Establishing a valid cohort of patients with acromegaly by combining the National Patient Register with the Swedish Pituitary Register.

PURPOSE: The aim of this study was to establish a valid national cohort of patients diagnosed with acromegaly by combining data from the general National Patient Register (NPR) and the disease-specific Swedish Pituitary Register (SPR). METHODS: Patients ≥ 18 years of age at diagnosis of acromegaly reported from 1991 to 2018 who were registered in the NPR and/or SPR were included. The diagnosis of acromegaly was considered correct for patients identified in both registers or confirmed through chart review. Medical records were reviewed in two of Sweden´s six health care regions if the patient was reported only in the NPR. An algorithm for the NPR, with criteria requiring multiple diagnosis registrations and tumour and/or surgery codes, was constructed to reduce the number of patients to review in the remaining four regions. RESULTS: A total of 1866 patients were identified. Among these, 938 were reported in both registers. After application of the algorithm and chart review, the diagnosis was confirmed for 83 of the 906 patients found only in the NPR. Among 22 patients only registered in the SPR, a review of medical records confirmed acromegaly in 13. This resulted in a total of 1034 cases with acromegaly during the study period. The incidence rate of acromegaly in Sweden 1991-2018 was calculated to 4.0/million/year in the entire population and 5.1/million/year among subjects ≥ 18 years of age. CONCLUSION: The combination of the SPR and NPR established a valid cohort of patients diagnosed with acromegaly and increased the estimated incidence in Sweden.

Multicentre observational study of the natural history of left-sided acute diverticulitis.

BACKGROUND: The natural history of acute diverticulitis (AD) is still unclear. This study investigated the recurrence rate, and the risks of emergency surgery, associated stoma and death following initial medical or surgical treatment of AD. METHODS: The Italian Study Group on Complicated Diverticulosis conducted a 4-year multicentre retrospective and prospective database analysis of patients admitted to hospital for medical or surgical treatment of AD and then followed for a minimum of 9 years. The persistence of symptoms, recurrent episodes of AD, new hospital admissions, medical or surgical treatment, and their outcome were recorded during follow-up. RESULTS: Of 1046 patients enrolled at 17 centres, 743 were eligible for the study (407 recruited retrospectively and 336 prospectively); 242 patients (32·6 per cent) underwent emergency surgery at accrual. After a mean follow-up of 10·7 years, rates of recurrence (17·2 versus 5·8 per cent; P < 0·001) and emergency surgery (6·9 versus 1·3 per cent; P = 0·021) were higher for medically treated patients than for those treated surgically. Among patients who had initial medical treatment, age less than 40 years and a history of at least three episodes of AD were associated with an increased risk of AD recurrence. There was no association between any of the investigated parameters and subsequent emergency surgery. The risk of stoma formation was below 1 per cent and disease-related mortality was zero in this group. The disease-related mortality rate was 0·6 per cent among patients who had surgical treatment. CONCLUSION: Long-term risks of recurrent AD or emergency surgery were limited and colectomy did not fully protect against recurrence.

Long-path second-harmonic interferometer with nanosecond time resolution: reliable diagnostic tool for electron density measurement in pulsed plasma devices.

We describe the performance of a second-harmonic interferometer (SHI) to measure, on an optical path exceeding 12 m, the electron plasma density of two plasmoids formed in separate theta-pinch chambers and then merged in a central compression chamber after undergoing acceleration and compression. The excellent mechanical stability and a time resolution better than 50 ns suggest the application of SHI, especially in pulsed plasma devices with limited optical accesses.

Dynamic formation of a hot field reversed configuration with improved confinement by supersonic merging of two colliding high-ß compact toroids.

A hot stable field-reversed configuration (FRC) has been produced in the C-2 experiment by colliding and merging two high-ß plasmoids preformed by the dynamic version of field-reversed θ-pinch technology. The merging process exhibits the highest poloidal flux amplification obtained in a magnetic confinement system (over tenfold increase). Most of the kinetic energy is converted into thermal energy with total temperature (T{i}+T{e}) exceeding 0.5 keV. The final FRC state exhibits a record FRC lifetime with flux confinement approaching classical values. These findings should have significant implications for fusion research and the physics of magnetic reconnection.

