increased in A375, it decreased above 1 nM for A549. A minimum of 18 h incubation with the drug was necessary for measurable effects and the radiosensitising effects were lost soon after its removal. There was no radiosensitisation if paclitaxel was added after the radiation, and, at the minimum effective concentrations, it caused only a minor and transient G2-M block. The pharmacokinetic calculations predict that 15 mg/m2 paclitaxel given as a 1 h infusion 5 days/week for 3 weeks during the radiotherapy should achieve both cytotoxicity and radiosensitisation. The mechanism of radiosensitisation by paclitaxel at the concentrations suggested by our results does not appear to be via a G2-M block and is probably concentration dependent. The results imply that low-dose, daily infusions of paclitaxel for as long as possible during a course of radiotherapy are more likely to result in radiosensitisation and prolonged cytotoxicity than high-dose infusions given once a week.

Multiple fraction per day radiation therapy for inoperable esophageal cancer.

Experience with a multiple fractions per day radiation therapy program for inoperable esophageal cancer is reported. The treatment program consisted of 3 daily fractions of 1.6 Gy, with a 4 hr interval between fractions, for 5 consecutive days (24 Gy). After a rest period of 2 weeks, a second course of radiation was given with the same dose and fractionation for a total dose of 48 Gy in an overall treatment time of 4 weeks. Thirty-four patients were treated between February 1981 and July 1983. Acute reactions consisted of mild esophagitis noted in 30% of patients. No treatment related complications were reported. Median survival was 7 months and the 2- and 5-year survival rates were 12 and 9%, respectively. Tumor size and Karnofsky performance status were found to be the most important prognostic indicators for prolonged survival. Prompt palliation of symptoms was noted. Thirty-three per cent of patients had complete resolution and 41% had partial improvement of symptoms after completion of treatment. Four patients (12%) obtained complete tumor regression with negative biopsy at endoscopic examination and 2 of them are free of disease at 58 and 64 months. A partial response was reported in 12 patients (35%) for a median duration of 5 months (3-26). Treatment with multiple fractions per day was feasible in patients with esophageal cancer and could be preferred to more conventional fractionations for promptness of palliation and the shorter treatment time. The expected therapeutic gain is discussed.

Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer.

Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m2) (arm B). An overall response rate of 58.9% was observed in arm A and 50.6% in arm B, respectively. No differences in the pattern of relapse were noted between the two treatment groups. Median time to progression was 10.6 months for arm A and 14.2 months for arm B. Median survivals were 10.3 months and 9.97 months, respectively. Toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant advantage of the combined treatment over radiation therapy only was found. The encouraging results achieved in some trials together with the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological basis of the combined treatment.

Radiation treatment of glottic squamous cell carcinoma, stage I and II: analysis of factors affecting prognosis.

PURPOSE: At least in some European Countries, there is still considerable controversy regarding the choice between surgery and radiotherapy for the treatment of patients with early laryngeal-glottic carcinoma. METHODS AND MATERIALS: Two hundred and forty-six patients with laryngeal-glottic neoplasms, Stage I-II, were treated with radical radiotherapy. Before radiotherapy the patients were evaluated to determine the surgical procedure of choice. Either 66-68.4 Gy (33-38 fractions) or 63-65 Gy (28-29 fractions) of radiation therapy (RT) were administered. The overall disease free survival was determined for each subgroup of patients. Univariate and multivariate analyses were performed to determine significant prognostic variables. RESULTS: Five- and 10-year overall survival rates were 83 and 72%, respectively. At a median follow-up of 6 years 204 patients are alive and disease free. No patient developed distant metastases. One patient died of a large local recurrence, 38 patients died of causes unrelated to their tumor, and 3 patients were lost to follow-up. The multivariate analysis confirmed that performance status (PS), macroscopic presentation of the lesion, and persistence of dysphonia after radiotherapy are significant prognostic factors. CONCLUSIONS: According to the multivariate analysis, the patients with PS > 80 and with exophytic lesions are eligible for radical RT. The surgical procedure proposed for each patient was not found to be an independent prognostic factor.

Radiotherapy enhanced by cis-platinum in stage III non-small cell lung cancer: a phase II study.

