Abnormal tyrosine metabolism in chronic cluster headache.

Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

Mindfulness and pharmacological prophylaxis have comparable effect on biomarkers of inflammation and clinical indexes in chronic migraine with medication overuse: results at 12 months after withdrawal.

Chronic migraine (CM) is a disabling condition arising from a complex mixture of interconnected biological, psychological and social factors, and is often associated with medication overuse (MO). Mindfulness is emerging as a helpful treatment for pain, and one study showed that the longitudinal 12 months' course of CM-MO patients that attended mindfulness-based treatment alone was similar to that of patients receiving medical prophylaxis alone; in this study, we describe the course of biomarkers of inflammation. Our results provide initial evidence of sustained similar effects on reduced concentration of biomarkers of inflammation, although not sizeable enough to reach statistical significance. Whether more intensive treatment and/or larger samples would lead to greater changes is unknown, but these encouraging preliminary findings suggest further research is warranted.

Analysis of combined CSF biomarkers in AD diagnosis.

BACKGROUND: The new proposed diagnostic criteria for early diagnosis of Alzheimer's Disease (AD) underline the value of cerebrospinal fluid (CSF) biomarkers. The first aim of the study was to determine the diagnostic accuracy of CSF biomarker Abeta1-42, T-tau, and P-tau in differentiating AD patients in our cohort by means of "pure" biomarkers and in form of a combined analysis of these biomarkers. The second aim of the study was to determine the diagnostic accuracy of these markers for predicting incipient AD in patients with mild cognitive impairment (MCI). METHODS: We studied 102 CSF samples: 33 AD [mean age at baseline 71.2 (54-86)], 16 MCI [mean age at baseline 71.3 (57-78)], 24 non AD dementia, including 7 vascular dementia, 4 frontotemporal degeneration, 5 dementia with Lewy Body, and 8 with other dementia [mean age at baseline 72.7 (51-87)] and 32 non-demented neurological patients [mean age at baseline 71.3 (45-87) referred to as control (CO) later in the text]. A double sandwich ELISA (Innotest beta amyloid Abeta1-42, hTau and P-tau181 by Innogenetics, Gent, Belgium) was performed to quantify the concentration of the above biomarkers. The three biomarkers were then combined in the IATI index [(measured Ab1-42)/(240 + 1.18 *measured tau)], and in the ratios Abeta1-42/T-tau, Abeta1-42/P-tau, T-tau/Abeta1-42 and P-tau/Abeta1-42. RESULTS: Abeta1-42, T-tau and P-tau181 concentration showed statistically significant differences between AD and CO (327.2 pg/mL +/- 150.2 pg/mL and 659.4 pg/mL +/- 254.2 pg/mL; 508.2 pg/mL +/- 360.2 pg/mL and 305.3 pg/mL +/- 228.9 pg/mL; 82.2 pg/mL +/- 26.1 pg/mL and 45.3 pg/mL +/- 26.4 pg/mL, respectively, p < 0.05), while the difference between AD and MCI was statistically different only for Abeta1-42 (327.2 pg/mL +/- 150.2 pg/mL and 600.8 +/- 271.9 pg/mL, respectively, p < 0.05). The IATI index was 0.5 +/- 0.3 in AD, 0.9 +/- 0.6 in MCI, 1.37 +/- 0.9 in non AD dementia and 1.26 +/- 0.8 in non-demented neurological patients. With a cut-off fixed at 1 the sensitivity and specificity of the IATI index in discriminating AD from CO was 84% and 52%, respectively. CONCLUSIONS: This study confirms the great significance of CSF biomarker measurements in AD diagnosis in clinical routine. It is understood that a clinical diagnostic work-up is necessary in the process. Moreover, a biochemical profile of CSF biomarkers requires further investigations.

Tryptamine levels are low in plasma of chronic migraine and chronic tension-type headache.

The primary aim of this study (TA-CH, Tryptophan Amine in Chronic Headache) was to investigate a possible role of tryptophan (TRP) metabolism in chronic migraine (CM) and chronic tension-type headache (CTTH). It is not known if TRP metabolism plays any role in CM and/or CTTH. Plasma levels of serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), metabolite of 5-HT, and tryptamine (TRY) were tested in 73 patients with CM, 15 patients with CTTH and 37 control subjects. Of these, plasmatic TRY was significantly lower in CM (p < 0.001) and in CTTH (p < 0.002) patients with respect to control subjects, while 5-HIAA levels in plasma were within the same range in all groups. 5-HT was undetectable in the plasma of almost all subjects. Our results support the hypothesis that TRP metabolism is altered in CM and CTTH patients, leading to a reduction in plasma TRY. As TRY modulates the function of pain matrix serotonergic system, this may affect modulation of incoming nociceptive inputs from the trigeminal endings and posterior horns of the spinal cord. We suggest that these biochemical abnormalities play a role in the chronicity of CM and CTTH.