Neuroendocrine effects of citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans.

OBJECTIVE: Serotonergic system contributes to the regulation of hypothalamus-pituitary-adrenal axis. In humans, serotonergic agonists increase PRL, ACTH, and cortisol, while serotonin (5HT) influence on GH is controversial. Central 5HT activity and neuroendocrine function change during lifespan. DESIGN: To clarify the neuroendocrine response to 5HT across lifespan, we assessed ACTH, cortisol, DHEA, PRL, and GH responses to citalopram (CT) in young adults (YA) (no.=12, 29.2±1.7 yr mean±SEM), middle aged (MA) (no.=12, 54.3±0.9 yr), and elderly (ES) (no.=12, 69.3±0.9 yr) males. All the subjects received placebo (saline iv over 120 min) or CT (20 mg iv over 120 min). Blood samples were taken every 15 min up to 240 min. RESULTS: During placebo, ACTH, cortisol, GH, and PRL were similar in all groups while DHEA showed an age-dependent reduction from middle age (p<0.001). During CT, ACTH, and cortisol were higher than during placebo in YA (p<0.05) and even more in MA (p<0.01 vs placebo, p<0.05 vs YA); in ES, the increase of both ACTH and cortisol (p<0.05 vs placebo) was lower than in MA (p<0.05) and higher than in YA (p<0.05 for cortisol only). No changes were observed for DHEA, GH, and PRL in any group. CONCLUSIONS: Corticotrope response to CT is age-dependent in normal men, being amplified starting from middle age, suggesting precocious changes in the serotonergic neuroendocrine control during lifespan. CT is a useful tool to evaluate the age-dependent serotonergic function in humans.

In-vacuum Faraday isolation remote tuning.

In-vacuum Faraday isolators (FIs) are used in gravitational wave interferometers to prevent the disturbance caused by light reflected back to the input port from the interferometer itself. The efficiency of the optical isolation is becoming more critical with the increase of laser input power. An in-vacuum FI, used in a gravitational wave experiment (Virgo), has a 20 mm clear aperture and is illuminated by an almost 20 W incoming beam, having a diameter of about 5 mm. When going in vacuum at 10(-6) mbar, a degradation of the isolation exceeding 10 dB was observed. A remotely controlled system using a motorized lambda=2 waveplate inserted between the first polarizer and the Faraday rotator has proven its capability to restore the optical isolation to a value close to the one set up in air.

Diode-pumped passively mode-locked Yb:YLF laser.

We demonstrate passive mode-locking by means of a semiconductor saturable-absorber mirror in a diode-pumped Yb:YLF laser. We present crystal growth process, spectroscopic measurements, and investigation of mode-locking performance. Pulse trains with minimum duration of 196 fs, average power of 54 mW and a repetition rate of 55 MHz were obtained. The optical spectrum, centered at 1028 nm, has a 7.1-nm bandwidth leading to nearly transform-limited pulses.

Hypothalamus-pituitary-adrenal axis evaluation in patients with hypothalamo-pituitary disorders: comparison of different provocative tests.

BACKGROUND: The insulin tolerance test (ITT) is the gold standard test to evaluate hypothalamic-pituitary-adrenal (HPA) axis in suspected ACTH insufficiency. When contraindicated, alternative tests have been proposed such as metyrapone and ACTH stimulation test. 250 microg ACTH is a supramaximal dose and unreliable in this setting. The diagnostic reliability of 1.0 microg ACTH test is controversial and very low doses have been proposed. DESIGN: In 31 patients with hypothalamo-pituitary disorders and normal basal cortisol, we compared the diagnostic sensitivity, specificity and accuracy of metyrapone [metyrapone test (MET) 30 mg/kg p.o.], high (HDT, 250 microg i.v.), low (LDT, 1.0 microg i.v.) and very-low (VLDT, 0.06 microg i.v.) dose ACTH tests. Receiver operator curve (ROC) analysis was applied with ITT as reference test. RESULTS: MET approached the best pairs of values for highest sensitivity (71.4% and 64.3%) and highest specificity (100% and 82.4%) using ACTH and 11-deoxycortisol (11-DOC) cut-off of 17.3 pmol/l and 144.3 nmol/l. Either HDT or LDT sensitivity approached 71.4% with a specificity of 82.4% or 73.3% with a specificity of 80% for cortisol cut-off of 582.1 or 477.3 nmol/l. VLDT approached the highest sensitivity (57.1%) and highest specificity (88.2%) for a cortisol cut-off of 364.2 nmol/l. CONCLUSION: Neither MET nor ACTH test can be considered completely reliable for the diagnosis of secondary hypoadrenalism, when compared with ITT that remains the best test. Either MET or ACTH stimulation test, at both high and low dose, show an overall similar reliability, provided that appropriated cut-off values were considered; testing with very low ACTH doses seems to be misleading.

