Association of B-cell activating factor gene variants with serum anti-JCV antibody positivity in male patients with multiple sclerosis under natalizumab treatment: Implications for progressive multifocal leukoencephalopathy risk stratification.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients. METHODS: 162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR. RESULTS: While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment. CONCLUSIONS: Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.

ES-SCLC Patients with PD-L1+ CTCs and High Percentages of CD8+PD-1+T Cells in Circulation Benefit from Front-Line Immunotherapy Treatment.

SCLC is an aggressive cancer type with high metastatic potential and bad prognosis. CTCs are a valuable source of tumor cells in blood circulation and are among the major contributors to metastasis. In this study we evaluated the number of CTCs that express PD-L1 in treatment-naïve ES-SCLC patients receiving ICI in a front-line setting. Moreover, we explored the percentages of different immune T-cell subsets in circulation to assess their potential role in predicting responses. A total of 43 patients were enrolled-6 of them with LS-SCLC, and 37 with ES-SCLC disease. In addition, PBMCs from 10 healthy donors were used as a control group. Different T-cell subtypes were examined through multicolor FACS analysis and patients' CTCs were detected using immunofluorescence staining. SCLC patients had higher percentages of PD-1-expressing CD3+CD4+ and CD3+CD8+ T-cells, as well as elevated PD-1 protein expression compared to healthy individuals. Additionally, in ES-SCLC patients, a positive correlation between CD3+CD8+PD-1+ T-cells and PD-L1+ CTCs was detected. Importantly, patients harboring higher numbers of CD3+CD8+PD-1+ T-cells together with PD-L1+CTCs had a survival advantage when receiving front-line immunotherapy. Thus, this study proposes, for first time possible, immune cell-CTCs interaction, as well as a potential novel clinical biomarker for ICI responses in ES-SCLC patients.

B-cell activating factor gene variants in multiple sclerosis: Possible associations with disease susceptibility among females.

Although B cells and B cell activating factor (BAFF) have been previously implicated in MS pathogenesis, data regarding the genetic influence of BAFF polymorphisms on MS susceptibility are limited. Here we aim to explore whether BAFF polymorphisms could contribute to MS susceptibility. 156 RRMS patients fulfilling the revised McDonald criteria for MS diagnosis and 220 HCs were enrolled. Clinical, laboratory, and imaging characteristics were recorded. BAFF rs9514827, rs1041569, and rs9514828 polymorphisms were assessed by RFLP-PCR in DNA samples extracted from whole peripheral blood. The BAFF rs1041569 TT genotype along with the CTT and TTC haplotypes were associated with significantly increased risk for MS development in female MS patients compared to healthy female counterparts. These findings were not confirmed in males. The rs1041569 BAFF variant together with the CTT and TTC BAFF haplotypes derived from the BAFF rs9514827, rs1041569, and rs9514828 polymorphisms may represent novel genetic contributors to the development of MS in females.

MRI evidence of extraocular muscle atrophy and fatty replacement in myasthenia gravis.

PURPOSE: The aim of the study was to evaluate extraocular muscle (EOM) atrophy and fatty replacement in ocular myasthenia gravis (OMG) and generalized myasthenia gravis (GMG) patients with chronic and untreated ocular symptoms or with inadequate response to immunotherapy and unprovoked ocular exacerbations despite chronic immunotherapy. METHODS: Nineteen patients with either OMG or GMG and 19 healthy age-matched controls underwent an orbital MRI. Visually obvious muscle atrophy and muscle fatty replacement were evaluated by two raters independently. Maximum thickness of EOM was measured. Measurements of the muscles of each participant were added up, in order to calculate the total thickness. RESULTS: Eleven patients suffered from AChR-positive GMG, and 8 patients from OMG. All patients had chronic ocular symptoms or inadequate response to corticosteroids and unprovoked ocular exacerbations in spite of immunotherapy. Fatty replacement was reported in 6/19 (31.6%) patients and 0/19 (0%) controls (p = 0.02). Obvious atrophy in at least one muscle was reported in 8/19 (42.1%) patients and 1/19 (5.3%) controls (p = 0.019). Statistically significant differences between the two groups were also found in the mean total thickness, as well as in the thickness of superior recti, levator palpebrae, inferior recti, and superior oblique muscles. CONCLUSION: EOM atrophy and fatty replacement were seen frequently in our series of MG patients with treatment difficulties and frequent relapses of ocular involvement.

