Alterations of Inflammatory and Matrix Production Indices in Celiac Disease With Low Bone Mass on Long-term Gluten-free Diet.

BACKGROUND: A clinically meaningful impairment of bone mass secondary to malabsorption is frequent in untreated celiac disease. In adult patients, a rigorous gluten-free diet (GFD) significantly improves, but does not always normalize, bone mineral density (BMD). The reason for this marginal response is unclear. Accordingly, we evaluated the role of both local and systemic factors for bone loss in celiac patients on long-term GFD. STUDY: In a prospective cohort, 22 patients with low lumbar and/or femoral BMD and 22 with normal BMD underwent bone and mineral metabolism evaluation: we tested calcium, phosphate, parathyroid hormone, and vitamin D; telopeptide of type I collagen, a bone resorption index; propeptide of type I procollagen, a bone neoformation index; receptor antagonist of NF-kB ligand, an osteoclast-stimulating factor; osteoprotegerin (OPG), a decoy receptor for RANKL. Sunlight exposure and physical exercise were measured. RESULTS: Patients with bone loss showed prevalently osteopenia, severe osteoporosis was rare. In comparison with normal BMD patients, they showed higher serum OPG, telopeptide, and lower serum propeptide, suggesting an increased bone turnover. Lumbar T-score was negatively correlated with OPG, telopeptide and RANKL and positively with propeptide. Propeptide was negatively correlated with OPG and telopeptide. OPG was positively correlated with telopeptide. CONCLUSIONS: The persistent activation of inflammation should be considered the main pathophysiological mechanism for bone defect in celiac disease patients with bone loss on long-term GFD. High levels of OPG, an attempt at protective mechanism, and low levels of propeptide of type I procollagen, reflecting an insufficient matrix production, characterize this subgroup of patients.

Breath Methane Excretion Is not An Accurate Marker of Colonic Methane Production in Irritable Bowel Syndrome.

OBJECTIVES: The role of colonic methane production in functional bowel disorders is still uncertain. In small samples of irritable bowel syndrome (IBS) patients, it was shown that methane breath excretion correlates with clinical presentation and delayed gastrointestinal transit time. The aim of this study was to evaluate the relationship between intestinal production and breath excretion of CH4 and to correlate CH4 production with the presence and the severity of symptoms, in a large cohort of IBS patients and in a group of healthy volunteers. METHODS: A group of 103 IBS patients and a group of 28 healthy volunteers were enrolled. The presence and severity of symptoms and gastrointestinal transit were evaluated in all subjects, who underwent breath H2/CH4 measurement for 7 h after lactulose to identify breath excretors of these gases; H2 and CH4 were also measured in rectal samples to identify colonic producers. Cumulative H2 and CH4 excretion and production were evaluated by the area under the time-concentration curve calculation (AUC). RESULTS: In IBS patients, CH4 was detected in rectal samples in 48 patients (47%), but only 27 of them (26% of the 103 enrolled patients) excreted this gas with breath. In CH4 producers, the prevalence and severity of symptoms and gastrointestinal transit time were not significantly different with respect to non-producers. IBS subtypes were homogeneously represented in CH4 producers and in non-producers. Healthy volunteers, compared with IBS patients, showed a significantly lower prevalence of CH4 excretion, whereas no difference was found in the prevalence of colonic CH4 production; moreover, in healthy volunteers compared with IBS, CH4 breath excretion and CH4 production were not different in quantitative terms. CONCLUSION: Our data show that colonic CH4 production is not associated with clinical presentation in IBS patients and does not correlate with symptom severity or with gastrointestinal transit time. Clinical inferences based on breath CH4 excretion should undergo an in-depth revision, as this method is not a good marker of CH4 colonic production.

Fasting and postprandial gastric sensorimotor activity in functional dyspepsia: postprandial distress vs. epigastric pain syndrome.

