How reliable is assessment of true vocal cord-arytenoid unit mobility in patients affected by laryngeal cancer? a multi-institutional study on 366 patients from the ARYFIX collaborative group.

PURPOSE: In clinical practice the assessment of the "vocal cord-arytenoid unit" (VCAU) mobility is crucial in the staging, prognosis, and choice of treatment of laryngeal squamous cell carcinoma (LSCC). The aim of the present study was to measure repeatability and reliability of clinical assessment of VCAU mobility and radiologic analysis of posterior laryngeal extension. METHODS: In this multi-institutional retrospective study, patients with LSCC-induced impairment of VCAU mobility who received curative treatment were included; pre-treatment endoscopy and contrast-enhanced imaging were collected and evaluated by raters. According to their evaluations, concordance, number of assigned categories, and inter- and intra-rater agreement were calculated. RESULTS: Twenty-two otorhinolaryngologists evaluated 366 videolaryngoscopies (total evaluations: 2170) and 6 radiologists evaluated 237 imaging studies (total evaluations: 477). The concordance of clinical rating was excellent in only 22.7% of cases. Overall, inter- and intra-rater agreement was weak. Supraglottic cancers and transoral endoscopy were associated with the lowest inter-observer reliability values. Radiologic inter-rater agreement was low and did not vary with imaging technique. Intra-rater reliability of radiologic evaluation was optimal. CONCLUSIONS: The current methods to assess VCAU mobility and posterior extension of LSCC are flawed by weak inter-observer agreement and reliability. Radiologic evaluation was characterized by very high intra-rater agreement, but weak inter-observer reliability. The relevance of VCAU mobility assessment in laryngeal oncology should be re-weighted. Patients affected by LSCC requiring imaging should be referred to dedicated radiologists with experience in head and neck oncology.

Correlation between pelvic bone marrow radiation dose and acute hematological toxicity in cervical cancer patients treated with concurrent chemoradiation.

PURPOSE: To evaluate the association between pelvic bone marrow (BM) dose volume parameters and probability of acute hematological toxicity (HT), a cohort of cervical cancer patients receiving definitive chemoradiation (CRT) was assessed. MATERIALS AND METHODS: Medical records of patients treated by CRT (45 Gy in 25 fractions, without dose constraints applied to the BM) were reviewed. Baseline and weekly hematological parameters were collected. BM was retrospectively delineated and divided into sub-sites: iliac crests, lower pelvis, lumbosacral region. BM volumes (V) receiving 5, 10, 20, 30, 40 Gy (V5, V10, V20, V30, V40, respectively) and mean dose (Dm) were calculated. Logistic regression was used to analyze associations between HT and dose-volume histograms parameters. RESULTS: 114 patients were included. 75.4% were treated with 3D radiation therapy and 24.6% were receiving intensity modulated radiation therapy (IMRT). Neither age, chemotherapy regimen (cisplatin vs carboplatin), number of chemotherapy cycles, performance status, body mass index, or para-aortic irradiation were associated with HT. In univariate analysis, more frequent grade 3+ leukopenia was found in the IMRT group (odds ratio [OR]: 3.5; 95% CI, 1.4-9.1; p=0.007). In multivariate analysis, grade 4 HT was associated with lower pelvis V5>95% (OR 4.1; 95% CI, 1.6-14. p=0.02), lower pelvis V20>45% (OR 3.5; 95% CI, 1.1-13.4; p=0.05), total pelvic bone V20>65%, and iliac crests Dm >31 Gy (OR 4.5; 95% CI, 1.4-14.7; p=0.02). CONCLUSION: The following dose constraints could be proposed to decrease acute HT risk: lower pelvis V5<95%, lower pelvis V20≤45%, total pelvic bone V20<65%, and iliac crests Dm <31 Gy.

Gata3 hypermethylation and Foxp3 hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut-sensitized mice.

