The Clinical Effect of Octreotide Combined with Upper Endoscopy in the Treatment of Peptic Ulcer Complicated with Upper Gastrointestinal Hemorrhage.

Background: With the development of endoscopic technology, the application of upper endoscopy can quickly target the lesion site of patients with peptic ulcer complicated with upper gastrointestinal bleeding. Objective: This study aims to discuss the clinical effect of octreotide combined with upper endoscopy in treating peptic ulcer complicated with upper gastrointestinal hemorrhage. Methods: A total of 82 patients diagnosed with peptic ulcer complicated with upper gastrointestinal hemorrhage were recruited as study objects in the researchers' hospital. According to the treatment method, this retrospective study divided the patients into a control group (n=41, receiving adrenaline injection under upper endoscopy only) and a treatment group (n=41, receiving adrenaline injection under upper endoscopy and Octreotide intravenously). Results: After treatment, the volume of blood loss, average hemostasis time, hospital stay, and time of occult blood turning negative in the treatment group were shorter than those in the control group (P < .05). After treatment, the clinical efficacy of the treatment group was better than that of the control group (P < .05). The levels of prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) levels in the treatment group were lower than those in the control group, with significant differences (P < .05). Conclusion and Relevance: Combining octreotide and upper endoscopy has affirmative efficacy and good hemostatic effect on treating peptic ulcer complicated with upper gastrointestinal hemorrhage with less pain and short recovery time, which is worthy of clinical application.

Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments.

Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [131I]MIBG and [177Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [131I]MIBG and [177Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [131I]MIBG or [177Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.

Palliative Management of Inoperable Malignant Bowel Obstruction: Prospective, Open Label, Phase 2 Study at an NCI Comprehensive Cancer Center.

CONTEXT: Malignant bowel obstruction (MBO) is a common complication of intra-abdominal cancer, frequently seen in advanced gastrointestinal and gynecologic cancer. Management of MBO can be challenging, particularly if the patient is not a surgical candidate. No consensus exists on how best to manage these patients medically. Retrospective studies suggest that the combination of dexamethasone, octreotide and metoclopramide may lead to relief of obstruction and improvement in symptoms associated with the obstruction. OBJECTIVES: This study seeks to prospectively evaluate the combination of drug "triple therapy" dexamethasone 4 mg BID, metoclopramide 10 mg Q6 and octreotide 300 mcg TID to assess tolerability, safety, and effect on symptoms and deobstruction. METHODS: Adults admitted at Roswell Park Comprehensive Cancer Center with malignant bowel obstruction were eligible. Eligible patients who constented to the study were started on the triple therapy with close monitoring of symptoms and for adverse effects. RESULTS: A total of 15 patients enrolled in the study. Two patients experienced bradycardia as adverse effect and there was no incidence of bowel perforation. All patients who completed the study had complete resolution of their nausea, and improvement in other symptoms including pain, constipation, tolerance of oral intake and resumption of bowel movements. Only two of the 15 patients were alive to complete the six-month post study follow up. CONCLUSION: "Triple therapy" with dexamethasone, metoclopramide, and octreotide for management of nonsurgical MBO in this small sample size appears safe and well tolerated however a diagnosis of inoperable MBO remains associated with poor prognosis and death within months.

3p-C-NETA: A versatile and effective chelator for development of Al18F-labeled and therapeutic radiopharmaceuticals.