The Prognostic Significance of the Hedgehog Signaling Pathway in Colorectal Cancer.

Despite significant advances in the management of colorectal cancer (CRC) the identification of new prognostic biomarkers continues to be a challenge. Since its initial discovery, the role of the Hedgehog (Hh) signaling pathway in carcinogenesis has been extensively studied. We herein review and comment on the prognostic significance of the Hh signaling pathway in CRC. The differential expression of Hh pathway components between malignant and nonmalignant conditions as well as correlation of Hh activation markers with various clinicopathological parameters and the effect on disease-free survival, overall survival, and disease recurrence in patients with CRC is summarized and discussed. According to the studies reviewed herein the activation of the Hh pathway seems to be correlated with adverse clinicopathological features and worse survival. However, to date study results show significant variability with regard to the effect on outcomes. Such results need to be interpreted carefully and emphasize the need for further well designed studies to characterize the actual influence of the Hh pathway in CRC prognosis.

Nutritional status, acute phase response and depression in metastatic lung cancer patients: correlations and association prognosis.

BACKGROUND AND AIM: Cancer cachexia is a metabolic syndrome related with poor outcome. Cytokines play a key role in the pathophysiology of that syndrome. The aim of this study was to investigate the potential correlations between nutritional status, systemic inflammation, and psychological distress in cancer patients. The prognostic significance of the recorded parameters was also assessed. PATIENTS AND METHODS: Patients with metastatic lung cancer were eligible. Mini Nutritional Assessment (MNA) was used for the evaluation of nutritional status, Glasgow Prognostic Score (GPS) for the estimation of systemic inflammation, and Hospital Anxiety and Depression Scale (HADS) for psychological assessment. RESULTS: Totally, 122 patients were enrolled (71.3% with NSCLC and 28.7% with SCLC). The following correlations were observed: MNA and GPS (r = 0.289, p = 0.001), MNA and HADS (depression scale) (r = 0.275, p = 0.002), GPS and HADS (depression scale) (r = 0.256, p = 0.004), and GPS and HADS (anxiety scale) (r =0.194, p =0.033). In univariate analysis, GPS (p = 0.002) and MNA (p = 0.010) emerged as significant predictors of survival. In multivariate analysis, both MNA (p = 0.032) and GPS (p = 0.020) retained their importance. CONCLUSIONS: This study highlights the associations between nutritional status, systemic inflammation, and psychological distress, supporting their common underlying pathophysiological mechanisms and further suggesting the necessity of a holistic anti-cachectic approach.

Cecal obstruction due to primary intestinal tuberculosis: a case series.

INTRODUCTION: Primary intestinal tuberculosis is a rare variant of tuberculosis. The preferred treatment is usually pharmaceutical, but surgery may be required for complicated cases. CASE PRESENTATION: We report two cases of primary intestinal tuberculosis where the initial diagnosis was wrong, with colonic cancer suggested in the first case and a Crohn's disease complication in the second. Both of our patients were Caucasians of Greek nationality. In the first case (a 60-year-old man), a right hemicolectomy was performed. In the second case (a 26-year-old man), excision was impossible due to the local conditions and peritoneal implantations. Histopathology revealed an inflammatory mass of tuberculous origin in the first case. In the second, cell culture and polymerase chain reaction tests revealed Mycobacterium tuberculosis. Both patients were given anti-tuberculosis therapy and their post-operative follow-up was uneventful. CONCLUSIONS: Gastrointestinal tuberculosis still appears sporadically and should be considered in the differential diagnosis along with other conditions of the bowel. The use of immunosuppressants and new pharmaceutical agents can change the prevalence of tuberculosis.

Massive variceal bleeding secondary to splenic vein thrombosis successfully treated with splenic artery embolization: a case report.