BACKGROUND: Epicutaneous immunotherapy (EPIT) is a promising method for treating food allergies. In animal models, EPIT induces sustained unresponsiveness and prevents further sensitization mediated by Tregs. Here, we elucidate the mechanisms underlying the therapeutic effect of EPIT, by characterizing the kinetics of DNA methylation changes in sorted cells from spleen and blood and by evaluating its persistence and bystander effect compared to oral immunotherapy (OIT). METHODS: BALB/c mice orally sensitized to peanut proteins (PPE) were treated by EPIT using a PPE-patch or by PPE-OIT. Another set of peanut-sensitized mice treated by EPIT or OIT were sacrificed following a protocol of sensitization to OVA. DNA methylation was analyzed during immunotherapy and 8 weeks after the end of treatment in sorted cells from spleen and blood by pyrosequencing. Humoral and cellular responses were measured during and after immunotherapy. RESULTS: Analyses showed a significant hypermethylation of the Gata3 promoter detectable only in Th2 cells for EPIT from the 4th week and a significant hypomethylation of the Foxp3 promoter in CD62L+ Tregs, which was sustained only for EPIT. In addition, mice treated with EPIT were protected from subsequent sensitization and maintained the epigenetic signature characteristic for EPIT. CONCLUSIONS: Our study demonstrates that EPIT leads to a unique and stable epigenetic signature in specific T-cell compartments with downregulation of Th2 key regulators and upregulation of Treg transcription factors, likely explaining the sustainability of protection and the observed bystander effect.

Does PSA reduction after antibiotic therapy permits postpone prostate biopsy in asymptomatic men with PSA levels between 4 and 10 ng/mL?

PURPOSE: We investigated the effect of antibiotics on PSA in asymptomatic patients with mild PSA elevation. MATERIALS AND METHODS: We prospectively evaluated, in a non-randomized design, 106 asymptomatic patients with PSA of 4-10 ng/mL, with a negative digital rectal examination and with no urinary tract infection evidence for 2 years. Patients were divided into two groups: those treated with antibiotics for 3 weeks (G1) and those who were not treated (G2). PSA was taken six weeks after and prostate biopsy was performed in all patients. RESULTS: PCa was diagnosed in 25 of 106 patients (23.6%): 16 (25.0%) in G1 and 9 (21.4%) in G2 (p>0.05). PSA normalization was experienced in 24.5%. In G1, PSA returned to <4 ng/mL in 15 (23.4%) patients compared to 11 (26%) patients in G2. In the patients with a positive biopsy, no significant variation was noted in PSA, fPSA, %fPSA and DPSA after antibiotic treatment. A significantly lower cancer detection rate was noted with decreased PSA, fPSA, and DPSA after antibiotic use. A PSA reduction rate of ≥ 10% occurred in 58.5%, and this was similar in both G1 and G2 groups. The sensibility, specificity and accuracy of PSA reduction of ≥ 10% were 31%, 23% and 25%, respectively. CONCLUSION: Empirical antibiotic therapy in asymptomatic male patients is not related to PSA reduction. The greater than 10% PSA reduction after antibiotic in this population cannot postpone prostate biopsy.

Does PSA reduction after antibiotic therapy permits postpone prostate biopsy in asymptomatic men with PSA levels between 4 and 10ng/mL?

Purpose We investigated the effect of antibiotics on PSA in asymptomatic patients with mild PSA elevation. Materials and Methods We prospectively evaluated, in a non-randomized design, 106 asymptomatic patients with PSA of 4-10ng/mL, with a negative digital rectal examination and with no urinary tract infection evidence for 2 years. Patients were divided into two groups: those treated with antibiotics for 3 weeks (G1) and those who were not treated (G2). PSA was taken six weeks after and prostate biopsy was performed in all patients. Results PCa was diagnosed in 25 of 106 patients (23.6%): 16 (25.0%) in G1 and 9 (21.4%) in G2 (p>0.05). PSA normalization was experienced in 24.5%. In G1, PSA returned to <4ng/mL in 15 (23.4%) patients compared to 11 (26%) patients in G2. In the patients with a positive biopsy, no significant variation was noted in PSA, fPSA, %fPSA and DPSA after antibiotic treatment. A significantly lower cancer detection rate was noted with decreased PSA, fPSA, and DPSA after antibiotic use. A PSA reduction rate of ≥10% occurred in 58.5%, and this was similar in both G1 and G2 groups. The sensibility, specificity and accuracy of PSA reduction of ≥10% were 31%, 23% and 25%, respectively. Conclusion Empirical antibiotic therapy in asymptomatic male patients is not related to PSA reduction. The greater than 10% PSA reduction after antibiotic in this population cannot postpone prostate biopsy. .

Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy.