Background: Radiolabeled somatostatin analogues (e.g. [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [18F]AlF-NOTA-octreotide, a promising 18F-labeled somatostatin analogue and potential alternative for 68Ga-DOTA-peptides, is under clinical evaluation. However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar (e.g. Al18F-method in combination with therapeutic radiometals 213Bi/177Lu) or identical (e.g. complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients. In this study we evaluated 3p-C-NETA, as potential theranostic Al18F-chelator and present first results of radiosynthesis and preclinical evaluation of [18F]AlF-3p-C-NETA-TATE. Methods: 3p-C-NETA was synthesized and radiolabeled with diagnostic (68Ga, Al18F) or therapeutic (177Lu, 161Tb, 213Bi, 225Ac and 67Cu) radionuclides at different temperatures (25-95 °C). The in vitro stability of the corresponding radiocomplexes was determined in phosphate-buffered saline (PBS) and human serum. 3p-C-NETA-TATE was synthesized using standard solid/liquid-phase peptide synthesis. [18F]AlF-3p-C-NETA-TATE was synthesized in an automated AllinOne® synthesis module and the in vitro stability of [18F]AlF-3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum. [18F]AlF-3p-C-NETA-TATE pharmacokinetics were evaluated using µPET/MRI in healthy rats, with [18F]AlF-NOTA-Octreotide as benchmark. Results: 3p-C-NETA quantitatively sequestered 177Lu, 213Bi and 67Cu at 25 °C while heating was required to bind Al18F, 68Ga, 161Tb and 225Ac efficiently. The [18F]AlF-, [177Lu]Lu- and [161Tb]Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over the study period. In contrast, [67Cu]Cu- and [225Ac]Ac-, [68Ga]Ga-3p-C-NETA were stable in PBS, but not in human serum. [18F]AlF-3p-C-NETA-TATE was obtained in good radiochemical yield and radiochemical purity. [18F]AlF-3p-C-NETA-TATE displayed good in vitro stability for 4 h in all tested conditions. Finally, [18F]AlF-3p-C-NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [18F]AlF-NOTA-Octreotide. Conclusions: 3p-C-NETA is a versatile chelator that can be used for both diagnostic applications (Al18F) and targeted radionuclide therapy (213Bi, 177Lu, 161Tb). It has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine.

A Randomized Trial Evaluating Patient Experience and Preference Between Octreotide Long-Acting Release and Lanreotide for Treatment of Well-Differentiated Neuroendocrine Tumors.

PURPOSE: Somatostatin analogs octreotide long-acting release (octLAR) and lanreotide are equally acceptable in National Comprehensive Cancer Network guidelines for neuroendocrine tumors (NETs). Lanreotide is more expensive and given by deep subcutaneous injection, whereas octLAR is given intramuscularly. We evaluated patient preference between these agents in terms of injection site pain. MATERIALS AND METHODS: Randomized, single-blinded study. Patients with NETs received injections every 4 weeks. Arm 1: octLAR × 3, then lanreotide × 3; arm 2: reverse order. Self-reported injection site pain scores (range, 0-10) were obtained after each of the first three injections. Primary end point was comparison of mean pain scores over the first three injections. Secondary end points included patient-reported preference. RESULTS: Fifty-one patients enrolled (26 in arm 1 and 25 arm 2), all evaluable for primary end point. No significant difference was identified in the mean pain score over the first three injections (2.4 ± 1.9 v 1.9 ± 1.5, P = .5). Thirty-four of 51 (67%) patients (15 in arm 1 and 19 in arm 2) completed post-therapy questionnaires and were evaluable for secondary end points. Seven patients (47%) in arm 1 and eight patients (42%) in arm 2 indicated no drug preference at the end of treatment. In the other 19 patients, more patients indicated mild or strong preference for octLAR over lanreotide. CONCLUSION: We found minimal pain with octLAR and lanreotide and no significant pain score differences between the two. Patients indicating a drug preference trended toward favoring octLAR.

Octreotide-based therapies effectively protect mice from acute and chronic gastritis.

Gastritis is a common inflammation of stomach with multiple pathogenesis. This study was designed to investigate the protective effects of oral octreotide (OCT) against ethanol-induced acute gastric injury and H. pylori-induced chronic gastritis via promoting gastric mucosa restoration, reducing gastric acid secretion and inflammation. Male C57BL/6J mice were randomly divided and treated with three doses of OCT (0.5, 2.5, 10 mg/kg) alone or combined respectively with 10 mg/kg omeprazole (OME), 0.2 g/L metronidazole (MTZ)/0.1 g/L clarithromycin (CLR) in drinking water. Oxidative stress analysis, bacterial load analysis, qPCR, gastric histopathology examinations were performed in our study. Ethanol-induced acute gastric ulcer was restored by OCT alone at doses of 2.5 mg/kg, or combined with OME as indicated by markedly reducing Gastrin, Il-6 and Il1b expression through induction of Muc5ac and Occludin, significantly improving hyperacidity and gastric bleeding. As well, OCT combined with MTZ/CLR restored the integrity of gastric mucosa damaged by H. pylori via elevating the expression of Muc5ac and somatostatin receptor 2, decreasing inflammation and increasing the number of chorionic or glands. Besides, OCT is more suitable for long-term medication in the treatment of chronic gastritis than OME. In conclusion, our results proved that the newly developed oral OCT-based therapies were more effective to reverse gastric mucosa damage and inflammation in ethanol and H. pylori infection-induced gastric injury, it is of great significance for supplementing new clinical regimens for the treatment of acute and chronic gastritis.