Primary hyperaldosteronism is associated with derangement in the regulation of the hypothalamus-pituitary-adrenal axis in humans.

Hippocampal mineralocorticoid receptors (MR) play a major role in the control of hypothalamus- pituitary-adrenal (HPA) axis. The functional profile of HPA axis and the impact of MR blockade under chronic exposure to mineralocorticoid excess are unknown. To clarify this issue, ACT H, cortisol, and aldosterone secretions were studied in 6 patients with primary hyperaldosteronism (HA) and 8 controls (NS) during placebo, placebo+human CR H (hCR H) (2 microg/kg iv bolus at 22:00 h), potassium canrenoate (CAN, 200 mg iv bolus at 20:00 h followed by 200 mg infused over 4 h) or CAN+hCR H. During placebo, both aldosterone and ACT H levels were higher (p<0.01) in HA than in NS, while cortisol levels were not significantly different. Both HA and NS showed significant ACT H and cortisol responses to hCR H (p<0.004), although the hormonal responses in HA were higher (p<0.02) than in NS. CAN infusion did not modify aldosterone levels in both HA and NS. Under CAN infusion, ACT H showed progressive rise in NS (p<0.05) but not in HA, while cortisol levels showed a significant (p<0.05) but less marked and delayed increase in HA compared to NS. CAN enhanced hCRH-induced ACTH and cortisol responses in NS (p<0.05), but not in HA. In conclusion, in humans primary hyperaldosteronism is associated with deranged function of the HPA axis. In fact, hyperaldosteronemic patients show basal and hCR H-stimulated HPA hyperactivity that is, at least partially, refractory to further stimulation by mineralocorticoid blockade with canrenoate. Whether this hormonal alteration can influence the clinical feature of hypertensive patients with primary hyperaldosteronism needs to be clarified.

Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck.

BACKGROUND: In 1992, we reported the first analysis of a randomized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck. The results of that 3-year analysis indicated that the combined treatment had superior efficacy. PURPOSE: After an additional 2 years of follow-up, we again compared the efficacy of the two treatment regimens, with attention paid to differences in overall survival, progression-free survival, and locoregional relapse-free survival. METHODS: One hundred fifty-seven patients with untreated, unresectable squamous cell carcinoma of the head and neck were randomly assigned to receive either chemotherapy (four courses of cisplatin [20 mg/m2] and fluorouracil [200 mg/m2], given daily for 5 consecutive days during weeks 1, 4, 7, and 10) plus radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy per day during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total dose, given in fractions of 2 Gy per day, 5 days per week). Eighty patients received the combined therapy, and 77 were treated with radiotherapy alone. Responses, failures, and toxic effects associated with the two treatment regimens were compared. Overall survival, progression-free survival, and locoregional relapse-free survival were calculated according to the Kaplan-Meier method; the logrank test was used to compare survival parameters between the two patient groups. Reported P values are two-sided. RESULTS: As reported previously, toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects; however, the incidence and severity of mucositis were nearly identical among patients in the two treatment arms. The combined treatment was associated with a statistically significant increase in the frequency of complete response (i.e., the disappearance of clinically detectable disease for at least 4 weeks) (43% for the combined-treatment group compared with 22% for the radiotherapy-only group; P = .037, chi-squared test). Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24% (95% confidence interval [CI] = 14%-40%) and 10% (95% CI = 4%-24%), respectively (P = .01, logrank test). The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21% (95% CI = 11%-37%) and 9% (95% CI = 3%-22%), respectively (P = .008, logrank test). Finally, the 5-year estimates of locoregional relapse-free survival were 64% (95% CI = 36%-84%) in the combined-treatment group and 32% (95% CI = 10%-65%) in the radiotherapy-only group (P = .038, logrank test). CONCLUSIONS AND IMPLICATIONS: The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years. However, additional trials must be conducted before considering the combined approach as standard therapy.

