Hypoxia and tissue destruction in pulmonary TB.

BACKGROUND: It is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1). METHODS: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition. RESULTS: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion. CONCLUSIONS: Human TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.Medical Research CouncilThis is the final version of the article. It first appeared from the British Medical Journal via https://doi.org/10.1136/thoraxjnl-2015-20740

Neoadjuvant peptide receptor radionuclide therapy and modified multivisceral transplantation for an advanced small intestinal neuroendocrine neoplasm: an updated case report

Small intestinal neuroendocrine neoplasms (SINEN) frequently metastasise to regional lymph nodes, and surgery is the mainstay of therapy for such patients. However, despite the possible use of advanced surgical techniques, the resection of both primary and locoregional diseases is not always attainable. Intestinal and multivisceral transplantation has been performed in a small number of patients with conventionally nonresectable, slow-growing tumours threatening the mesenteric root but has remained controversial. The use of donor skin in “sentinel flaps” in transplantation theoretically offers advantages in tailoring immunosuppression and monitoring for rejection. We represent (with extended followup) the first case of a patient with inoperable extensive mesenteric metastases from SI-NEN, who underwent neoadjuvant peptide receptor radionuclide therapy before a modified multivisceral transplant with a concomitant vascularised sentinel forearm flap. At 48 months after transplantation, our patient remained at full physical activity with no evidence of disease recurrence on either tumour biochemistry or radiological imaging

Prevalence of Allergic Disorders among Primary School-Aged Children in Madinah, Saudi Arabia: Two-Stage Cross-Sectional Survey

There are limited data on the epidemiology of allergic disorders in Saudi Arabia. Such data are needed for, amongst other things, helping to plan service provision at a time when there is considerable investment taking place in national healthcare development. We sought to estimate the prevalence of atopic eczema, allergic rhinitis and asthma in primary school children in Madinah, Saudi Arabia.We conducted a two-stage cross-sectional survey of schoolchildren in Madinah. Children were recruited from 38 randomly selected schools. Questionnaires were sent to the parents of all 6,139 6-8 year old children in these schools. These parental-completed questionnaires incorporated questions from the International Study of Asthma and Allergies in Childhood (ISAAC), which had previously been validated for use in Arab populations. We undertook descriptive analyses, using the Generalized Estimating Equation (GEE) to calculate 95% confidence intervals. The overall response rate was 85.9% (n = 5,188), 84.6% for girls and 86.2% for boys, respectively. Overall, parents reported symptoms suggestive of a history of eczema in 10.3% (95%CI 9.4, 11.4), rhinitis in 24.2% (95%CI 22.3, 26.2) and asthma in 23.6% (95%CI 21.3, 26.0) of children. Overall, 41.7% (95%CI 39.1, 44.4) of children had symptoms suggestive of at least one allergic disorder, with a substantial minority manifesting symptoms indicative of co-morbid allergic disease. Comparison of these symptom-based prevalence estimates with reports of clinician-diagnosed disease suggested that the majority of children with eczema and asthma had been diagnosed, but only a minority (17.4%) of children had been diagnosed with rhinitis. International comparisons indicated that children in Madinah have amongst the highest prevalence of allergic problems in the world.Symptoms indicative of allergic disease are very common in primary school-aged children in Madinah, Saudi Arabia, with figures comparable to the highest risk regions in the world

FDG uptake by prosthetic arterial grafts in large vessel vasculitis Is not specific for active disease

OBJECTIVES: This study investigated the incidence and clinical significance of arterial graft-associated uptake of fluorodeoxyglucose in large-vessel vasculitis (LVV). BACKGROUND: The role of (18)F-labeled fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) in the management of LVV remains to be defined. Although [(18)F]FDG uptake at arterial graft sites raises concerns regarding active arteritis or infection, its clinical significance in LVV has never been formally studied. METHODS: An observational prospective study sought to identify patients with Takayasu arteritis (TA) undergoing [(18)F]FDG-PET/CT more than 6 months after graft surgery from a large cohort of patients from 2 tertiary referral centers. [(18)F]FDG uptake by the graft and native arteries was scored on a scale of 0 to 3 relative to hepatic uptake, and periprosthetic maximum standardized uptake value (SUVmax) was calculated. Periprosthetic [(18)F]FDG uptake in active disease was compared with that in inactive disease, and arterial progression was assessed by prospective magnetic resonance angiography (MRA). RESULTS: Twenty-six subjects with TA were enrolled. All were afebrile with negative blood culture. Periprosthetic uptake was significant in 23 of 26 patients, and the mean SUVmax was 4.21 ± 1.46. Median periprosthetic [(18)F]FDG uptake score (3; interquartile range [IQR]: 3 to 3) was higher than in native aorta (1; IQR: 0 to 1; p < 0.001). Graft-specific [(18)F]FDG uptake was unrelated to disease activity. Despite the high frequency of graft-associated [(18)F]FDG uptake, sequential MRAs did not reveal arterial progression in 25 of 26 patients; the 1 remaining case showed minor progression limited to native arteries. Nine patients underwent repeated PET/CT scanning without showing changes in graft-specific uptake, despite increased treatment. CONCLUSIONS: Significant [(18)F]FDG uptake that is confined to arterial graft sites in patients with LVV does not reflect clinically relevant disease activity or progression. To minimize exposure to immunosuppression and in the face of negative blood culture, clinically quiescent arteritis, normal or stably raised C-reactive protein levels, we elected not to escalate treatment and monitor progression with MRA