Comparison of Nausea and Vomiting Associated With Amino Acid Formulations Coinfused With Peptide Receptor Radionuclide Therapy: Commercial Parenteral Nutrition Formulas Versus Compounded Arginine/Lysine.

OBJECTIVES: Positively charged amino acids (AA) such as arginine/lysine are coinfused with radiolabeled somatostatin analogs to reduce rates of nephrotoxicity. In the phase 3 NETTER-1 trial, commercial AA formulations were used in association with 177Lu-DOTA-0-Tyr3-Octreotate (DOTATATE). These formulations were also used in an early-access program (EAP) before regulatory approval of 177Lu-DOTATATE. Our program transitioned to compounded l-arginine 2.5%/l-lysine 2.5% in 0.9% NaCl after commercial approval of 177Lu-DOTATATE. We sought to compare rates of nausea/vomiting with arginine/lysine versus commercial parenteral AA formulations. METHODS: Rates of nausea/vomiting of all 20 EAP patients who received commercial AAs (15% Clinisol) were compared with the first 29 patients to receive 177Lu-DOTATATE after commercial approval and coinfused with arginine/lysine. Other parameters reviewed included infusion rates, need for PRN nausea medications, and other toxicities. RESULTS: Seventeen percent of patients who received compounded arginine/lysine experienced nausea, compared with 100% of patients in the EAP group (P < 0.0001). Infusion-related reactions occurred in 3% of the arginine/lysine cohort versus 35% in the EAP group. Infusion durations were substantially shorter in the arginine/lysine cohort (reduced by 61%). CONCLUSIONS: Coinfusions of arginine/lysine with radiolabeled somatostatin analogs result in substantially lower rates of nausea/vomiting compared with commercial AA formulations designed for parenteral nutrition.

High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

Pharmacological Acromegaly Treatment: Cost-Utility and Value of Information Analysis.

OBJECTIVES: To conduct a cost-utility analysis comparing drug strategies involving octreotide, lanreotide, pasireotide, and pegvisomant for the treatment of patients with acromegaly who have failed surgery, from a Brazilian public payer perspective. METHODS: A probabilistic cohort Markov model was developed. One-year cycles were employed. The patients started at 45 years of age and were followed lifelong. Costs, efficacy, and quality of life parameters were retrieved from the literature. A discount rate (5%) was applied to both costs and efficacy. The results were reported as costs per quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICERs) were calculated when applicable. Scenario analyses considered alternative dosages, discount rate, tax exemption, and continued use of treatment despite lack of response. Value of information (VOI) analysis was conducted to explore uncertainty and to estimate the costs to be spent in future research. RESULTS: Only lanreotide showed an ICER reasonable for having its use considered in clinical practice (R$ 112,138/US$ 28,389 per QALY compared to no treatment). Scenario analyses corroborated the base-case result. VOI analysis showed that much uncertainty surrounds the parameters, and future clinical research should cost less than R$ 43,230,000/US$ 10,944,304 per year. VOI also showed that almost all uncertainty that precludes an optimal strategy choice involves quality of life. CONCLUSIONS: With current information, the only strategy that can be considered cost-effective in Brazil is lanreotide treatment. No second-line treatment is recommended. Significant uncertainty of parameters impairs optimal decision-making, and this conclusion can be generalized to other countries. Future research should focus on acquiring utility data.