INTRODUCTION: Splenic vein thrombosis results in localized portal hypertension called sinistral portal hypertension, which may also lead to massive upper gastrointestinal bleeding. Symptomatic sinistral portal hypertension is usually best treated by splenectomy, but interventional radiological techniques are safe and effective alternatives in the management of a massive hemorrhage, particularly in cases that have a high surgical risk. CASE PRESENTATION: We describe a 23-year-old Greek man with acute massive gastric variceal bleeding caused by splenic vein thrombosis due to a missing von Leiden factor, which was successfully managed with splenic arterial embolization. CONCLUSIONS: Interventional radiological techniques are attractive alternatives for patients with a high surgical risk or in cases when the immediate surgical excision of the spleen is technically difficult. Additionally, surgery is not always successful because of the presence of numerous portal collaterals and adhesion. Splenic artery embolization is now emerging as a safe and effective alternative to surgery in the management of massive hemorrhage from gastric varices due to splenic vein thrombosis, which often occurs in patients with hypercoagulability.

Acute contact appendicitis due to a migrated pericardial drain: a case report.

INTRODUCTION: The literature is replete with articles of foreign-body appendicitis and periappendicitis, but to our knowledge there are only two reports of extraintestinal foreign bodies causing contact appendicitis. CASE PRESENTATION: A 47-year old woman presented to the emergency department with a 24-hour history of right iliac fossa pain, nausea and vomiting, high fever and palpable right iliac fossa mass. The patient had an anamnestic of systemic lupus erythematosus, that caused acute pericarditis with effusion, that was treated with pericardiotomy and a pericardial drain. The laboratory tests showed leukocytosis The plain abdomen film showed no radiologic signs corresponding to acute abdomen, while the computed tomography revealed a radio-opaque formation in the right iliac fossa, corresponding to the palpable mass. Exploratory laparotomy revealed a pericardial drain. The microbiologic analysis of the abscess revealed Salmonella. The postoperative course of the patient was uneventful. CONCLUSION: Acute appendicitis due to a foreign body, without an anamnestic of either surgery or injury may cause a severe diagnostic dilemma. The computed tomography images may lead to logic riddles that have to be solved by an explorative laparotomy. Foreign bodies rarely cause acute abdomen, nevertheless the probability has to be considered when an interventional technique has been applied even if the location of the intervention is far from the abdominal cavity.

Intra-abdominal pressure alterations after large pancreatic pseudocyst transcutaneous drainage.

BACKGROUND: Acute pancreatitis leads to abdominal hypertension and compartment syndrome. Weeks after the episodes pancreatic fluids sometimes organize to pseudocysts, fluid collections by or in the gland. Aims of the present study were to evaluate the intra-abdominal pressure (IAP) induced by large pancreatic pseudocysts and to examine the effect of their transcutaneous drainage on IAP. METHODS: Twenty seven patients with a pancreatic pseudocyst were included. Nine patients with pseudocysts greater than 1l (group A) had CT drainage and eighteen (volume less than 1l) were the control group. The measurements of group A were taken 6 hours before and every morning after the drainage, while for group B, two measurements were performed, one at the day of the initial CT and one 7 days after. Abdominal compliance (Cabd) was calculated. Data were analyzed using student's t-test. RESULTS: Baseline IAP for group A was 9.3 mmHg (S.D. 1.7 mmHg), while the first post-drainage day (PDD) IAP was 5.1 mmHg (S.D. 0.7 mmHg). The second PDD IAP was 5.6 mmHg (S.D. 0.8 mmHg), the third 6.4 mmH (S.D. 1.2 mmHg)g, the fourth 6.9 mmHg (S.D. 1.6 mmHg), the fifth 7.9 mmHg (S.D. 1.5 mmHg), the sixth 8.2 mmHg (S.D. 1.4 mmHg), and the seventh 8.2 mmHg (S.D. 1.5 mmHg). Group B had baseline IAP 8.0 mmHg (S.D. 1.2 mmHg) and final 8.2 mmHg (S.D. 1.4 mmHg). Cabd after drainage was 185.6 ml/mmHg (SD 47.5 ml/mmHg). IAP values were reduced between the baseline and all the post-drainage measurements in group A. IAPs seem to stabilize after the 5th post-drainage day. Baseline IAP was higher in group A than in group B, while the two values, at day 7, were equivalent. CONCLUSION: The drainage of large pancreatic pseudocyst reduces IAP. Moreover, the IAP seems to rise shortly after the drainage again, but in a way that it remains inferior to the initial value. More chronic changes to the IAP are related to abdominal cavity's properties and have to be further studied.