OBJECTIVES: Little information is available on the mechanisms responsible for dyspeptic symptoms in postprandial distress syndrome (PDS), characterized by the presence of prevalently meal-related early satiation and fullness, and the epigastric pain syndrome (EPS), characterized by the prominent symptom of epigastric pain, generally not meal related. In a group of PDS patients, the presence of hypersensitivity to gastric distension in both fasting and postprandial phases was described as the main pathophysiological mechanism; on the contrary, we have no information on the pathophysiology of EPS. METHODS: Sixty Helicobacter pylori (HP)-negative, irritable bowel syndrome (IBS)-negative, and gastroesophageal reflux disease (GERD)-negative patients with functional dyspepsia according to Rome III criteria underwent symptom, anxiety, depression, and somatization evaluation, gastric barostat test, and gastric emptying time evaluation for solids. Fifteen age- and sex-matched healthy volunteers (HVs) were also enrolled as a control group. RESULTS: In PDS patients, the prevalence of both fasting and postprandial hypersensitivity was higher than in EPS patients, and the extent of postprandial reduction of discomfort threshold was significantly correlated with symptom severity. In EPS patients, gastric volume at fasting discomfort threshold and fasting compliance were significantly lower than in PDS patients. Gastric emptying time and gastric accommodation were similar between the two dyspeptic groups. Dyspeptic patients showed a higher prevalence of psychiatric disorders than HVs, but the prevalence was similar between PDS and EPS patients. CONCLUSIONS: Fasting and postprandial hypersensitivity characterize PDS patients and a reduction of gastric compliance is present in EPS patients. However, the pathophysiology of EPS appears more complex than PDS and further studies are needed to analyze central processing and integration of afferent pathways in order to clarify the role of the central nervous system in this condition.

Tumour burden at diagnosis as the main clinical predictor of cell resistance in patients with early stage, favourable Hodgkin lymphoma treated with VBM chemotherapy plus radiotherapy.

We verified whether early resistance to treatment can be predicted in a subset of patients with very favourable, early stage Hodgkin lymphoma, treated with VBM (vinblastine, bleomycin and methotrexate) chemotherapy and involved-field radiotherapy, an effective combination with very low early and late toxicity. The relative tumour burden (rTB) was volumetrically measured from the staging computed tomography and analysed together with the parameters of pre-therapy evaluation in 61 patients enrolled into the protocol MH-1b of the Gruppo Italiano Studio Linfomi between 1996 and 2003. Early failure, codified by either less than complete remission (i.e. partial/null response or progression) or early relapse (within 12 months from the end of therapy), was considered as clinical expression of resistance to treatment. Logistic regression and failure-free survival were the statistical tools for the analysis. The rTB demonstrated to be the best predictor of early failure, outperforming every other pre-treatment parameter, International Prognostic Score included. With a mean rTB value of 44.964 ± 34.788 cm(3)/m(2) in the 53 patients successfully treated and of 130.185 ± 63.993 cm(3)/m(2) in the eight with early treatment failure, the risk of resistance showed fivefold and 10-fold increases at rTB of 52.002 and 74.497 cm(3)/m(2), respectively. Only two patients relapsed more than 12 months after the end of therapy; both had a high initial rTB. The rTB is the best predictor of resistance also in the subset of patients with very favourable, early stage disease. Safe rTB limits are proposed for successful administration of VBM chemotherapy plus involved-field radiotherapy.

Tumour burden predicts treatment resistance in patients with early unfavourable or advanced stage Hodgkin lymphoma treated with ABVD and radiotherapy.

The purpose of the work was to investigate the factors predicting early resistance to treatment in Hodgkin lymphoma. Many staging parameters, including relative tumour burden (rTB), were analysed in 246 patients with Hodgkin lymphoma in relation to early failure, that is, less than complete remission (i.e. partial response, null response or progression) or occurrence of early relapse, as clinical expressions of resistance to treatment. Patients with early unfavourable disease were 129 and were treated with four to six cycles of ABVD + involved field radiotherapy; 117 patients with advanced stage disease received six cycles of ABVD + optional irradiation to no more than two sites. The rTB was volumetrically measured through the evaluation of staging computed tomography for all the lesions except bone marrow involvement, which was quantified by calculation. The relationship with early resistance was analysed with logistic regressions. The rTB demonstrated to be the best predictor of early failure in both patient subsets, being superior to the multiparameter International Prognostic Score. The rTB showed a significant exponential relationship with the relative risk of early failure, and with inclusion of the extranodal involvement into the model, a single equation became adequate to predict resistance in both early unfavourable and advanced stage patients. The conclusions are that the rTB is the best pretreatment factor related to the risk of resistance to combined ABVD + radiotherapy and that this relationship can be mathematically expressed in an easy way. A simplified assessment of rTB is highly desirable.

Polysorbate 80 add-on therapy in the treatment of Helicobacter pylori infection: Polysorbate 80 and HP antibiotic resistance.