Palliative Medical Management of Inoperable Malignant Bowel Obstruction With "Triple Therapy": Dexamethasone, Octreotide, and Metoclopramide.

CONTEXT: Malignant bowel obstruction (MBO) is a complication of advanced malignancy. For inoperable patients, symptoms are often treated using analgesics, anticholinergics, and anti-emetics. There are, however, few published guidelines for the medical management of MBO. OBJECTIVE: To measure the effect of the combination of dexamethasone, octreotide, and metoclopramide ("triple therapy") in patients with MBO, compared to patients who received none of the 3 medications ("no drug therapy"). METHODS: A retrospective cohort study of patients with MBO admitted in a single-center comprehensive cancer center. Patients who received dexamethasone, octreotide, and metoclopramide during their hospitalization for treatment of inoperable MBO were selected for analysis. Patients were excluded if they received a venting gastric tube. Rate of de-obstruction as well as time to de-obstruction were measured. RESULTS: There were 20 patients identified who received all 3 drugs of interest, and 29 patients identified who received none of the 3 medications. There was no statistically significant difference in rates of de-obstruction between the 2 groups, though there was a non-significant trend toward patients who received triple therapy were more likely to reach de-obstruction, compared to patients who had no drug therapy (95% vs. 83%, p = 0.379); there was no significant difference in adjusted analysis. CONCLUSION: In patients with inoperable MBO, there was no statistically significant difference in rates of de-obstruction with triple drug therapy compared to patients who received none of the 3 drugs, though the study may not have been powered to detect a difference and further investigation is warranted.

[Refractory Watery Diarrhea Due to an End-Stage Vasoactive Intestinal Peptide Production Tumor Treated with Opium Tincture-A Case Report].

A female patient aged 77 years had refractory watery diarrhea caused by a vasoactive intestinal peptide production tumor. She had impaired consciousness. After presenting to our hospital, we administered opium tincture, after which the diarrhea ceased. Intravenous feeding was able to be stopped along with the potassium load and the infusion of octreotide, and loperamide. The antidiarrheal effects continued after opium tincture was stopped, and the patient was discharged home. These results reveal that opium tincture can be efficacious in treating end-stage refractory diarrhea.

68Ga-DOTATATE and 123I-mIBG as imaging biomarkers of disease localisation in metastatic neuroblastoma: implications for molecular radiotherapy.

PURPOSE: Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) and lutetium-177-labelled DOTATATE (Lu-DOTATATE) are used for molecular radiotherapy of metastatic neuroblastoma. These are taken up by the noradrenaline transporter (NAT) and the somatostatin receptor subtype 2 (SSTR-2), respectively. Scintigraphy of iodine-123-labelled meta-iodobenzylguanidine (I-mIBG) and gallium-68 DOTATATE (Ga-DOTATATE) PET are used to select patients for therapy. These demonstrate the extent and location of tumour, and avidity of uptake by cells expressing NAT and SSTR-2, respectively. This study compared the similarities and differences in the anatomical distribution of these two imaging biomarkers in an unselected series of patients with metastatic neuroblastoma undergoing assessment for molecular radiotherapy. METHODS: Paired whole-body planar I-mIBG views and Ga-DOTATATE maximum intensity projection PET scans of metastatic neuroblastoma patients were visually compared. The disease extent was assessed by a semiquantitative scoring method. RESULTS: Paired scans from 42 patients were reviewed. Ga-DOTATATE scans were positive in all patients, I-mIBG scans were negative in two. In two patients, there was a mismatch, with some lesions identified only on the I-mIBG scan, and others visible only on the Ga-DOTATATE scan. CONCLUSION: Ga-DOTATATE and I-mIBG scans yield complementary information. For a more comprehensive assessment, consideration could be given to the use of both I-mIBG and Ga-DOTATATE imaging scans. Because of the heterogeneity of distribution of molecular targets revealed by these techniques, a combination of both I-mIBG and Lu-DOTATATE molecular radiotherapy may possibly be more effective than either alone.

Sequential Duo-Peptide Receptor Radionuclide Therapy With Indigenous 90Y-DOTATATE and 177Lu-DOTATATE in Large-Volume Neuroendocrine Tumors: Posttherapy Bremsstrahlung and PET/CT Imaging Following 90Y-DOTATATE Treatment.