Association of APC gene mutations and histological characteristics of colorectal adenomas.

Fifty-nine colonic adenomas and 6 hyperplastic colonic polyps were analyzed by single-strand conformation polymorphism analysis for mutations in the adenomatous polyposis coli gene (APC). Frameshifts and premature stop codons in at least one copy of APC were detected in 25 of these adenomas. Five adenomas carried 2 APC mutations. No mutations in APC were found in any of the 6 hyperplastic polyps. The detection of APC mutations increased with size and degree of dysplasia and in rectal as compared to colonic adenomas, although the association was not statistically significant. The frequency of detectable APC mutations was higher in tubulovillous and villous adenomas (10 of 13) than in tubular adenomas (15 of 45) (odds ratio, 6.67; 95% confidence limits, 1.39-41.83; P = 0.005). The significance of the association between the detection of APC mutations and a villous architecture was confirmed in multivariate analysis (relative risk, 6.67; 95% confidence limits, 1.54-28.8; P = 0.005). In conclusion, APC mutation plays a role in adenoma progression; its frequency is significantly higher in lesions with a more villous morphology.

Sequential versus alternating chemotherapy and radiotherapy in stage III-IV squamous cell carcinoma of the head and neck: a phase III study.

A cooperative randomized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment, arm A, with an alternation of chemotherapy and radiotherapy (three courses of 20 Gy in ten daily fractions), arm B. The same chemotherapy was used in both arms: 6 mg/m2, vinblastine, hour 0; 30 mg, bleomycin, hour 6; 200 mg, methotrexate, hours 24 to 26; 45 mg, leucovorin, hour 48. One hundred sixteen patients entered the study, 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck (SCCHN). Forty-five patients had stage III and 71 had stage IV disease. The two arms were fully comparable. As of April 1986, 116 patients were evaluable for survival, while 112 were evaluable for toxicity and 105 for response. Response analysis shows that there were 14 complete responses (CR) and 11 partial responses (PR), for an overall response rate (ORR) of 52% in arm A, and 30 CRs and seven PRs, for an ORR of 64.9% in arm B. The difference in terms of CR between the two arms was statistically significant (P less than .03). Progression-free survival (PFS) was also statistically different, with an advantage for arm B (P less than .05), but without differences in overall survival. Arm B correlates with a significant increase in mucositis compared with arm A (P less than .001).

Predictive value of rectal bleeding for distal colonic neoplastic lesions in a screened population.

The aim of this study was to determine the diagnostic value of rectal bleeding for distal colorectal cancer (CRC), or large (> or =10 mm) adenomas among an average-risk population. A cross-sectional survey was conducted among individuals aged 55-64 years, who attended sigmoidoscopy (FS) screening in the context of a multicentre randomised trial of FS screening for CRC. Sensitivity, specificity and positive predictive value (PPV) of rectal bleeding for large distal adenomas or CRC were calculated. Rectal bleeding was reported by 8.8% of 8507 patients examined (15% of those with large adenomas and 29% of those with CRC). The risk of CRC was increased when bleeding was associated with an altered bowel habit: odds ratio (OR)=10.42; 95% Confidence Interval (CI): 4.08-26.59; the corresponding OR for isolated bleeding was 5.29 (95% CI: 2.28-12.30). Rectal bleeding carries an increased risk of distal neoplastic lesions. However, most lesions are detected among asymptomatic subjects. This finding suggests that screening represents the optimal strategy to detect CRC or large adenomas in the distal colon in the targeted age range.