Polysorbate 80, a sorbitan derivate, is a surfactant used as an emulsifier in some foods in concentrations of up to 0.5%. It was recently shown in vitro that polysorbate 80 decreases the minimum bactericidal concentrations of clarithromycin and metronidazole and may also revert antibiotic resistance. We report the case of an adult man, suffering from symptomatic Helicobacter pylori (HP) infection resistant to two courses of treatment with PPI plus amoxicillin and clarithromycin, and PPI plus clarithromycin and metronidazole. He was treated with a further antibiotic approach consisting of two-week administration of clarithromycin, metronidazole, PPI and polysorbate 80 as an add on therapy. Eradication of infection was confirmed by 13C-urea breath test two and five months after completion of the treatment course. Complete regression of symptoms was also achieved. To our knowledge, this is the first case of HP infection eradicated with a combination therapy based on polysorbate 80 added to antibiotics.

Pocket-size ultrasound device in cholelithiasis: diagnostic accuracy and efficacy of short-term training.

Pocket-size ultrasound devices (PSUD) are now widely available becoming a useful tool for diagnostic and therapeutic purposes. We aim to investigate the accuracy of PSUD in diagnosing cholelithiasis as compared to traditional ultrasonography. Moreover, we tested the reliability of PSUD when performed by inexperienced internal medicine residents after a short-term training. We consecutively enrolled inpatients and outpatients referred to undergo abdominal ultrasonography for signs or symptoms of gallbladder diseases in two different hospitals. Every patient underwent two independent examinations with PSUD by both expert (EXPPSUD) and nonexpert operators (N-EXPPSUD), and a conventional examination with traditional abdominal ultrasound (AUS). Every naive operator underwent a short-term training with a 2-h theoretical lesson, and a practical training focused on gallbladder under expert operator supervision. Overall, 146 patients were consecutively enrolled. Considering conventional AUS as the reference standard, sensitivity and specificity of EXPPSUD were, respectively, 93.75 and 100%. Sensitivity and specificity of N-EXPPSUD were, respectively, 75 and 91.25%. Nevertheless, when considering outpatients, PSUD has a high diagnostic accuracy even when performed by N-EXPPSUD with sensitivity of 93% and specificity of 88%. PSUD is a reliable tool for the diagnosis of cholelithiasis when used by expert operators potentially reducing the need for further diagnostic tests. It can even be successfully used by non-expert operators in outpatients setting after a short focussed training.

The effect of gluten on intestinal fermentation, gastric and gallbladder emptying in healthy volunteers.

BACKGROUND: The relationship between gluten ingestion and gastrointestinal tract function is a matter of debate. AIM: We analysed the effect of gluten on gastric and gallbladder emptying and intestinal fermentation in healthy volunteers. METHODS: Ultrasound measurement of gastric and gallbladder emptying after both gluten-containing and gluten-free meals was performed in 18 volunteers (8 women, age 25.0±2.5 years; BMI 22±1.9). Breath hydrogen excretion after a gluten-containing meal, a gluten-free meal and a gluten-free meal with added gluten powder was measured in 16 volunteers (10 women, age 25.2±2.7 years; BMI 22±1.8). The severity of symptoms was monitored. RESULTS: Gluten presence in the meals was not recognised. Gastric emptying time was 81.6±13.8min after gluten-containing and 73.9±21.6min after gluten-free meals (p=0.11). Percentage ejection fraction after gluten-containing meals was 60±9% and 60.6±6% after gluten-free meals (p=0.68). Peak and cumulative hydrogen excretion were significantly higher after gluten-containing than after gluten-free meals (peak: 12.5±7.3 vs 6.5±5.1 parts-per-million, p<0.01; and cumulative: 2319±1720 vs 989±680 parts-per-million/minute, respectively; p<0.01). Adding gluten powder to the gluten-free meal did not modify fermentation. Symptoms were mild and not different after the meals. CONCLUSIONS: In healthy volunteers, gluten may induce gastrointestinal alterations. Further studies are needed to clarify which patients could benefit from dietary modification.

Bone mass and mineral metabolism alterations in adult celiac disease: pathophysiology and clinical approach.