The efficacy of Lu-DOTATATE in large neuroendocrine tumors (NETs) is reduced because of the lower energy (Eßmax 0.497 MeV) and shorter range of Lu. The pure ß-emitter Y with its longer ß range is more effective in larger tumors. This should be balanced with the greater risk of Y-DOTATATE-related nephrotoxicity. Sequential duo-peptide receptor radionuclide therapy may result in a better response with minimal adverse effects in large-volume heterogeneous NETs. A 56-year-old man with large rectal NET liver metastases, treated with Y-DOTATATE and Lu-DOTATATE and sequential duo-peptide receptor radionuclide therapy, presented with post-Y-DOTATATE bremsstrahlung and PET/CT in comparison with Ga-DOTATATE PET/CT and Lu-DOTATATE scans.

Investigation of the Effects of Octreotide Agent on Oxidative Stress, 8-Hydroxy Deoxyguanosine in Experimental Hepatic Carcinogenesis Rat Model.

INTRODUCTION: 2-AAF and DEN are well-known liver toxicants commonly used to stimulate tumors in laboratory animals. AIM: The aim of this study was to investigate the effect of octreotide on DEN-induced and 2-AAF-supplemented hepatocarcinogenesis in Wistar albino rats. MATERIALS AND METHODS: In this study, 64 Wistar albino rats were divided into 8 groups. DEN (175 mg/kg) initiated and 2-AAF (20 mg/kg) promoted liver carcinogenesis in rats. The tumor growth inhibitor octreotide (300 µg/kg) was used. Rats were sacrificed at the end of experiment and their liver tissues were taken for the study. SOD, GSH-Px, CAT activities, NO and MDA levels were measured spectrophotometrically. Also, Hsp70 and 8-OHdG was measured by the ELISA method. RESULTS: In group 7, MDA, 8-OHdG, and Hsp70 levels were significantly increased. In addition, SOD, GSH-Px activity was significantly reduced in this group. MDA, 8-OHdG and Hsp70 levels were significantly reduced in Group 8, which received octreotide for treatment. CONCLUSION: DEN and 2-AAF cause very serious liver damage. Octreotide protects the liver from carcinogenesis, increases the activity of cellular antioxidant enzymes and helps reduce DNA damage. Therefore, octreotide may be an inhibitor in tumor cells and may reduce oxidative stress.

A Massive Chylous Ascites With Severe Morbidity After Laparoscopic Donor Nephrectomy and Successful Treatment With Total Parenteral Nutrition and Octreotide.

Kidney transplant is a choice option for treatment of chronic kidney failure because it is associated with cost-effective and normal quality of life. To increase the number of living kidney donors, laparoscopic and minimal invasive modalities have been introduced. Here, we present a case of a living donor with an extremely rare complication after laparoscopic donor nephrectomy that presented as massive chylous ascites. Kidney donor operation can be performed with the use of 3 modalities: traditional open, laparoscopic, and open with minimally invasive. All 3 modalities may be associated with some complications, including wound infection, hemorrhaging, and deep vein thrombosis. With regard to rare complications of chylous ascites after laparoscopic donor nephrectomy, few cases have been reported. To our knowledge, only 5 such cases have been reported thus far. Our patient, a 29-year-old male donor, received left donor nephrectomy via laparoscopy and was discharged 4 days later in good condition and without any problems. However, 3 weeks later, he presented with abdominal pain. During evaluation, massive ascites in the abdomen was observed and he was hospitalized. Abdominal paracentesis was performed and chylous ascites was diagnosed, and he was treated with conservative treatment, which included combined total parenteral nutrition, paracentesis, and octreotide. For this rare complication of massive chylous ascites afterlaparoscopic donor nephrectomy, treatment with total parenteral nutrition and octreotide can be used; however, care must be taken regarding clipping of the lymph vessel of hilum of the kidney during nephrectomy.

Description of a transient proximal tubulopathy induced by amino acids perfusion in peptide receptor radionuclide therapy: A case report.

