Monitoring non-small cell lung cancer progression and treatment response through hyaluronic acid in sputum.

We evaluated whether hyaluronan (HA) levels in the sputum could be used as a noninvasive tool to predict progressive disease and treatment response, as detected in a computed tomography scan in non-small cell lung cancer (NSCLC) patients. Sputum samples were collected from 84 patients with histological confirmation of NSCLC, 33 of which were in early-stage and 51 in advanced-stage disease. Patients received systemic chemotherapy (CT) after surgery (n=36), combined CT and immunotherapy (IO) (n=15), or targeted therapy for driver mutation and disease relapse (N=4). The primary end-point was to compare sputum HA levels in two different concentrations of hypertonic saline solution with overall survival (OS) and the secondary and exploratory end-points were radiologic responses to treatment and patient outcome. Higher concentrations of HA in the sputum were significantly associated to factors related to tumor stage, phenotype, response to treatment, and outcome. In the early stage, patients with lower sputum HA levels before treatment achieved a complete tumor response after systemic CT with better progression-free survival (PFS) than those with high HA levels. We also examined the importance of the sputum HA concentration and tumor response in the 51 patients who developed metastatic disease and received CT+IO. Patients with low levels of sputum HA showed a complete tumor response in the computed tomography scan and stable disease after CT+IO treatment, as well as a better PFS than those receiving CT alone. HA levels in sputum of NSCLC patients may serve as a candidate biomarker to detect progressive disease and monitor treatment response in computed tomography scans.

Exergame training-induced neuroplasticity and cognitive improvement in institutionalized older adults: A preliminary investigation.

BACKGROUND: Prior research has reported cognitive improvements in elderly individuals when mental and physical exercise are practiced simultaneously, as in exergaming. However, the molecular mechanisms driving this beneficial response remain unclear. Moreover, there is robust evidence that regular exercise increases neurotrophic factors and promotes neuroplasticity, contributing to cognitive improvement. This research aimed to assess the impact of a 6-week Xbox 360 Kinect exergame protocol on cognitive function and brain-derived neurotrophic factor (BDNF) levels in institutionalized older individuals. METHODS: Participants living in a long-term care facility were included. The intervention (Xbox 360 Kinect exergame protocol) was conducted individually and consisted of two sessions per week (40 min each) over 6 weeks. Participants' cognitive function (Montreal Cognitive Assessment, MoCA) was evaluated before and after the intervention. Blood samples (15 ml) were collected at the same time to measure BDNF levels. RESULTS: Although there were no changes in total MoCA scores, exergame training improved the "language" domain and demonstrated a tendency toward an improvement in the "abstraction" and "memory/delayed recall" domains. Furthermore, BDNF levels were significantly increased after the intervention. CONCLUSION: BDNF enhancement might mediate, at least in part, the cognitive changes induced by a 6-week Xbox 360 Kinect exergame protocol in institutionalized older adults.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update.

BACKGROUND: To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up. PATIENTS AND METHODS: Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs. RESULTS: With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation. CONCLUSIONS: With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.

Monitoring non-small cell lung cancer progression and treatment response through hyaluronic acid in sputum

We evaluated whether hyaluronan (HA) levels in the sputum could be used as a noninvasive tool to predict progressive disease and treatment response, as detected in a computed tomography scan in non-small cell lung cancer (NSCLC) patients. Sputum samples were collected from 84 patients with histological confirmation of NSCLC, 33 of which were in early-stage and 51 in advanced-stage disease. Patients received systemic chemotherapy (CT) after surgery (n=36), combined CT and immunotherapy (IO) (n=15), or targeted therapy for driver mutation and disease relapse (N=4). The primary end-point was to compare sputum HA levels in two different concentrations of hypertonic saline solution with overall survival (OS) and the secondary and exploratory end-points were radiologic responses to treatment and patient outcome. Higher concentrations of HA in the sputum were significantly associated to factors related to tumor stage, phenotype, response to treatment, and outcome. In the early stage, patients with lower sputum HA levels before treatment achieved a complete tumor response after systemic CT with better progression-free survival (PFS) than those with high HA levels. We also examined the importance of the sputum HA concentration and tumor response in the 51 patients who developed metastatic disease and received CT+IO. Patients with low levels of sputum HA showed a complete tumor response in the computed tomography scan and stable disease after CT+IO treatment, as well as a better PFS than those receiving CT alone. HA levels in sputum of NSCLC patients may serve as a candidate biomarker to detect progressive disease and monitor treatment response in computed tomography scans.