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Feasibility and long-term results of focused radioguided parathyroidectomy using a "low" 37 MBq (1 mCi) (99m)Tc-sestamibi protocol

Aim of the present study was to investigate the feasibility and long-term results of focused radioguided parathyroidectomy using a "low" 37 MBq (1 mCi) (99m)Tc-sestamibi dose protocol compared to conventional "high 740 MBq (20 mCi) (99m)Tc-sestamibi dose protocol" in patients with primary hyperparathyroidism (PHPT). The data of focused radioguided surgery obtained in a group of 320 consecutive PHPT patients with high probability of the presence of a solitary parathyroid adenoma (PA) were studied. All patients underwent preoperative imaging work-up of double-tracer (99m)Tc-pertechnetate/(99m)Tc-sestamibi subtraction parathyroid scintigraphy (Sestamibi scintigraphy) and high resolution neck ultrasound (US). In 301/320 patients (96.6%) focused minimally invasive radioguided surgery was successfully performed by administering a "low" 37 MBq (1 mCi) (99m)Tc-sestamibi dose in the operating room 10 minutes before operation. No major intraoperative complications were recorded. Focused radioguided surgery required a mean time of 32 min and a mean hospital stay of 1.2 days. Local anesthesia was applied in 75 patients, 66 of whom (88%) were patients older than 65 years with comorbidities contraindicating general anesthesia. No case of persistent or recurrent PHPT was observed during post-surgical follow-up (range = 18–70 months; mean +/- SD = 15.3 +/- 9.1 months). Radiation exposure dose to the operating surgeon was 1.2 μSi/hour with the "low 37 MBq (1 mCi) (99m)Tc-sestamibi dose", and less than 1.0 μSi/hour for the other operating-room personnel. Focused low dose radioguided parathyroidectomy is a safe and effective means to localize parathyroid adenomas in patients affected by solitary PA thus reducing by 20 fold the radiation exposure dose to the patients and operating room personnel

Neglected Tropical Diseases of the Middle East and North Africa: Review of Their Prevalence, Distribution, and Opportunities for Control

The neglected tropical diseases (NTDs) are highly endemic but patchily distributed among the 20 countries and almost 400 million people of the Middle East and North Africa (MENA) region, and disproportionately affect an estimated 65 million people living on less than US$2 per day. Egypt has the largest number of people living in poverty of any MENA nation, while Yemen has the highest prevalence of people living in poverty. These two nations stand out for having suffered the highest rates of many NTDs, including the soil-transmitted nematode infections, filarial infections, schistosomiasis, fascioliasis, leprosy, and trachoma, although they should be recognized for recent measures aimed at NTD control. Leishmaniasis, especially cutaneous leishmaniasis, is endemic in Syria, Iran, Iraq, Libya, Morocco, and elsewhere in the region. Both zoonotic (Leishmania major) and anthroponotic (Leishmania tropica) forms are endemic in MENA in rural arid regions and urban regions, respectively. Other endemic zoonotic NTDs include cystic echinococcosis, fascioliasis, and brucellosis. Dengue is endemic in Saudi Arabia, where Rift Valley fever and Alkhurma hemorrhagic fever have also emerged. Great strides have been made towards elimination of several endemic NTDs, including lymphatic filariasis in Egypt and Yemen; schistosomiasis in Iran, Morocco, and Oman; and trachoma in Morocco, Algeria, Iran, Libya, Oman, Saudi Arabia, Tunisia, and the United Arab Emirates. A particularly noteworthy achievement is the long battle waged against schistosomiasis in Egypt, where prevalence has been brought down by regular praziquantel treatment. Conflict and human and animal migrations are key social determinants in preventing the control or elimination of NTDs in the MENA, while local political will, strengthened international and intersectoral cooperative efforts for surveillance, mass drug administration, and vaccination are essential for elimination

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11