RATIONALE: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a targeted internal radiotherapy method used to treat tumors expressing somatostatin receptors. Concomitant amino acids perfusion is systematically performed in order to inhibit the proximal tubular uptake of the radionuclide and thus prevent nephrotoxicity. PATIENT CONCERNS:: a 67-year-old woman with an intestinal neuroendocrine tumor with multiple lymphadenopathies and liver metastases. The patient displayed a carcinoid syndrome with flushes including facial erythrosis and paresthesia. During the treatment, the patient exhibited emesis and severe cramps. DIAGNOSIS: We describe incomplete proximal tubulopathy induced by an amino acid therapy with [177Lu]-DOTA0-Tyr3-octreotate, which was reversible after treatment discontinuation. This diagnosis relies on metabolic acidosis, hypophosphatemia due to renal loss, tubular proteinuria and generalized aminoaciduria. Serum creatinine remained stable during and after the procedure. INTERVENTIONS: PRRT with radiolabeled somatostatin analog ([177Lu]-DOTA0-Tyr3-octreotate). In order to prevent PRRT induced nephrotoxicity, we used a solution of 20 amino acids including 22 g/L Lysine and 16.8 g/L Arginine. Metoclopramide was successfully used to control vomiting. During the treatment and at the time of cramps, the blood sample showed hypophosphatemia at 0.3 mmol/L justifying intravenous phosphate supplementation. The cramps disappeared after this infusion. OUTCOMES: Hypophosphatemia with low TmPO4/GFR was observed as well as an increase in ß2-microglobulinuria, urinary polyclonal light chains, and amino aciduria involving all amino acids. All these disturbances disappeared the day after the treatment and there was no acute kidney injury after 5 PRRT sessions. Six months after PRRT discontinuation, the patient had neither renal failure nor proximal tubulopathy. Aminoacid induced tubulopathy involves the main ligands of the megalin receptor. It has recently been demonstrated that cilastatin is a megalin inhibitor in the proximal tubule and therefore could represent an attractive alternative to amino acids for this purpose. LESSONS: This case report is a description of a nephroprotective strategy in which partial, and transient tubulopathy is induced, in order to decrease proximal absorption of a tubulotoxic molecule. This little known strategy could be used to prevent proximal tubular injury caused by others megalin-mediated nephrotoxicity medication.

Development and characterization of octreotide-modified curcumin plus docetaxel micelles for potential treatment of non-small-cell lung cancer.

We prepared octreotide (OCT)-modified curcumin plus docetaxel micelles to enhance active targeting and inhibit tumor metastasis by destroying vasculogenic mimicry (VM) channels. Soluplus was applied as an amphiphilic material to form micelles via film dispersion. The cytotoxic effects, active cellular targeting, and inhibitory effects on metastasis were systematically evaluated in vitro using A549 cells, and in vivo antitumor effects were evaluated using xenograft tumor-bearing mice. In vitro assays indicated that the OCT-modified curcumin plus docetaxel micelles showed robust cytotoxicity on A549 cells and effectively inhibited VM channels and tumor metastasis. Studying the mechanism of action indicated that OCT-modified curcumin plus docetaxel micelles downregulated MMP-2 and HIF-1α. In vivo assays indicated that OCT-modified curcumin plus docetaxel micelles increased drug accumulation at tumor sites and showed obvious antitumor efficacy. The developed OCT-modified curcumin plus docetaxel micelles may offer a promising treatment strategy for non-small-cell lung cancer.

Eficacia y seguridad de octreotide de liberación lenta (octreotide LAR) comparado con placebo para el tratamiento de tumor neuroendocrino gastrointestinal o de origen primario desconocido, metastásico o no resecable, sin tratamiento sistémico previo / Efficacy and safety of slow-release octreotide (octreotide LAR) compared to placebo for the treatment of metastatic or unresectable gastrointestinal neuroendocrine tumor of unknown primary origin without prior systemic therapy