From January 1984 to December 1986, 94 patients with unresectable, locally advanced, non-small cell lung cancer (NSCLC) were treated to assess both the efficacy and the toxicity of a combined modality treatment including radiation therapy (45 Gy/15 fractions/3 weeks) and daily low dose cDDP (6 mg/m2). The overall response rate for the 90 evaluable patients was 54.3% with 16.6% of complete responses. At a minimum follow-up of 4 years, the overall median survival time was 12 months. Provided adequate hydration is ensured, the cDDP regimen chosen as a radiosensitizer can be safely combined with radiation therapy.

Accelerated split course regimen in the treatment of brain metastases.

Between July 1981 and December 1983, 63 patients, with brain metastases were treated with an accelerated split course regimen; irradiation was given to the whole brain in 3 daily fractions of 160 cGy each (with 4-h interval between the fractions), for 5 days a week. The cycle was repeated after 2 weeks to a total dose of 4800 cGy. Male-female ratio was 3:1 (48 males and 15 females). Median age was 58 years (range 24 to 75). The most frequent site of primary tumor was lung (squamous cell carcinoma in 33 patients and oat cell carcinoma in 8 patients), breast in 6 patients, melanoma in 3 patients, other sites in 8 patients and unknown cancer in 5 patients. Thirty-five patients had multiple brain metastases localizations. In 33 patients (52.3%), metastases were present in other sites outside the central nervous system. Two patients failed to complete the scheduled treatment: one because of early death and the other by refusal of therapy during treatment. We obtained complete remission (CR) in 4 patients and partial remission (PR) in 24 patients. The median survival time was 21 weeks. The overall response rate was 42.5%. Toxicity was not considerable. The treatment results were not influenced by the site of primary tumor or by disease spreading; only the neurologic status before radiotherapy and the response to treatment influenced survival. The results we obtained are similar to those reported by other studies; however, with the accelerated split course regimen the treatment time was reduced and a shorter period of hospitalization was required.

The effect of granulocyte colony-stimulating factor on oral mucositis in head and neck cancer patients treated with hyperfractionated radiotherapy.

We investigated the effect of granulocyte colony-stimulating factor (G-CSF) administration on radiotherapy (RT)-induced oral mucositis in 26 consecutive patients with head and neck neoplasms, stages III and IV, treated with hyperfractionated RT. The first 13 patients were treated with RT alone and the remainder with RT + G-CSF. The two groups of patients were similar in age, sex, PS, primary site, stage, RT schedule and RT volume. Daily mucositis, median mucositis score, day of highest mucositis, requirement of parenteral nutrition, weight loss, treatment break, number of days of RT interruption were analyzed during RT treatment. No statistically significant differences were found between the two groups except for the number of patients who interrupted the treatment: 9/13 patients (69%) in the RT alone group versus 3/13 (23%) in the RT + G-CSF group (p < 0.05). Our observations indicate that G-CSF did not appear to have influenced the objective mucositis although it reduced the number of treatment breaks. In consideration of the cost of G-CSF, its prophylactic administration should be reserved only for patients at high risk of RT interruption.

Combined radiotherapy and bleomycin in patients with inoperable head and neck cancer with unfavourable prognostic factors and severe symptoms.

The aim of this study was to assess the feasibility of concurrent split course radiotherapy and low-dose bleomycin in the treatment of unresectable head and neck cancer with unfavourable prognostic factors and severe symptoms. The clinical outcome of the treatment was assessed in terms of local disease control, symptom relief and toxicity. Between 1990 and 1996, 58 patients with squamous cell carcinoma of the head and neck, stage III or IV, were treated by radiotherapy (50 Gy/20 fractions) and simultaneous bleomycin (60 mg/6 fractions). Local control of disease, overall response, symptom relief and acute toxicity were evaluated. The rate of disease local control was 69% with a median response duration of 7 months (range 2-43+). The symptom relief rate was 81%. Mucositis was the prominent toxicity: G3 mucositis was reported in 27 patients. In conclusion, the treatment was feasible. A good palliation of symptoms and a good rate of local response were obtained. Moreover, toxicity was tolerable and the rate of hospitalisation was low.

Nasopharyngeal cancer WHO type II-III: monoinstitutional retrospective analysis with standard and accelerated hyperfractionated radiation therapy.