Pulmonary thromboembolism in childhood leukemia: 8-years' experience in a pediatric hematology center.

PURPOSE: To assess the occurrence and possible causes of pulmonary thromboembolism (PTE) in children with hematologic malignancies evaluated in a single pediatric hematology center. PATIENTS AND METHODS: Four hundred fifty-two patients admitted for leukemia in different stages of disease were evaluated whenever they presented with PTE-related acute respiratory failure (ARF). Diagnosis was based on a perfusional lung scan and a digital pulmonary angiography in most cases. When necessary, patients with ARF were transferred to the pediatric intensive care unit (ICU) for cardiorespiratory monitoring and support. Thrombolytic treatment was usually performed with urokinase at a loading dose of 2,000 to 4,560 IU/kg as single bolus followed by 2,000 to 4,530 IU/kg/h for 12 to 42 hours. Before thrombolytic therapy was discontinued, heparin was started at a daily dose of 100 to 500 IU/kg as a continuous infusion and continued for 6 to 26 days. RESULTS: Twelve of 452 children developed 17 PTE episodes, which were resolved completely after appropriate therapy in 15 cases. Univariate analysis showed a statistical correlation between PTE and the diagnosis of acute myeloid leukemia (AML) (P < .001). No major bleeding was observed after thrombolytic treatment. CONCLUSION: Our findings indicate that PTE is not an extremely rare event in children with leukemia and should be ruled out when sudden tachypnea develops in patients with risk factors such as previous tumor lysis, central venous catheter (CVC) malfunction, coagulation abnormalities, and drug-induced pulmonary toxicity. Complete resolution of PTE may be obtained in a high proportion of cases with early diagnosis and proper treatment.

Comorbidity of psychiatric diagnoses in anorexia nervosa.

The comorbidity of psychiatric diagnoses was examined with the Diagnostic Interview Schedule in 62 women who participated in a 10-year follow-up study of anorexia nervosa. Sixty-two age- and sex-matched controls, their parents, and parents of the anorectic probands were also interviewed with the Diagnostic Interview Schedule. There was a statistically significant comorbidity of the affective and anxiety disorders with anorexia nervosa. The first-degree relatives of the anorectic probands had significantly more alcoholism and total number of psychiatric diagnoses compared with the first-degree relatives of controls. There were two mothers with bulimia nervosa, two cases of anorexia nervosa and two of bulimia nervosa in other first-degree relatives of anorectic probands, and no cases of eating disorders in the first-degree relatives of controls.

Relationship of clinical factors to caloric requirements in subtypes of eating disorders.

Caloric requirements for weight gain in subgroups of anorectic patients (anorectic restrictors, anorectic binge-purgers) and weight maintenance in subgroups of anorectic and bulimic patients (bulimics with and without a prior history of anorexia nervosa) were studied in a total of 36 patients. No significant differences were found between subgroups of anorectic patients either in calories to gain weight or to maintain a normal weight. Bulimic patients, as a group, were found to require significantly fewer [corrected] calories than the group of anorectic patients to maintain a normal weight. Bulimic patients with a prior history of anorexia nervosa were found to require more calories for weight maintenance than bulimics with no such prior history. In the entire eating disorder population, there was a significant negative correlation between highest premorbid body mass index (BMI) and calories required to maintain weight. These findings suggest that differences in energy metabolism may be present in the eating disorder subgroups.