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de octreotide de liberación lenta (Octreotide LAR, del inglés Octreotide long-acting release) comparado con placebo, para el tratamiento de tumores neuroendocrinos gastrointestinales o de origen primario desconocidos, metastásicos o no resecables, sin tratamiento sistémico previo. Los tumores neuroendocrinos (TNE) son neoplasias infrecuentes originadas en el sistema neuroendocrino. Tienen características tanto de células nerviosas como de células endocrinas que explican el cuadro clínico de síndrome carcinoide. Pueden aparecer en el tracto digestivo con mayor frecuencia en la quinta década de vida y se subdividen en dos categorías: TNE gastrointestinal y TNE pancreáticos. El tratamiento de los TNE puede focalizarse en el control de los síntomas producto del síndrome carcinoide o en el control del crecimiento y progresión tumoral que mejoren la sobrevida y calidad de vida de estos pacientes. Para el tratamiento de estos tumores (sin especificar si es para el control de síntomas o control del crecimiento y progresión tumoral), EsSalud cuenta con octreotide (análogo de somatostatina) 0.2 mg/ml, y octreotide acetato 20 mg de liberación lenta (en adelante octreotide LAR). No obstante, octreotide LAR no está incluido en el Petitorio Nacional Único de Medicamentos Esenciales (PNUME), a pesar de su amplio uso en pacientes con TNE. Ante ello, es necesario evaluar si el uso de octreotide LAR presenta beneficios clínicos en el control de síntomas carcinoides y/o control del crecimiento y progresión tumoral, así como evaluar el adecuado perfil de seguridad en pacientes que por sus características clínicas sean candidatos a recibirlas. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva y jerárquica de la literatura con respecto a la eficacia y seguridad del uso de octreotide LAR comparado con placebo en pacientes adultos con tumor neuroendocrino gastrointestinal o de origen primario desconocido, metastásico o no resecable, sin tratamiento sistémico previo. Asimismo, con el propósito de complementar la evidencia y describir la tecnología sanitaria de interés, se revisó en primer lugar la información de etiqueta disponible de entes reguladores y normativos de autorización comercial como la FDA y EMA, así como la DIGEMID en el Perú. Se empleó el motor de búsqueda para las bases de datos bibliográficas de PubMed, Cochrane Library, LILACS (Literatura Latinoamericana de Información en Ciencias de la Salud) y en el metabuscador de medicina basada en evidencia Turning Research Into Practice (TRIP). Se realizó adicionalmente, una búsqueda en la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y Google Advanced, y una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica como el National Institute for Health and Care Excellence (NICE), la Agency for Health Care Research and Quality (AHRQ), Guidelines International Network (GIN), Canadian Agency for Drugs and Technologies in Health (CADTH) de Canadá, Scottish Medicines Consortium (SMC), Scottish Intercollegiate Guidelines Network (SIGN), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Institute for Clinical and Economic Review (ICER) el Ministerio de Salud de Perú, y de sociedades o asociaciones especializadas en oncología: National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), American Cancer Society, European Society for Medical Oncology (ESMO), Association of Cancer Physicians, Association of European Cancer Leagues, Cancer Australia, Cancer Council Australia, Canadian Cancer Society, Health Canada, e Instituto Nacional de Enfermedades Neoplásicas (Perú). Por último, se buscaron ensayos clínicos en desarrollo o que no hayan sido publicados aún, en ClinicalTrials.gov (www.clinicaltrials.gov) y en el International Clinical Trials Registry Platform de la Organización Mundial de la Salud (http://apps.who.int/trialsearch/) que contengan estudios acerca de la tecnología evaluada y así disminuir el riesgo de sesgo de publicación (Jones et al. 2014). RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica, sin restricción temporal ni de idioma, relacionada al uso de octreotide LAR comparado con placebo en pacientes adultos con tumor neuroendocrino gastrointestinal o de origen primario desconocido, metastásico o no resecable, sin tratamiento sistémico previo. En la presente sinopsis se presenta la evidencia disponible según el tipo de publicación priorizada en los criterios de inclusión: CONCLUSIONES: En el presente documento se evaluó la evidencia científica publicada hasta febrero 2019 en relación al uso de octreotide LAR comparado con placebo en pacientes adultos con tumor neuroendocrino gastrointestinal o de origen primario desconocido, bien diferenciado, metastásico o no resecable, sin tratamiento sistémico previo. A la fecha, la evidencia acerca del uso de octreotide LAR para la población de la pregunta PICO de interés del presente dictamen, recaen sobre un ECA fase III (PROMID). El estudio PROMID publicado por Rinke et al. (2009 y 2017), es un ensayo clínico de fase III aleatorizado, doble ciego, controlado con placebo, multicéntrico, financiado por Novartis, en el cual se evaluó la eficacia y seguridad de octreotide LAR en pacientes con TNE del intestino medio o de origen desconocido. Se evaluó como desenlace primario al tiempo hasta la progresión tumoral y como desenlaces secundarios a la sobrevida global, la calidad de vida, la reducción de los síntomas carcinoides, y los eventos adversos. Los resultados de eficacia no mostraron diferencias estadísticamente significativas en la sobrevida global entre octreotide LAR y placebo al término del estudio ni en los promedios de las puntuaciones del cuestionario QLQ-C30 ni en la respuesta sintomática de reducción del rubor, reducción de deposiciones, y dolor abdominal. El principal resultado de octreotide LAR se basa en el efecto encontrado en la TTP, sin embargo, el valor clínico de este desenlace es cuestionable debido a su baja correlación con desenlaces de relevancia clínica como la SG o calidad de vida. Finalmente, no se encontraron diferencias en la frecuencia de eventos adversos entre octreotide LAR y placebo. De este modo, octreotide LAR en TNE intestinal o de origen primario desconocido, bien diferenciado, metastásico o no resecable, sin tratamiento sistémico previo, no ha demostrado tener un beneficio positivo en la sobrevida global o en la calidad de vida comparado con placebo, ni en desenlaces de interés para la pregunta PICO del presente dictamen como el control de síntomas neuroendocrinos. Octretida LAR solo ha mostrado tener efectos en desenlaces de cuestionable relevancia clínica como el tiempo hasta la progresión tumoral, para el cual la evidencia disponible actualmente no ha mostrado una asociación predictiva con una mejor sobrevida global o calidad de vida. En consecuencia, la evidencia proveniente del estudio PROMID no permite identificar un beneficio neto de octreotide LAR, frente al placebo, en nuestra población y desenlaces de interés. Así, en la actualidad, con la evidencia disponible, no se disponen de los argumentos técnicos que respalden una recomendación favorable para el uso de octreotide LAR en la población de la pregunta PICO de interés el presente dictamen. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI no recomienda el uso de octreotide LAR en pacientes adultos con TNE intestinal o de origen primario desconocido, metastásico o no resecable, sin tratamiento sistémico previo.