A case of umbilical cord hemangioma: Doppler studies and review of the literature.

Hemangiomas of the umbilical cord are extremely rare benign vascular tumors, not always detected prenatally. They have been associated with increased alpha-fetoprotein (AFP), hydramnios, congenital anomalies, and increased perinatal mortality. Impaired umbilical circulation has been proposed as the predisposing factor for fetal compromise. We report a case of an antenatally detected umbilical cord hemangioma with one artery crossing the tumor, and we reviewed the literature. Close surveillance with Doppler flow studies of the umbilical vessels were carried out throughout the pregnancy. All indices were normal, except from the intra-tumoral part of the umbilical artery under discussion that showed increasing resistance from 32 weeks onwards. Our review confirmed the reported association with increased AFP and hydramnios. The placental end of the cord was the preferred site of location, and the umbilical artery the commonest vessel of origin. Association with cutaneous vascular malformations, and single umbilical artery were assessed.

Inguinal endometriosis: three cases and literature review.

Three cases of endometriosis infiltrating the round ligament are presented. The initial diagnosis was irreducible hernia, since this rare nosologic entity often causes unusual preoperative symptoms and diagnostic problems. Diagnosis is frequently made by histologic examination. The rarity of inguinal endometriosis should not exclude it from a possible diagnosis in cases with a painful mass in the inguinal region in a fertile woman, especially if the groin mass is associated in size and tenderness with menstrual variability. Surgery is the treatment of choice and is curative; laparoscopy is suggested during the same operation to evaluate the intraperitoneal conditions.

Hematemesis, a very rare presentation of solid pseudo-papillary tumors of the pancreas: a case report.

INTRODUCTION: Solid pseudo-papillary tumors of the pancreas are rare and typically present in young female patients. They are slowly growing masses that may attain large size, and are of low malignant potential. Surgical resection is usually curative. CASE PRESENTATION: A 71-year-old woman presented to the emergency department with an episode of hematemesis but was otherwise hemodynamically stable. Emergency gastroscopy revealed a bleeding mass projecting to the duodenum. Fluid, blood and electrolyte resuscitation followed. Computed tomography revealed a small mass in the head of the pancreas. A Whipple operation was performed. Pathology revealed a solid pseudo-papillary tumor. The postoperative course of the patient was uneventful and no recurrence was present a year after the operation. CONCLUSION: In our case, the most noteworthy observations concern the small size of the tumor, the age of the patient and the presenting symptom. However, pancreaticoduodenectomy in a 71-year-old woman is a major effort and should only be undertaken by centers and surgeons experienced in complex hepatobiliary surgery. Furthermore, the unique nature of this case reminds every clinician that each patient has to be considered separately and with extreme caution.

Anterior chest wall tuberculous abscess: a case report.

The granulomatous inflammation of tuberculosis usually involves the lungs and the hilar lymph nodes. Musculoskeletal tuberculosis (TB) occurs in 1-3% of patients with TB, while TB of the chest wall constitutes 1% to 5% of all cases of musculoskeletal TB. Furthermore, nowadays it is rarer to find extrapulmonary TB in immunocompetent rather that non-immunocompetent patients. The present case reports a fifty-six-year-old immunocompetent man with an anterior chest wall tuberculous abscess. The rarity of the present case relates both to the localization of the tuberculous abscess, and to the fact that the patient was immunocompetent. The diagnosis of musculoskeletal tuberculous infection remains a challenge for clinicians and requires a high index of suspicion. The combination of indolent onset of symptoms, positive tuberculin skin test, and compatible radiographic findings, strongly suggests the diagnosis. TB, however, must be confirmed by positive culture or histologic proof. Prompt diagnosis and treatment are important to prevent serious bone and joint destruction.