The role of tyrosine metabolism in the pathogenesis of chronic migraine.

OBJECTIVE: The pathogenesis of chronic migraine (CM) remains largely unknown. We hypothesized that anomalies of tyrosine metabolism, found in migraine without aura (MwwA) patients, play an important role in the transformation of MwwA into CM, since the increase in the number of MwwA attacks is the most predisposing factor for the occurrence of CM. METHODS: To test our hypothesis we measured the plasma levels of dopamine (DA), noradrenaline (NE) and trace amines, including tyramine (TYR) and octopamine (OCT), in a group of 73 patients with CM, 13 patients with chronic tension-type headache (CTTH) and 37 controls followed in the Headache Centers of the Neurology Departments of Asti, Milan and Vicenza hospitals in Italy. RESULTS: The plasma levels of DA and NE were several-fold higher in CM patients compared with control subjects ( P > 0.001). The plasma levels of TYR were also extremely elevated ( P > 0.001); furthermore, these levels progressively increased with the duration of the CM. CONCLUSIONS: Our data support the hypothesis that altered tyrosine metabolism plays an important role in the pathogenesis of CM. The high plasma levels of TYR, a potent agonist of the trace amine associated receptors type 1 (TAAR1), may ultimately down-regulate this receptor because of loss of inhibitory presynaptic regulation, therein resulting in uncontrolled neurotransmitter release. This may produce functional metabolic consequences in the synaptic clefts of the pain matrix implicated in CM.

Is migraine a risk factor for the occurrence of eating disorders? Prevalence and biochemical evidences.

The eating disorders (ED), anorexia nervosa (AN) and bulimia nervosa (BN), are severe psychiatric and somatic conditions occurring mainly in young woman. Although the aetiology is largely unknown, same evidences suggest that biological and psychological factors play a relevant role in the pathogenesis, along with monoamine, indole and same hypothalamic hormonal dysfunctions. Migraine is characterized by similar metabolic and psychological anomalies suggesting that a possible relationship exists between the two pathological conditions. To understand the possible relationship between migraine and ED, we have investigated the prevalence of migraine and the other primary headaches in a large group of AN and BN patients. In addition, we have studied the role of tyrosine metabolism in the same group of AN and BN young woman sufferers. In particular, we measured plasma levels of elusive amines: tyramine (Tyr) and octopamine (Oct) and catecholamines: noradrenalin (NE), dopamine (DA). The results of this study show that the prevalence of migraine in the woman affected by ED is very high (<75 %). The levels of Tyr and DA were higher and levels of NE were lower in the ED patients in respect to the control subjects. These biochemical findings suggest that abnormalities of limbic and hypothalamic circuitries play a role in the pathogenesis of ED. The very high prevalence of migraine in our group of ED sufferers and the biochemical profile of migraine, similar to that of ED patients shown in this study, suggest that migraine may constitute a risk factor for the occurrence of ED in young females. This hypothesis is supported by the onset of migraine attacks that initiated, in the majority of the patients, before the occurrence of ED symptoms.

miRNome Profiling Detects miR-101-3p and miR-142-5p as Putative Blood Biomarkers of Frailty Syndrome.

Frailty is an aging-related pathology, defined as a state of increased vulnerability to stressors, leading to a limited capacity to meet homeostatic demands. Extracellular microRNAs (miRNAs) were proposed as potential biomarkers of various disease conditions, including age-related pathologies. The primary objective of this study was to identify blood miRNAs that could serve as potential biomarkers and candidate mechanisms of frailty. Using the Fried index, we enrolled 22 robust and 19 frail subjects. Blood and urine samples were analysed for several biochemical parameters. We observed that sTNF-R was robustly upregulated in the frail group, indicating the presence of an inflammatory state. Further, by RNA-seq, we profiled 2654 mature miRNAs in the whole blood of the two groups. Expression levels of selected differentially expressed miRNAs were validated by qPCR, and target prediction analyses were performed for the dysregulated miRNAs. We identified 2 miRNAs able to significantly differentiate frail patients from robust subjects. Both miR-101-3p and miR-142-5p were found to be downregulated in the frail vs. robust group. Finally, using bioinformatics targets prediction tools, we explored the potential molecular mechanisms and cellular pathways regulated by the two miRNAs and potentially involved in frailty.