Combined polychemotherapy and radiotherapy in advanced inoperable squamous cell carcinoma of the head and neck.

Between August 1979 and August 1984, 46 untreated, inoperable patients with advanced squamous cell carcinoma of the head and neck were submitted to a combined modality of treatment based on four courses of polychemotherapy (vincristine, bleomycin, and methotrexate), rotated with three courses of radiotherapy, 20 Gy each. Forty-six patients entered the study: 45 were evaluable for their response to the treatment and 46 for toxicity effects. We observed 26 complete responses (57.7%) and 14 partial responses (31.1%); overall actuarial survival was 28% at 55 months. Mucositis occurred in 11 patients, 3 patients suffered from nausea and vomiting, 2 patients developed fever, and 1 had a platelet count of 50,000/mm3. One toxic death occurred: one patient developed an acute renal failure related to Methotrexate.

Association between breast and colorectal cancer in a sample of surgical patients.

The frequency of adenomatous polyps and adenocarcinomas of the large bowel in 95 patients mastectomized for breast cancer, and the prevalence of breast cancer in 77 women previously operated on for colorectal cancer were evaluated by means of a case-control study. The mastectomized patients as well as the control group, underwent a left-sided colonoscopy. The latter had been selected among women spontaneously referring to our gastroenterological out-patients clinic. The choice of this self selected control group could produce a under-estimation of the relative for colon cancer in mastectomized patients. Among mastectomized patients the frequency of adenomatous polyps and colorectal cancer was 10.5% and 5.3% respectively; while the control group showed 8.5% frequency for adenomatous polyps and 3.9% frequency for cancer. These figures are not statistically different. Patients operated on for colorectal cancer and the control group underwent clinical and mammographic examination. The prevalence of breast cancer among colorectal cancer patients and the control group women was 5.2% and 0.3% respectively (10 times higher): the difference was statistically significant (P less than 0.006). In spite of the relatively small number of studied cases, our finding are consistent with the hypothesis of a correlation between breast cancer and colorectal cancer.

Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone.

AIM: To evaluate the efficacy of periocular triamcinolone acetonide for the treatment of thyroid associated ophthalmopathy (TAO), and the presence of ocular or systemic adverse effects. METHODS: A multicentre prospective pilot study was performed on patients diagnosed with Graves' ophthalmopathy less than 6 months before entry to the study. Patients were admitted to the study and were randomised into two groups: treatment and control. The treatment group received four doses of 20 mg of triamcinolone acetate 40 mg/ml in a peribulbar injection to the inferolateral orbital quadrant. Both groups were evaluated by measuring the area of binocular vision without diplopia on a Goldmann perimeter and the size of the extraocular muscles on computed tomography (CT) scans. Ophthalmological and systemic examinations were done to rule out ocular and systemic adverse effects. Follow up was 6 months for both groups. RESULTS: 50 patients were eligible for the study. 41 patients completed the study. There was an increase in the area of binocular vision without diplopia in the treatment group (Sigma initial: mean 231.1 (SD 99.9) and final absolute change, mean 107.1 (SD 129.0)) compared to the control group (Sigma initial: mean 350.7 (SD 86.5) and final absolute change, mean -4.5 (SD 67.6)). The sizes of the extraocular muscles were reduced in the treatment group (mean (inferior rectus initial values): 1.3 (0.7), final percentage change: -13.2 (25.7), medial rectus initial values: 1.2 (0.6), final percentage change: -8.2 (20.7), superior rectus-levator palpebrae initial values: 1.2 (0.6), final percentage change: -9.5 (29.1), lateral rectus initial values: 1.0 (0.4), final percentage change: -11.5 (20.6)) compared to the control group (inferior rectus initial values: 0.9 (0.3), final percentage change: -4.0 (21.5), medial rectus initial values: 0.9 (0.3), final percentage change: 0.6 (22.4), superior rectus-levator palpebrae initial values: 0.9 (0.3), final percentage change: 12.5 (37.5), lateral rectus initial values: 0.9 (0.4), final percentage change: -0.5 (31.6)). Both measurements (degree of diplopia and muscle thickness) were statistically significant between groups (initial - final). No systemic or ocular adverse effects were found. CONCLUSIONS: Triamcinolone administered as a periocular injection is effective in reducing diplopia and the sizes of extraocular muscles in TAO ophthalmopathy of recent onset. This form of treatment is not associated with systemic or ocular side effects.