Successful management of anemia with sirolimus in blue rubber bleb nevus syndrome: case report and update.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder with characteristic skin hemangiomas and vascular malformations, mostly in the gastrointestinal (GI) tract. The GI lesions are mainly located in the stomach and small intestine, usually more than a hundred, leading to gastrointestinal bleeding and severe chronic anemia. Parenteral iron infusions and scheduled transfusions are frequently necessary. We describe the case of a 21-year-old male with anemia secondary to BRBNS, who becomes unresponsive to octreotide and shows an excellent response to sirolimus (SRL), dismissing the intravenous iron supplementations and being free of transfusions. During the treatment, the patient presents avascular hip necrosis, which is adequately treated with an injection of stem cells with complete recovery, and without the suspension of SRL. Two years later, adequate response persists with no other relevant side effects.

Successful Management of a Child With Drug-induced Necrotizing Pancreatitis During Acute Lymphoblastic Leukemia Therapy: A Case Report.

Acute pancreatitis in children acute lymphoblastic leukemia is commonly caused by drugs, for example, L-Asparaginase, pegapargase, steroids. The incidence of this complication is estimated at 6.7% to 18%. Although the majority of drug-induced acute pancreatitis cases are mild, severe cases can rarely occur. This work presents a case of successful management of a child with drug-induced necrotizing pancreatitis during acute lymphoblastic leukemia therapy. This case illustrates that comprehensive care and immediate intensive treatment can rescue patient despite poor prognosis. Administration of octreotide may serve a role in limiting the severity of the disease.