Patterns of postoperative radiotherapy for head and neck cancer in Italy: a prospective, observational study by the head and neck group of the Italian Association for Radiation Oncology (AIRO).

AIMS AND BACKGROUND: Our previous survey showed that the patterns of postoperative radiotherapy (PORT) for head and neck cancer (HNC) in Italy might be suboptimal. A prospective observational study was therefore designed to evaluate this issue in greater detail. METHODS: All radiotherapy centers involved in the HNC Working Group of the Italian Radiation Oncology Association were asked to enter into the study all patients treated with PORT during a 6-month period. RESULTS: A total of 200 patients were accrued by 24 centers from December 2008 to May 2009. Larynx (38%) and oral cavity (34%) were the most common primary sites. The median time between surgery and the start of radiotherapy was 69 days (range, 25-215 days). Seventy-nine percent of cases with no evidence of risk factors for local recurrence were treated with high-dose radiotherapy to the primary site. In about 75% of cases the pN0 neck was included in the target volume. Concomitant chemotherapy was delivered to about 60% of patients with major risk factors and 21% of patients with no risk factors. CONCLUSIONS: Three issues emerged from our study as potential targets for future investigations: the impact on clinical outcome of the interval between surgery and the start of PORT; factors driving radiation oncologists to overtreat volumes at low risk of recurrence; and problems associated with the delivery of concomitant chemotherapy.

Impact of residual setup error on parotid gland dose in intensity-modulated radiation therapy with or without planning organ-at-risk margin.

PURPOSE: To estimate the dosimetric impact of residual setup errors on parotid sparing in head-and-neck (H&N) intensity-modulated treatments and to evaluate the effect of employing an PRV (planning organ-at-risk volume) margin for the parotid gland. PATIENTS AND METHODS: Ten patients treated for H&N cancer were considered. A nine-beam intensity-modulated radiotherapy (IMRT) was planned for each patient. A second optimization was performed prescribing dose constraint to the PRV of the parotid gland. Systematic setup errors of 2 mm, 3 mm, and 5 mm were simulated. The dose-volume histograms of the shifted and reference plans were compared with regard to mean parotid gland dose (MPD), normal-tissue complication probability (NTCP), and coverage of the clinical target volume (V95% and equivalent uniform dose [EUD]); the sensitivity of parotid sparing on setup error was evaluated with a probability-based approach. RESULTS: MPD increased by 3.4%/mm and 3.0%/mm for displacements in the craniocaudal and lateral direction and by 0.7%/ mm for displacements in the anterior-posterior direction. The probability to irradiate the parotid with a mean dose > 30 Gy was > 50%, for setup errors in cranial and lateral direction and < 10% in the anterior-posterior direction. The addition of a PRV margin improved parotid sparing, with a relative reduction in NTCP of 14%. The PRV margin compensates for setup errors of 3 mm and 5 mm (MPD < or = 30 Gy in 87% and 60% of cases), without affecting clinical target volume coverage (V95% and EUD variations < 1% and < 1 Gy). CONCLUSION: The parotid gland is more sensitive to craniocaudal and lateral displacements. A setup error of 2 mm guarantees an MPD < or = 30 Gy in most cases, without adding a PRV margin. If greater displacements are expected/accepted, an adequate PRV margin could be used to meet the clinical parotid gland constraint of 30 Gy, without affecting target volume coverage.

Migraine prevalence in eating disorders and pathophysiological correlations.