Osteoporosis affects many patients with celiac disease (CD), representing the consequence of calcium malabsorption and persistent activation of mucosal inflammation. A slight increase of fracture risk is evident in this condition, particularly in those with overt malabsorption and in postmenopausal state. The adoption of a correct gluten-free diet (GFD) improves bone derangement, but is not able to normalize bone mass in all the patients. Biomarkers effective in the prediction of bone response to gluten-free diet are not yet available and the indications of guidelines are still imperfect and debated. In this review, the pathophysiology of bone loss is correlated to clinical aspects, defining an alternative proposal of management for this condition.

The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer.

BACKGROUND: The aim of this study was to investigate the prognostic role of diagnostic delay and clinical presentation (regarding pain, jaundice, and weight loss) in pancreatic carcinoma. METHODS: One hundred and seventy patients with pancreatic cancer were diagnosed and treated in the decade 2001-2010 (100 males and 70 females, with a mean age of 65.8 years [range, 36-91]). Patients were staged with spiral computed tomography and 75% were found to have advanced disease (28 stage III, 99 stage IV disease). Ductal adenocarcinoma was diagnosed in 147 cases, other subtypes of carcinoma in the remaining 23. Fifty patients were operated with radical intent, 19 had palliative surgery, 101 were considered inoperable because of advanced disease or heavy anesthesiologic risk; 31 of these inoperable patients underwent biliary decompression by insertion of an endoluminal or percutaneous stent. Gemcitabine-containing regimens were administered to 143 patients and radiotherapy was combined in 19. Overall and relative survival were the parameters studied. Multivariate analysis was performed by multiple regressions applied to proportional-hazards model. RESULTS: From all the clinical, pathological and therapeutical factors evaluated the statistically significant ones were time to diagnosis and surgery. Among symptoms pain was related to the shortest mean time to diagnosis, weight loss to the longest, with corresponding differences in survival. These differences of observed survival were substantially confirmed in terms of relative survival. CONCLUSIONS: The poor prognosis of pancreatic carcinoma seems to depend, in part, on diagnostic delay and this, in turn, is influenced by the type of presenting symptoms.

Tumor burden in Hodgkin's lymphoma can be reliably estimated from a few staging parameters.

The relative tumor burden (rTB), the tumor burden normalized to body surface area, is of prime clinical and prognostic value in Hodgkin's lymphoma. However, its measurement is rather complicated and a bedside computation cannot be proposed. We investigated the possibility of estimating, instead of measuring, rTB from elementary parameters of the initial staging. The rTB of 507 patients, treated with therapeutic protocols of the Gruppo Italiano Studio Linfomi according to their staging characteristics, was measured through their pre-therapy computed tomographies. The relationships between rTB and staging characteristics were analyzed with simple and multiple regressions both in a training sample (254 patients) for a selection of predictive parameters, and in a test sample (253 patients) for validation of the results. The number of involved sites, bulky mass and the IPI score were the variables best related to rTB. The resulting final equation {estimated rTB=-4.3+8.3xIPI2+22.7x[no. of involved sites (+3 if a bulky mass is present)]} provided the maximal approximation to the measured rTB (R2=0.671). The validity of the equation was confirmed on the test sample and the predictive superiority of the estimated rTB over IPI was still evident in terms of failure-free survival in both groups of patients. The estimated rTB is accurate enough to retain most of the prognostic advantage of the measured rTB over the IPI score. It can be easily calculated, allows a valid approximation of the measured rTB, and can be proposed as a useful tool for clinical research and practice.

Prolonged survival in advanced thymoma: Effectiveness of sequential multiple lines of chemotherapy in an inoperable case.

A standard therapeutic approach for advanced malignant thymoma has yet to be defined given the rarity of this condition. We present a patient with advanced thymoma, evaluated as inoperable at diagnosis due to multiple serosal metastases. The strong constitution and determination of the patient allowed treatment with six distinct and subsequent chemotherapy regimens, all administered on an outpatient basis. A survival of 64 months from diagnosis was achieved. A favorable clinical response was obtained after the first three treatment lines, with the disappearance of all lesions on both computed tomography and positron emission tomography (PET) images. However, this result was not confirmed by surgical exploration of the thorax, undertaken with the aim of radical excision of possible residual disease. The presence of multiple pleural nodules, not evident on the imaging techniques, prevented even limited tumor debulking. The chemotherapy lines administered following detection of the lessions, stabilized the disease for a further 2 years, while a satisfactory quality of life was maintained. Only in the last months did the tumor progress and signs of cardiotoxicity appear, with the latter constituting the eventual cause of death. This case is important since the medical literature does not indicate non-cross-resistant regimens for advanced thymoma following second-line chemotherapy, and the sequence of regimens presented in this case study may serve as a feasible outline program. Moreover, we highlight the known possibility of false-negative PET studies, which can occur despite the claimed glucose avidity of thymoma tissue.