Genetic events in sporadic colorectal adenomas: K-ras and p53 heterozygous mutations are not sufficient for malignant progression.

Twenty-four sporadic colorectal adenomas were analysed for the presence of allelic loss on the short arm of chromosome 17 as well as mutations in the K-ras and p53 genes. Chromosome 17p13 allelic loss was not present in 14 out of 14 informative cases. K-ras mutations were observed in 15 out of 24 cases. A p53 gene mutation (GGC-->GAC at codon 245) was detected in two biopsies taken at a four year interval from a recurrent rectal villous adenoma. Both biopsies also contained the same K-ras gene mutation (GGT-->GTT at codon 12). The data from the recurrent rectal adenoma provide in vivo evidence that K-ras and p53 heterozygous mutations confer a proliferative advantage but together are not sufficient for malignant transformation.

Incidence of Barrett's adenocarcinoma in an Italian population: an endoscopic surveillance programme. Gruppo Operativo per lo Studio delle Precancerosi Esofagee (GOSPE).

BACKGROUND: Barrett's oesophagus is a premalignant condition leading to adenocarcinoma. The incidence of adenocarcinoma of the oesophagus and the gastrooesophageal junction is rapidly increasing in the USA, northern and central Europe. Data from southern Europe are still unavailable. OBJECTIVE: To evaluate the incidence of oesophageal adenocarcinoma in a large cohort of Italian patients with Barrett's oesophagus. METHODS: A total of 344 patients (253 males and 91 females, age range 19-75 years) with histologically proven Barrett's oesophagus (length of metaplasia > or = 3 cm) were enrolled from November 1987 to June 1995. Endoscopic and histological examinations were scheduled at yearly intervals. RESULTS: One hundred and eighty-seven patients complied with the follow-up. The mean duration of the follow-up period was 36 months (total follow-up 562 patient-years; range 12-90 months). Low grade dysplasia was found in five patients at the initial examination. During the surveillance period, dysplasia increased in frequency as well as in severity and was found exclusively in the intestinal type of Barrett's oesophagus. In all, dysplastic changes were found in seven patients (five low grade and two high grade) and adenocarcinoma developed in three patients during the follow-up. In a single case, both adenocarcinoma and specialized columnar epithelium developed without any evidence of dysplasia or intestinal metaplasia at the previous follow-up examination. This prospective study shows an incidence of adenocarcinoma in Barrett's oesophagus of 1/187 patient-years. When only patients with specialized columnar epithelium were considered, the risk of adenocarcinoma was 1/88 patient-years. CONCLUSION: The present report shows that the incidence of adenocarcinoma in Italian Barrett's oesophagus patients is in the range of that reported from other Western countries.

Intraluminal high dose rate brachytherapy combined with external radiotherapy in the treatment of oesophageal cancer.

Twenty eight patients with previously untreated oesophageal carcinoma without distant metastases were divided into two groups: Group A consisted of 18 pts. treated with conventional external radiotherapy only. Another group of 10 pts. (Group B) received treatment with external beam irradiation with further high dose rate intraluminal brachytherapy up to a dose of 4-12 Gy delivered in 2-3 sessions of 4 Gy (one session a week). All pts. were evaluated clinically, radiologically and endoscopically every 3 months. At the end of treatment there was a marked difference in relief of dysphagia (39% in Group A vs. 90% in Group B), local control (56.7% in Group A vs. 100% in Group B) and time to progression of dysphagia (20.8 weeks in Group A vs. 67.7 weeks in Group B). No marked difference was observed in overall survival. The complication rate was low in both groups and major complications were observed in pts. treated with external radiotherapy alone (two fistulas). The association of external beam and intraluminal radiotherapy can give a better local control of the disease, improving the quality of life.