The eating disorders (ED): anorexia nervosa (AN) and Bulimia nervosa (BN) are severe psychiatric and somatic conditions occurring mainly in young woman. Although the etiology is largely unknown, same evidences suggest that biological and psychological factors play a relevant role in the pathogenesis, along with monoamine, indole and same hypothalamic hormonal dysfunctions. Migraine is characterized by similar metabolic and psychological anomalies suggesting that a possible relationship exists between the two pathological conditions. In order to understand the possible relationship between migraine and ED, we have investigated the prevalence of migraine and the other primary headaches in a large group of AN and BN patients. In addition, we have studied the role of tyrosine metabolism in the same group of AN and BN young woman sufferers. In particular, we measured plasma levels of elusive amines: tyramine (Tyr) and octopamine (Oct) and catecholamines: noradrenalin (NE), dopamine (DA). The results of this study show that the prevalence of migraine in the woman affected be EA is very high (>75%). The levels of Tyr and DA were higher and levels of NE were lower in the ED patients with respect to the control subject. These biochemical findings suggest that abnormalities of limbic and hypothalamic circuitries play a role in the pathogenesis of ED. The very high prevalence of migraine in our group of ED sufferers and the biochemical profile of migraine, similar to that ED patients have shown in this study, suggest that migraine may constitute a risk factor for the occurrence of ED in the young females. This hypothesis is supported by the onset of migraine attacks that initiated, in the majority of the patients, before the occurrence of ED symptoms.

Surgery and radiotherapy in the treatment of malignant parotid tumors: a retrospective multicenter study.

AIMS AND BACKGROUND: Major salivary gland cancers are rare, with many histologic types and subtypes. The low incidence and heterogeneity of primary parotid carcinomas makes their outcome difficult to evaluate. Treatment remains primarily surgical, but optimal therapeutic regimens have yet to be fully realized. The present study reviews the experience of three Italian institutions in the treatment of primary parotid carcinomas in order to describe the clinicopathological presentation and treatment options with emphasis on radiotherapy and to analyze the factors influencing survival. METHODS AND STUDY DESIGN: The records of 110 patients with primary parotid neoplastic lesions treated at three Italian institutions from 1993 to 2004 were retrospectively reviewed. Six patients were excluded from the study: 3 received surgery alone and 3 were not assessable, for a total of 104 assessable patients. Acute and late toxicity of radiotherapy was quantified following the recommendations of the RTOG/EORTC. Survival was analyzed by the actuarial Kaplan-Meier product-limit method. The influence of selected factors on 10-year disease-specific survival was analyzed. RESULTS: The 104 assessable patients were treated as follows: 11 patients received radiotherapy as their only treatment (3 with a palliative purpose) and 93 had postoperative radiotherapy. Thirty-two patients underwent neck dissection: neck lymph node metastases were found in all them. Their mean age was 60 years (range, 14-92). According to the UICC/2002 TNM Classification, 8 patients were stage I, 19 stage II, 34 stage III, 25 stage IVA, 5 stage IVB, 3 recurrent and 10 not assessable (Tx). The most frequent histologies were adenoid cystic carcinoma (n = 16), mucoepidermoid carcinoma (n = 15), and acinic cell carcinoma (n = 15). Twenty-three patients had recurrences: 10 had local recurrences, 3 neck recurrences, 9 distant metastases, and 1 patient had both local recurrence and distant metastases. No factors were observed that would negatively influence the prognosis. Actuarial 10-year disease-specific survival was 71% and actuarial 10-year local control 82%. CONCLUSIONS: The treatment of salivary gland malignancies remains primarily surgical. Our study confirms the results of the literature with surgery and adjunctive radiotherapy in patients with advanced-stage disease. No variables were observed to influence the prognosis.

HPLC analysis of HbA1c in dried blood spot samples (DBS): a reliable future for diabetes monitoring.

To simplify collection and transport of blood for HbA1c measuring, we have studied the use of a special paper that absorbs a defined volume of capillary blood and quickly dries it (dried blood-spot, DBS). The DBS can be sent to a central laboratory using regular postal service and without temperature control. This system differs greatly from other proposed DBS methods for HbA1c because it overcomes the haemoglobin alterations during the drying and storing processes, that otherwise make this analysis unreliable. We have developed a special treatment of the paper before collection that stabilises the HbA1c molecule excellently in dried blood samples, allowing accurate HPLC analysis even two weeks after collection. This method has been applied in a "blind" study in which HbA1c values determined in 97 DBS coming from an hospital diabetes care centre were compared with those obtained from parallel venous blood samples.

Prospective evaluation of quality of life after interstitial brachytherapy for localized prostate cancer.