Tumors of the gastroesophageal junction have intermediate prognosis compared to tumors of the esophagus and stomach, but share the same clinical determinants.

The issue of whether carcinoma of the gastroesophageal junction (GEJ) should be considered a distal esophageal, a proximal gastric or an independent tumor, at least with regards to clinical evaluation and management remains controversial. This study included 613 retrospective consecutive patients with carcinoma of the upper digestive tract, 64 of the esophagus, 58 of the GEJ and 491 of the stomach. The prognostic impact of the main clinical and histological parameters was analyzed in relation to relative survival as an estimate of the excess mortality. Relative survival and standardized mortality ratio (SMR) were calculated from the observed survival and the expected survival of the general population with identical age, gender and calendar years of observation. Multivariate analyses were applied to the proportional hazards model of the relative survival. The excess mortality, expressed by the relative survival and SMR of the patients with GEJ carcinoma are intermediate compared to those of patients with esophageal and gastric tumors. However, prognosis is not determined by tumor location, histology or administration of adjuvant chemotherapy, but mainly by stage and radical surgical resection. Gender has a minor but significant prognostic effect and age showed a slight inverse correlation with excess mortality. In conclusion, the excess mortality related to the tumors of the upper digestive tract is determined by stage, radical resection, gender and age. The intermediate prognosis of GEJ tumors mainly depends on a particular combination of such elementary determinants.

Improving the AJCC/TNM classification for use in early gastric cancer.

PURPOSE: The current TNM classification is still unsatisfactory for collecting all the prognostic information from the clinical presentation of early gastric cancer: "T" is limited to two levels, the classes of "N" are still wide and "M" is generally absent. PATIENTS AND METHODS: This study involved 99 patients who underwent radical gastric resection for early gastric cancer. Clinical and histological parameters were prognostically analyzed for both observed and relative survival. Univariate and multivariate analyses were applied to the proportional hazards model. RESULTS: Number of metastatic lymph nodes and measure of the largest diameter of the tumor were the only independent prognosticators of observed and relative survival. Their similar relative hazards allowed an additive use of them in the N class. Two cut-off values of this composite clinical parameter are proposed for a good discrimination of the relative survival. DISCUSSION: The number of metastatic lymph nodes is the cornerstone of the current TNM system and was confirmed as adequate. The possibility of adding tumor size to the number of the involved lymph nodes improves and amplifies the prognostic ability, which is presently limited by the rarity of lymph node involvement and the small number of the lymph nodes usually involved.

Role of conventional salvage multiple-drug chemotherapy in relapsed and refractory aggressive non-Hodgkin lymphomas.

Autologous stem cell transplantation is the standard care for patients with relapsed or refractory aggressive non-Hodgkin lymphomas. Of the patients who are sensitive to second-line chemotherapy, approximately 40-50% are likely to be cured using this approach. The optimal salvage regimen for pre-transplant debulking is controversial and these second-line chemotherapies are particularly important for patients who cannot undergo transplantation for various reasons including age, comorbidity and insufficient stem cell collection. Numerous reports regarding this topic are available. This study evaluated reports published in the last 5 years, focusing on conventional multiple-drug second-line chemotherapies (with or without rituximab), and disregarding single-agent investigational phase-II trials. Results are encouraging, particularly when considering that the more recent and less toxic combinations appear to be equivalent to or even more favourable than previous, more aggressive approaches. Previous results obtained using a combination of mitoxantrone, carboplatin, cytarabine and methylprednisolone, are further updated and included in this study. In conclusion, the most effective conventional chemotherapy currently available for patients with relapsed or refractory non-Hodgkin lymphomas obtains complete remission rates of up to 50-70%; the achievement of a complete remission is the most important factor associated with a better outcome. Although the addition of rituximab is beneficial and safe, it is more effective in patients who have previously not been exposed to this monoclonal antibody. The addition of cycles of salvage chemotherapy to those strictly required for mobilization of peripheral blood stem cells ultimately improves the response rate.