BACKGROUND: Genetic susceptibility and environmental influences are important contributors to the development of asthma and atopic diseases. Epigenetic mechanisms may facilitate gene by environment interactions in these diseases. METHODS: We studied the rural birth cohort PASTURE (Protection against allergy: study in rural environments) to investigate (a) whether epigenetic patterns in asthma candidate genes are influenced by farm exposure in general, (b) change over the first years of life, and (c) whether these changes may contribute to the development of asthma. DNA was extracted from cord blood and whole blood collected at the age of 4.5 years in 46 samples per time point. DNA methylation in 23 regions in ten candidate genes (ORMDL1, ORMDL2, ORMDL3, CHI3L1, RAD50, IL13, IL4, STAT6, FOXP3, and RUNX3) was assessed by pyrosequencing, and differences between strata were analyzed by nonparametric Wilcoxon-Mann-Whitney tests. RESULTS: In cord blood, regions in ORMDL1 and STAT6 were hypomethylated in DNA from farmers' as compared to nonfarmers' children, while regions in RAD50 and IL13 were hypermethylated (lowest P-value (STAT6) = 0.001). Changes in methylation over time occurred in 15 gene regions (lowest P-value (IL13) = 1.57*10(-8)). Interestingly, these differences clustered in the genes highly associated with asthma (ORMDL family) and IgE regulation (RAD50, IL13, and IL4), but not in the T-regulatory genes (FOXP3, RUNX3). CONCLUSIONS: In this first pilot study, DNA methylation patterns change significantly in early childhood in specific asthma- and allergy-related genes in peripheral blood cells, and early exposure to farm environment seems to influence methylation patterns in distinct genes.

[Quinquina and man]. / Du quinquina et des hommes.

Many great discoveries have been made by chance but some have been the result of human perseverance and ingenuity. A sterling example of the second case is quinquina that was discovered in Peru and is now produced in Java. Quinquina has gone through centuries without losing its medical efficacy that efficacy allowed the exploration and colonization of Africa and played a key role in the ability to conduct overseas military campaigns. Because of its strategic importance, it was a coveted resource. It led to the discovery of homeopathy and dyes, allowed the development of organic chemistry, and has been used to make alcoholic bitters and soft drinks.

[Impact of HIV infection on malaria in adults]. / Impact de l'infection VIH sur l'infection palustre chez l'adulte.

Malaria and HIV are two major public health issues, especially in sub-Saharan Africa. The impact of HIV infection on malaria depends on the patient's immune status: immunodepression level but also immunity against Plasmodium. HIV infection increases the incidence of clinical malaria, inversely correlated with the degree of immunodepression, but the severity and mortality are increased only in areas of unstable malaria. In severe malaria the level of parasitemia is similar in HIV-positive and HIV-negative patients. During pregnancy, HIV infection increases the incidence of clinical malaria, maternal morbidity, and fetal and neonatal morbi-mortality. Sulfa-based therapies reduce the risk of malaria, most importantly in pregnancy. HIV infection increases the risk of treatment failure, mainly with sulfa-based therapies, due to re-infection or parasitic recrudescence. Further studies are needed to determine the pathophysiological interactions between HIV infection and malaria.

Gene expression profiling in insulinomas of Men1 beta-cell mutant mice reveals early genetic and epigenetic events involved in pancreatic beta-cell tumorigenesis.

Mutations of the MEN1 gene lead to the occurrence of multiple endocrine neoplasia type 1 (MEN1). To gain insights into the mechanisms of the tumorigenesis related to MEN1 inactivation, we have used mice in which the Men1 gene was specifically disrupted in pancreatic beta-cells. In these mice, we observed full penetrance of insulinoma with defined histological characteristics of tumorigenesis. To identify the genetic factors taking part in the tumour development, we performed gene expression profiling analysis of these insulinomas at different stages. Here, we show that in late stage insulinomas, 56 genes are up-regulated and 194 are down-regulated more than fourfold compared with normal pancreatic islets. Clustering analysis reveals the deregulation of Hox gene family and the genes involved in cell proliferation and cell cycle control. The altered expression of Igf2, Igfbp3 and Igfbp6 as well as cyclin A2, B2 and D2 are confirmed by quantitative RT-PCR, with the overexpression of all the three cyclins found in early stage insulinomas. Moreover, an increased proportion of cyclin A2- and D2-expressing cells and the overexpression of insulin-like growth factor 2 (IGF2) protein are detected in mouse Men1 insulinomas by immunostaining. Interestingly, the analysis of DNA methylation patterns by quantitative serial pyrosequencing reveals that four specific CpGs in the intragenic differentially methylated region 2 (DMR2) region of the Igf2 gene known to augment transcription through methylation are significantly hypermethylated in insulinomas of Men1 beta-cell mutant mice at 6 and 10 months of age, even before IGF2 overexpression can be detected. Thus, our data indicate the involvement of both genetic and epigenetic mechanisms in early tumorigenesis of beta-cells related to MEN1 inactivation.