PURPOSE: Permanent interstitial brachytherapy (IB) has become an increasingly appealing therapeutic option for localized prostate cancer (LPC) among physicians and patients because it involves short hospitalization and treatment and its postulated low degree of toxicity may reduce its impact on the patients' quality of life (QoL). The aim of this prospective study was to assess the impact of IB on the QoL of patients with LPC. METHODS AND MATERIALS: A validated self-completed questionnaire was administered to the patients before and after IB and then at yearly intervals. The items allowed the identification of seven subscales exploring physical well-being (PHY), physical autonomy (POW), psychological well-being (PSY), relational life (REL), urinary function (URI), rectal function (REC), and sexual function (SEX). RESULTS: The assessment of the QoL of 147 patients treated between May 2000 and February 2005 revealed no relevant differences in the PHY scale scores 1 month after IB or later, and the same was true of the POW, PSY, and REL scales. Urinary function significantly worsened after IB and returned to pretreatment levels only after 3 years; the impact of the treatment on the URI scale was greater in the patients with good baseline urinary function than in those presenting more urinary symptoms before IB. Rectal and sexual functions were significantly worse only at the post-IB evaluation. CONCLUSIONS: The results of the present study confirm that the impact of IB on the patients' QoL is low despite its transient negative effects on some function, and extend existing knowledge concerning QoL after IB.

Long-term results of conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy in locoregionally advanced carcinoma of the oropharynx.

AIMS AND BACKGROUND: To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. METHODS AND STUDY DESIGN: Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). RESULTS: No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. CONCLUSIONS: The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.

"Method-specific" stability of serum C-peptide in a multicenter clinical study.

A Central laboratory that participates in multicenter clinical studies must consider and study the parameters that condition the in vitro stability of the analytes. We evaluated the effect of temperature on serum C-peptide storage during transport from clinical research centers to the Central laboratory. In particular, the stability for storage lengths from 0 to 24-48 hours at temperatures of between -20 degrees C and +37 degrees C were studied: the C-peptide assay was performed by means of a chemiluminescence and a RIA method. The tests confirmed that sample freezing is the gold standard for accurate determination of serum C-peptide and that storage at 37 degrees C may decrease the analyte levels. Instead, C-peptide stability at 2-8 degrees C appeared "method-specific"; while no apparent alteration was obtained with the chemiluminescence method up to 24 hours of storage, the RIA showed an early slight increase in C-peptide that is proportionate to storage time. Our work highlights that before starting up a multicenter clinical study it is always necessary to optimize and standardize biological sample storage and transport conditions to guarantee a high quality sample for analysis. Beyond this, it is even very useful to check the reliability of technical and instrumental resources that the Central laboratory will use during the study because molecular alterations of the analytes due to variable storage conditions can cause misleading results.

Phase I study of gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer.

PURPOSE: Although the use of radical transurethral resection followed by concurrent radiochemotherapy leads to a similar survival rate to that achieved after cystectomy, the number of long-term survivors is low in both cases. An improvement may be obtained by adding a new drug, such as gemcitabine, which is active in bladder cancer and acts as a radiosensitizer. However, because gemcitabine may be very toxic when associated with radiotherapy, we designed this dose-finding study in an attempt to find the dose that can be safely added to radiotherapy and concurrent cisplatin in patients treated with transurethral resection for infiltrating bladder cancer. PATIENTS AND METHODS: After undergoing macroscopically complete transurethral resections for transitional carcinoma of the bladder, patients staged pT2 or higher and without distant metastases concurrently received 54 Gy of fractionated radiotherapy over 6 weeks with cisplatin (100 mg/m(2) q.3 w), starting on Day 1 of radiotherapy. Concomitant gemcitabine was administered on Days 1, 8, and 15 q.3 w for 2 cycles at a dose of 200 mg/m(2), escalated to 500 mg/m(2), with a 100 mg/m(2) increase at each dose level. The maximum tolerated dose was defined as the dose of gemcitabine associated with dose-limiting toxic effects (febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 or 4 enteric toxicity, or Grade 4 nonhematologic toxicity) in 33% of the patients treated at that dose level. Six to 8 weeks after completing the therapy, the patients underwent cystoscopic reevaluation with multiple biopsies of the initial tumor site. RESULTS: Of our consecutive series of 16 patients, 5 received a gemcitabine dose of 200 mg/m(2)/week, 3 a dose of 300 mg/m(2)/week, 3 a dose of 400 mg/m(2)/week, and 5 a dose of 500 mg/m(2)/week for 6 weeks. No dose-limiting toxicity was observed at doses of up to 400 mg/m(2)/week. At the dose 500 mg/m(2)/week, 1 patient experienced an intestinal perforation that recovered after surgery, and another suddenly died after developing Grade 3 untreated diarrhea in the last treatment week. All of the 15 evaluable patients were microscopically disease free at the cystoscopic reevaluation; furthermore, the posttreatment computed tomography scans did not reveal any distant metastases. CONCLUSIONS: After transurethral resection for the conservative treatment of infiltrating bladder cancer, gemcitabine doses of up to 400 mg/m(2)/week seem to be safe in combination with cisplatin and radiotherapy in organ-sparing management. On the basis of the promising results of this Phase I study, we are currently conducting a Phase II trial to verify the possible improvement in local control resulting from the addition of gemcitabine.

Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.

PURPOSE: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS: No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

Variation in the dopaminergic response during the day in Parkinson disease.

OBJECTIVE: In many parkinsonian patients with fluctuating disease the early morning levodopa dose is more effective than the following dose on the same day. In this study we investigated whether the poor responsiveness to the early afternoon dose of levodopa depends only on peripheral and central levodopa pharmacokinetics or also on pharmacodynamic factors. METHODS: Ten parkinsonian patients experiencing postprandial drug-resistant off periods received two boluses of apomorphine by subcutaneous injection at 8 am and 3 pm on two nonconsecutive days. On day 2, therapy was stopped at 11 am. For each bolus we determined time to on, duration of the on state, magnitude of benefit, and levodopa and apomorphine plasma levels at baseline and immediately after patients reached the on state. RESULTS: The mean duration of on phases was significantly shorter and the apomorphine plasma level needed to reach the on state was significantly higher in the afternoon than in the morning (P<0.01 by paired t test). CONCLUSIONS: This study suggest that there is a change in responsiveness to dopaminergic stimulation during the day. The less effective dopaminergic response in afternoon depends on pharmacodynamic factors and not only on peripheral and central levodopa pharmacokinetic.

The role of brachytherapy in the management of oropharyngeal carcinomas: the Trento experience.

AIMS: This study was undertaken to determine the outcome of patients with oropharyngeal cancer treated at the Radiotherapy Department of the Santa Chiara Hospital (Trento, Italy) with brachytherapy alone or combined with external beam radiotherapy (EBRT). MATERIAL AND METHODS: We retrospectively reviewed the medical records of 87 patients with squamous cell carcinoma of the oropharynx treated by radiation therapy between January 1986 and September 1999. The median age was 59 years and all patients had a minimum follow-up of one year. Tumor locations were 46 tonsillar region, 31 soft palate and 10 base of the tongue. The patients were staged as follows: 41 T1, 35 T2, 11 T3 with 70 N0, 9 N1 and 8 N2. They received either brachytherapy alone (14 patients) or a combination of external beam irradiation and brachytherapy (73 patients) using an afterloading iridium technique in a plastic tube. RESULTS: Overall primary tumor control, including salvage surgery, was 81/87 (93%). Control of metastatic cervical adenopathy was as follows: clinical stage N1, 5/9 patients; N2, 2/8 patients. The estimated five-year cause-specific survival and overall survival rates were 81% and 47%, respectively. After interstitial irradiation severe complications were limited to one case of osteoradionecrosis of the mandible and seven cases of mucosal ulcer. CONCLUSION: This study confirms that iridium-192 interstitial implant alone or as a boost after external beam irradiation is a safe and effective therapy in the management of oropharyngeal carcinomas.

Trace amine metabolism in Parkinson's disease: low circulating levels of octopamine in early disease stages.

Recent evidence suggests that trace amines such as tyramine and octopamine, alternative products of tyrosine metabolism (an aminoacid parent of dopamine and noradrenaline), play a role in the homeostasis of the extrapyramidal system. However, the relevance of these trace amines in the pathogenesis of Parkinson's disease is still largely unknown. Here, we assessed the plasma levels of octopamine and noradrenaline in three sub-groups of PD patients, namely de novo, non-fluctuating and fluctuating patients, versus age-matched control subjects. We show that octopamine is detectable in plasma of all subjects, the mean levels of which are significantly lower in PD patients, including de novo patients, when compared to controls (p<0.001). Unlike this, no changes in plasmatic noradrenaline levels were found in the de novo patients, but only in plasma of fluctuating and non-fluctuating PD patients. These findings raise the possibility that Parkinson's disease is firstly characterized by abnormalities of tyrosine decarboxylase, rather than tyrosine hydroxylase, enzyme activity. Given the role of this enzyme in the production of trace amines, circulating octopamine levels may hold promise as a biomarker of early Parkinson's disease.