Pulmonary thromboembolism in leukaemic children undergoing bone marrow transplantation.

Of 67 leukaemic children transplanted in our BMT unit 3 presented with severe acute respiratory syndrome associated with pulmonary thromboembolism (PTE) as diagnosed by scintiscan and/or angiography in the first month after BMT. Intervention with continuous positive pressure ventilation, urokinase (loading dose, then continuous infusion for 12-18 h) and heparin (continuous infusion for an average of 10 days) has been carried out successfully in two cases. In conclusion, when evaluating patients undergoing BMT and developing early pulmonary complications, PTE must be considered. The pathogenesis of PTE is still difficult to ascertain but urokinase therapy may reduce early morbidity.

Hepatic glutathione determination after ethanol administration in rat: evidence of the first-pass metabolism of ethanol.

As a fraction of ingested ethanol is metabolized by gastric mucosa, different amounts of alcohol should reach the liver when the same dose is administered by oral or intravenous route. Therefore, we investigated the time-course of hepatic reduced glutathione (GSH) concentrations after intra-peritoneal or intra-gastric load of the same amount of ethanol in the rat. The test was also performed in fasted and Cimetidine-treated rats. The oral ethanol administration was followed by a less pronounced decrease and by a quicker recovery of hepatic content of GSH than after intraperitoneal route. In the fasted rat, basal hepatic GSH significantly decreased; after alcohol administration the decrease of hepatic GSH was more severe and prolonged than in the fed rat. Cimetidine was shown to be a potent inhibitor of gastric ADH. Pre-treatment with Cimetidine did not change the basal levels of hepatic GSH, but after oral ethanol load, the decrease of the hepatic GSH content was significantly (p < 0.005) more pronounced than in controls. This study demonstrates the beneficial effects of gastric ethanol metabolism on the liver. The reduced gastric ethanol metabolism, induced by fasting or by Cimetidine resulted in a decreased content and delayed recovery of liver GSH content.

Effects of interferon therapy on fibrosis serum markers in HCV-positive chronic liver disease.

OBJECTIVE: To evaluate serum levels of prolyl-hydroxylase and helical domain of Type IV collagen, markers of hepatic fibrogenesis, in patients with HCV-positive chronic liver disease and the effects of interferon therapy on these markers. DESIGN: Prolyl-hydroxylase and Type IV collagen were determined before therapy and each month during the treatment and follow-up. METHODS: Fifty-seven HCV-positive patients were studied. All the subjects received alpha2a recombinant interferon, 6 MU subcutaneously three times a week for 4 weeks, followed by 3 MU thrice weekly for 5 months. After cessation of treatment, each patient was followed for 12 months. Prolyl-hydroxylase and helical domain of Type IV collagen were measured by using immunoenzymatic methods. HCV-RNA and HCV genotype were determined according to the method of Okamoto. RESULTS: In the patients prolyl-hydroxylase (39.8+/-8.9 ng/ml) was not different from controls (39.1+/-5.9 ng/ml). On the contrary, the patients showed a mean Type IV collagen (133.6+/-93.3 ng/ml) significantly (P < 0.01) higher than controls (100.2+/-10.5 ng/ml). A good relationship between the degree of liver fibrosis and the Type IV collagen serum level was found (r = 0.68; P < 0.005). In both responders and non-responders the Type IV collagen levels decreased during interferon therapy. During the follow-up, in responders the Type IV collagen did not show modifications, while in non-responders/relapsers it returned rapidly to the pretreatment levels (139.1+/-100.7 ng/ml). CONCLUSION: In HCV-positive chronic liver disease, prolylhydroxylase is not a good marker of hepatic fibrosis, while Type IV collagen is a useful tool for evaluating fibrogenic activity. Interferon seems to be able to reduce the liver fibrosis even without the inhibition of viral replication and independently from liver necrosis.

Verrucous carcinoma in situ of the bladder, not associated with urinary schistosomiasis.