The aim of this study is to assess the impact of prognostic factors in patients with locoregionally advanced nasopharyngeal cancer (NPC), WHO type II-III, treated with two different radiation therapy (RT) schedules: standard radiation therapy (SRT), and accelerated hyperfractionated radiation therapy (HART), with or without sequential chemotherapy. Between January 1986 and December 1999, 78 consecutive NPC patients were treated either with SRT (until August 1993) or with HART (from September 1993). Of the 78 patients, 60 were males and 18 females, the median age was 56 years (range 14-83). Nine patients had a non-keratinizing carcinoma (WHO type II) and 69 an undifferentiated carcinoma (WHO type III). Five-year overall survival rate (OS) was 62%. Two months after RT, 73 patients were in complete remission. Disease-free survival (DFS) rates at 5 years were: 85% for the HART and 59% for the SRT group, respectively. A multivariate analysis, age (hazard ratio, HR=4.17 for > or = 60 vs. <50 years) and N-stage (HR=3.56 for N3a-N3b vs. N0-N1) were significant for survival, whereas N-stage (HR=8.23 for N3a-N3b vs. N0-N1) and RT schedule (HR=0.30 for HART vs. SRT) were significant for DFS. In our experience, HART achieved higher DFS rates than SRT; however, HART did not favourably affect OS. Toxicity was comparable in the two RT schedules.

The efficacy of radiotherapy in the treatment of intraocular metastases.

From January 1980 to May 1991, 28 patients with intraocular metastases were seen at our Institute. Three presented with bilateral metastases and two developed contralateral involvement. Out of the 33 ocular metastases 27 were managed by radiotherapy. The most common primary tumour sites were breast (18/28 patients) and lung (3/28). 22 patients were treated with an 8 MV linear accelerator, using a 4 x 4 cm anterior direct field. The median dose was 40 Gy/20 fractions (range 28 Gy/14 fractions to 50 Gy/25 fractions). Of the 27 treatments reported, 16 resulted in a complete response (59%), six in a partial response (22%) and five resulted in no change (19%). Complete and partial responses lasted for a median time of 13 months (range of 3-89+ months). The median survival time from the start of ocular treatment was 13 months. The aim of radiation treatment is either to prevent or to postpone the visual loss caused by intraocular metastases.

Combined modality treatment of locally advanced lung cancer.

This paper describes the mechanisms of action of ionizing radiations combined with antineoplastic drugs. Some relevant drugs for the combined modality treatments of locally advanced lung cancer are reported. The meta-analyses including randomized trials comparing single agent (radiotherapy or chemotherapy) versus combined chemotherapy and radiotherapy in patients with unresectable non small cell lung cancer and limited small cell lung cancer are then reviewed. The clinical outcome in relation to different schedules of chemoradiotherapy (sequential, alternating and concurrent) is also focussed.

Solitary thyroid metastasis from a renal cell carcinoma diagnosed and treated 12 years before: a case report.

The authors report a case of a solitary thyroid metastasis in a 62-year-old woman. The clinical history of the patient and the histologic findings are consistent with a renal origin of the tumor.

Radiation therapy combined with chemotherapy for inoperable pancreatic carcinoma.

From March 1985 to July 1989, 22 patients with unresectable pancreatic adenocarcinoma entered the study to receive external beam irradiation with chemotherapy. Radiation therapy consisted of 60 Gy in 3 courses (20 Gy each course) delivered over a period of 2 weeks, with a 2-week rest between the courses. Chemotherapy consisted of 5 fluorouracil, 500 mg/m2, plus cisplatinum, 20 mg/m2, administered on days 1, 2 and 3 of each radiation therapy course. Of the 22 evaluable patients, 10 were males and 12 females; their median age was 63 years (range, 32-77), and their median performance status was 80 (range, 60-90). After treatment, 12 partial remissions and 6 no changes were reported. In 4 cases, abdominal progression of disease during treatment required interruption of the therapy program. At the start of treatment, abdominal pain was the most important symptom in 17 patients; improvement of abdominal pain was observed in 10 cases (76%) after treatment and lasted for a median of 5 months. Median survival time was 7.5 months, and time to progression was 6.2 months. Median follow-up was 7 months (range, 14 days -38). In 2 cases, persistent hematologic toxicity did not permit completion of therapy, and in another 3 cases grade II hematologic toxicity required a 2-week rest period over the normal split-course program. In another 4 cases, grade I hematologic toxicity did not require any delay in the therapy program. Our results are comparable with those achieved in other major studies and are acceptable in terms of survival time, palliation of symptoms and toxicity. In our experience, the combination of radiotherapy plus 5-fluorouracil and cisplatinum does not seem to offer any advantage over the combination of radiation therapy and 5-fluorouracil.

Occult small cell lung cancer associated with paraneoplastic neurologic syndrome: case report.