Reconstruction of conjunctiva with amniotic membrane after excision of large conjunctival melanoma: a long-term study.

PURPOSE: To evaluate, on a long- term basis, the role of amniotic membrane in the reconstruction of large conjunctival defects after excision of large conjunctival melanoma. METHODS: Four consecutive patients with diffuse conjunctival melanoma involving both bulbar and palpebral conjunctiva were studied. Conjunctival melanoma was completely excised (with wide clinically disease-free margins) and amniotic membrane immediately sutured to the surrounding conjunctiva and sclera to cover the conjunctival defect. Minimum follow-up was 48 months. RESULTS: Successful conjunctival surface reconstruction and physiologic fornical depth were achieved in all patients within 6 weeks. No recurrence of primary melanoma was observed during long-term follow-up. CONCLUSIONS: Amniotic membrane transplantation is an effective alternative in ocular surface repairing surgery after removal of large conjunctival tumors.

[Granulomatous pneumocystis pneumonia]. / Pneumocystose à forme granulomateuse.

INTRODUCTION: Granulomatous pneumocystis pneumonia (PCP) is a rarity whose presentation may be misleading. CASE REPORT: We report the case of a patient suffering from chronic lymphatic leukaemia presenting with acute respiratory insufficiency, with a fatal outcome, due to granulomatous PCP. Broncho-alveolar lavage (BAL) remained negative and the diagnosis could only be made later by open lung biopsy. CONCLUSION: Although infrequent, granulomatous PCP should be recognised because in this situation the standard investigation (BAL) may be negative. New, more sensitive, methods of investigation such as the polymerase chain reaction (PCR) may permit earlier diagnosis.

Anti-inflammatory and antiallergic effects of ketorolac tromethamine in the conjunctival provocation model.

AIM: To study the effect of the topical anti-inflammatory drug, ketorolac, on (1) the clinical allergic reaction induced by the conjunctival provocation test (CPT); (2) the release of tryptase in tears; and (3) the expression of adhesion molecules on the conjunctival epithelium. METHODS: 10 allergic but non-active patients were challenged in both eyes with increasing doses of specific allergen to obtain a positive bilateral reaction and rechallenged, after 1 week, to confirm the allergic threshold dose response. After 2 weeks, a third CPT was then performed bilaterally 30 minutes after topical application of ketorolac in one eye and placebo in the contralateral eye in a double blind fashion. Clinical symptoms and signs were registered 5, 10, 15, and 20 minutes after challenge. The following objective tests were performed: tear tryptase measurement; tear cytology; and conjunctival impression cytology for immunohistochemical expression of ICAM-1 on epithelial cells. RESULTS: Compared with placebo, ketorolac significantly reduced the total clinical score and the itching score in the 20 minutes after challenge (p<0.0005). Tear levels of tryptase were significantly reduced in the ketorolac pretreated eyes compared with placebo (p<0.03). Eosinophils, neutrophils, and lymphocytes in tear cytology were significantly lower in ketorolac treated eyes compared with placebo. A significant difference in the epithelial expression of ICAM-1 was observed between placebo and ketorolac treated eyes (p<0.05). CONCLUSION: Ketorolac proved to be effective in reducing mast cell degranulation, as indicated by significantly decreased tryptase tear levels, as well as the clinical and cytological allergic reaction.

Renal artery angioplasty for renovascular hypertension and preservation of renal function: long-term angiographic and clinical follow-up.

OBJECTIVE: Percutaneous transluminal angioplasty of stenoses of the renal artery can be used to treat hypertension and renal insufficiency. Although many studies have been published on the short-term results of this procedure, few long-term studies are available. SUBJECTS AND METHODS: One hundred ninety-five patients (123 men and 72 women 19-79 years old; mean age, 56 years) with stenosis of the renal artery and hypertension underwent renal percutaneous transluminal angioplasty at our institution. The stenosis was unilateral in 66% of patients, bilateral in 26%, and in a solitary functioning kidney in 8%. Renal insufficiency was present in 31% of patients. After renal percutaneous transluminal angioplasty, long-term clinical and angiographic follow-up was evaluated by life-table analysis. RESULTS: In patients with fibromuscular disease, blood pressure returned to normal in 57%, improved in 21%, and was unchanged in 21%. In patients with atherosclerotic stenosis, blood pressure returned to normal in 12%, improved in 51%, and was unchanged in 37%. After percutaneous transluminal angioplasty, renal function improved in 48% of patients with renal insufficiency due to bilateral stenosis or stenosis in the single functioning kidney, whereas none of the patients with unilateral stenosis of renal artery and renal insufficiency had any notable improvement. Long-term follow-up showed a high rate (82%) of patency of revascularized arteries and a low rate (21%) of hypertension recurrence at 5 years. CONCLUSION: Renal percutaneous transluminal angioplasty is useful for treating hypertension and for reestablishing renal function. Its effects on blood pressure and renal function are long-lasting in the large majority of patients.