Verrucous carcinoma is a variant of well differentiated squamous cell carcinoma that rarely affects the bladder. The bladder localization of this carcinoma is usually associated with urinary schistosomiasis. In this work we report on a rare case of verrucous carcinoma of the bladder not associated with urinary schistosomiasis. To complete this study, analysis of DNA was carried out on the histologic sections of the tumour.

Low ureteral obstruction caused by umbilical ligament in a 37 year old man: a case report.

Arterial vascular anomalies rarely cause extrinsic ureteral obstruction and only 11 cases have been reported so far. This paper deals with an unusual extrinsic obstruction of the left ureter caused by a residue of the umbilical artery in a 37 years old man. The patient had left flank pain due to serious hydronephrosis on the same side. At operation a fibrous cord, a residue of the left umbilical artery, partially obstructed the distal left ureter. Partial left terminal ureterectomy with ureteroneocystostomy was performed. In the differential diagnosis of low extrinsic ureteral obstructions also the uncommon vascular anomalies of the umbilical artery should be taken into consideration.

[Spinal anesthesia in the surgery of inguinocrural hernias]. / L'anestesia spinale nella chirurgia delle ernie inguino-crurali.

The experience in the surgical treatment of inguinal and crural hernias with epidural and subarachnoidal anaesthesia over a period of fifteen years (1976-1989) is reported. Results obtained in 1,283 cases confirm the validity of the technique and the clinical course suggests that it could well be applied to cardiopathic, hypertensive, obese, bronchopneumopathic patients as well as to dysmetabolic diseases. Furthermore, advantages of spinal anaesthesia compared to general and local anaesthesia are emphasized. The use of ultrathin needles (24 gauge) in performing subarachnoidal anaesthesia is recommended to prevent headache.

Botulinum toxin type A versus phenol. A clinical and neurophysiological study in the treatment of ankle clonus.

AIM: To reduce ankle clonus in patients with spastic paresis either phenol nerve block of the tibialis posterior nerve or botulinum toxin type A (BTA) injection in triceps surae muscles can be used. This study aims to compare the efficacy over time of phenol nerve block and BTA injection in the inhibition of ankle clonus. METHODS: Twenty-two patients with spastic paresis presenting with ankle clonus were randomly treated with phenol nerve block of the tibialis posterior nerve or BTA injection in triceps surae muscles. Ankle passive dorsiflexion, clonus, M and H responses and H/M ratio were measured in all patients prior to treatment and 15 days afterwards, as well as one, three and six months later in 12 patients. Patient satisfaction was also recorded. RESULTS: Both patient groups showed significant clonus reduction over time with the effect of phenol being greater than that of BTA. In one month, the degree of passive dorsiflexion significantly increased in both groups without any significant difference between them. H/M ratio reduced after phenol treatment and remained almost constant during the following six months, whereas it remained at baseline level after BTA treatment. CONCLUSION: While both treatments led to reduction in ankle clonus, phenol showed greater clinical efficacy. The difference in the neurophysiological results suggests that the two drugs have different action mechanisms with a more prevalent reduction of alpha motoneuron excitability in phenol-treated patients.

Mutant Huntingtin induces activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3).

Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive neuronal death in the basal ganglia and cortex. Although increasing evidence supports a pivotal role of mitochondrial dysfunction in the death of patients' neurons, the molecular bases for mitochondrial impairment have not been elucidated. We provide the first evidence of an abnormal activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNip3) in cells expressing mutant Huntingtin. In this study, we show an abnormal accumulation and dimerization of BNip3 in the mitochondria extracted from human HD muscle cells, HD model cell cultures and brain tissues from HD model mice. Importantly, we have shown that blocking BNip3 expression and dimerization restores normal mitochondrial potential in human HD muscle cells. Our data shed light on the molecular mechanisms underlying mitochondrial dysfunction in HD and point to BNip3 as a new potential target for neuroprotective therapy in HD.