Cancer is often associated with paraneoplastic syndromes, which may be misinterpreted. We report a case of a patient with occult small cell lung cancer that was initially compounded by clinical features of a paraneoplastic neurologic syndrome. The presence of antineuronal antibodies and positron emission tomography scan guided the search for the underlying tumor. Following chemo-radiotherapy the patient showed no evidence of disease for the next 18 months, whereas only a slight improvement in the neurologic disorders was observed. The course of the small cell lung cancer was very indolent and the paraneoplastic neurologic syndrome did not worsen with the use of cisplatin.

Postoperative radiotherapy in locally advanced head and neck cancer.

This retrospective study was conducted on 255 consecutive patients with locally advanced squamous-cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx, treated at the Radiotherapy Department of Pordenone General Hospital between January 1975 and December 1985. All patients underwent radical surgery followed, after an interval ranging from 10 days to 2.9 months, by radiotherapy given either through a 6 MeV linear accelerator or a cobalt-60 unit. Field extension and dose delivered were comparable in relation to stage and involvement of the surgical resection margins. The aims of the study were to evaluate the survival rate and to analyze the clinical parameters which can influence the disease-free survival. The adjusted overall 5-year survival rate was 71%; stage, performance status at diagnosis, and site of the primary tumor were significant factors in determining patient prognosis, whereas infiltration of resection margins was not significant in determining loco-regional control of disease. Seventy-five patients relapsed and 67 died of cancer-related diseases whereas death in 52 patients was not related to the head and neck cancer. The combined modality treatment consisting of surgery followed by radiotherapy was well tolerated and proved to be effective in the treatment of locally advanced head and neck tumors.

Variations in tumor levels of cis-platinum through a course of fractionated radiotherapy in patients with non-small cell lung cancer.

AIMS AND BACKGROUND: Radiation has been shown to affect the uptake of micromolecules by the tissues within the radiation fields. We measured tumor drug uptake throughout a course of radiotherapy for stage III non-operable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty patients were treated with radiotherapy consisting of 15 fractions of 300 cGy given over 3 weeks. They were divided into groups of 2. At 1.5 hr before a given fraction of radiotherapy, one group was given i.v. a bolus of 6 mg/m2 CDDP (cis-diamminedichloroplatinum). Between 1.5 and 2 hr after radiotherapy, the patients underwent bronchoscopy, during which a biopsy was taken from the tumor mass. A similar procedure was carried out on a different group of 2 patients at each of the 15 radiotherapy fractions. The amount of platinum in the biopsy sample was measured by atomic absorption spectroscopy and expressed as ng platinum/mg tissue. In another 13 patients, a biopsy was taken before beginning the radiotherapy, and they served as controls. RESULTS: The quantity of platinum/g of tissue in the patients was 11 +/- 4.4 ng/mg tissue. During the course of fractionated radiotherapy, the quantity of platinum/g of tumor varied considerably between radiotherapy fractions. Maximum uptake was at fractions 8 and 9 (92 ng platinum/mg tissue) with the minima during the first few fractions and at fractions 10, 11 and 12 (an average 20 ng platinum/mg tissue). CONCLUSIONS: The cyclical variations in the uptake of CDDP by the tumor tissue during the protracted course of fractionated radiotherapy are probably due to the well-known effects of radiation on vascular function and capillary permeability. The results may have implications for future clinical protocols involving chemo- and radiotherapy for the treatment of the disease.

Squamous cell carcinoma of the hypopharynx treated with surgery and radiotherapy.

A series of squamous cell carcinomas (SCC) of the hypopharynx treated with combined surgery and radiotherapy is presented to highlight the results of treatment at an early stage of disease. A retrospective mono-institutional analysis was performed on 153 previously untreated patients with SCC of the hypopharynx, seen between 1980 and 1995 at our institution. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The overall five-year specific, and non-specific, disease survival rates were 68 per cent (95 per cent confidence interval, CI: 60-77) and 47 per cent (95 per cent CI: 39-56), respectively. Compared with other series, this study is characterized by treatment at an earlier stage, better prognosis, and a higher number of multiple malignancies. Twenty-two per cent of hypopharyngeal SCCs were diagnosed during the staging procedures for a different head and neck SCC and 14 per cent during the follow-up for a previous tumour. Multivariate survival analysis of clinical and pathological factors confirmed the clinical class of tumour (T) and node (N) and the nodal capsular rupture as prognosticators of disease.