[Bone cysts and continuous ambulatory peritoneal dialysis]. / Cisti ossee e dialisi peritoneale ambulatoriale continua.

The clinical and radiologic patterns of amyloid osteoarthropathy in long-term hemodialysis patients are well known. However, few studies about the incidence of dialysis-associated amyloidosis in continuous ambulatory peritoneal dialysis (CAPD) patients have been published to date. In a series of 27 CAPD patients, the authors found bone cysts in 63.6% of cases, at the beginning of their dialysis treatment. After a mean follow-up period of 20.9 +/- 13.8 months, carpal bone cysts were seen in 70.4% of cases and clinical patterns worsened in 26.3% of patients. Therefore, CAPD does not prevent the development of dialysis-associated amyloidosis; prolonged uremic state and decreased diuresis seem to be the main pathogenetic factors of osteoarthropathy. The incidence and the evolution of bone lesions were related to the clinical data of this series and then compared with those of a group of hemodialysis patients. This study confirms that plain wrist films are a simple and useful method in the early detection and in the follow-up of amyloidosis-related disease.

[Sarcomatoid nephrocarcinoma. Correlation of radiological, histopathological and prognostic features]. / Il nefrocarcinoma sarcomatoide. Correlazione tra il quadro radiologico, istopatologico e prognostico.

Fifteen patients with sarcomatoid renal cell carcinoma were studied from 1975 through 1987. For each case the radiological, sonographic (US), and histopathological features were reviewed. Neither ivp nor US detected any specific patterns, though demonstrating frequently-necrotic and infiltrating masses. Angiography and/or CT were more useful because they allowed the staging of the tumors and the evaluation of their vascularity. In particular, a frequent correlation was observed between the degree of vascularity and the percentage of sarcomatoid component at histopathology. Sarcomatoid renal cell carcinoma were hypo-avascular in 7 cases and hypervascular in 8. Six of the 7 hypo-avascular cases had a high percentage of sarcomatoid tissue (greater than 50%) and were highly malignant. Seven of the 8 hypervascular neoplasms had a low percentage of sarcomatoid component and presented radiological features similar to clear/granular cell tumors. The survival of the patients with sarcomatoid tumors was much shorter than that of the patients with other kidney carcinomas. Among sarcomatoid tumors, prognosis was worst for the patients with hypo-avascular neoplasms.

[Echography vs urography in the study of small-size renal carcinoma]. / Ecografia ed urografia a confronto nello studio dei nefrocarcinomi di piccole dimensioni.

Since 1981 we have studied 34 patients with renal cell carcinomas smaller than 3 cm, diagnosed by US and IVP, to evaluate the diagnostic viability of these 2 procedures. Their respective results were compared to pathologic findings and tumor grading. No correlation was found between the type of sonographic patterns and the pathologic findings. On the contrary the correlation between the acoustic pattern and the grading, performed on small tumors and on a control group of large tumors, showed that most tumors in the former group (70%) had lower grading than those in the latter. We conclude that the introduction of US has changed the approach to the diagnosis of renal tumors, allowing their early recognition and characterisation. It is thus hoped that the clinical course of such tumors will be improved.

[Papillary nephrocarcinoma: radiographic and echographic aspects]. / Nefrocarcinoma papillifero. Aspetti radiografici ed ecografici.

Between 1976 and 1987, 395 patients with kidney tumors were studied with radiological techniques and sonography. In 37 cases (9.4%) histopathology diagnosed pure papillary renal cell carcinoma. Analyzing the radiographic patterns of these neoplasms, the authors observed constantly diminished vascularity (100%), frequent calcifications (35.1%) and necrotic areas (51.3%). Such X-ray features are not specific: nevertheless, their coexistence is strongly suggestive of papillary renal cell cancer. No consistent US pattern was found; however, necrotic areas were easily demonstrated in most cases. It must be stressed how patients with papillary carcinoma experienced a longer postoperative survival; it has not yet been established whether such favorable behavior is due to low biological aggressiveness or to earlier diagnosis.