Aptamers and Antisense Oligonucleotides for Diagnosis and Treatment of Hematological Diseases.

Aptamers or chemical antibodies are single-stranded DNA or RNA oligonucleotides that bind proteins and small molecules with high affinity and specificity by recognizing tertiary or quaternary structures as antibodies. Aptamers can be easily produced in vitro through a process known as systemic evolution of ligands by exponential enrichment (SELEX) or a cell-based SELEX procedure. Aptamers and modified aptamers, such as slow, off-rate, modified aptamers (SOMAmers), can bind to target molecules with less polar and more hydrophobic interactions showing slower dissociation rates, higher stability, and resistance to nuclease degradation. Aptamers and SOMAmers are largely employed for multiplex high-throughput proteomics analysis with high reproducibility and reliability, for tumor cell detection by flow cytometry or microscopy for research and clinical purposes. In addition, aptamers are increasingly used for novel drug delivery systems specifically targeting tumor cells, and as new anticancer molecules. In this review, we summarize current preclinical and clinical applications of aptamers in malignant and non-malignant hematological diseases.

Arginine, glutamine, and fish oil supplementation in cancer patients treated with concurrent chemoradiotherapy: A randomized control study.

We evaluated the effectiveness of arginine, glutamine, and fish oil supplementation in patients' ability to adhere to the planned regimen and associated toxicities in patients who received concurrent chemoradiotherapy (CCRT). Eighty-eight cancer patients were randomized into 2 groups, A; regular diet and B; regular diet plus nutritional supplementation during their CCRT course. Logistic regression was used to assess the association between toxicity and the study groups. Survival analysis was performed using the Kaplan-Meier method, and log-rank tests were used to compare between the 2 groups. Among 88 patients, 45%, 32%, and 23% were head and neck cancer, esophageal cancer, and cervical cancer patients, respectively. Significantly higher grade 3-4 hematologic toxicities were found in group A than in group B (23% vs 5%, P= 0.03). The CCRT completion rate was lower in group A than in group B (75% vs 91%), but the difference was not statistically significant (P= 0.09). Adjusted for type of cancer and age, group B patients were associated with lower hematologic toxicities of CCRT, P= 0.03. Two-year overall survival was 47% for group A, and 61% for group B, P= 0.22. In conclusion, incidence of severe hematologic toxicities were significantly lower in patients with arginine, glutamine, and fish oil supplementation during CCRT. These findings, therefore, need further studies on the isocaloric design.

Is there truly an increase in risk of cardiovascular and hematological adverse events with vascular endothelial growth factor receptor tyrosine kinase inhibitors?

Objectives: Recent studies have shown an increase risk of cardiovascular and hematological adverse events associated with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs). The authors hypothesize that the original studies may have produced exaggerated results because of the small baseline risks involved.Methods: A meta-analysis that included 71 trials, 8 different VEGFR-TKIs, and 11 adverse events were re-analyzed. The outcome of interest was re-defined as the complementary outcome (i.e. remaining free of an adverse event). The inverse variance heterogeneity model was used to pool the effect size.Results: VEGFR-TKIs decreased the risk of remaining free of hypertension by 7% (RR 0.93; 95%CI:0.88-0.97). Specific VEGFR-TKIs; pazopanib, regorafenib, and nintedanib were associated with a decrease risk of remaining free of an arterial thrombotic event (RR 0.96; 95%CI:0.93-0.99), thrombocytopenia (RR 0.91; 95%CI:0.89-0.93), and bleeding (RR 0.96; 95%CI:0.93-0.99) respectively. VEGFR-TKIs were not associated with the thrombotic event, myocardial infarction, stroke, venous thrombotic event, pulmonary embolism, left ventricular dysfunction, or QTc interval prolongation.Conclusion: VEGFR-TKIs are associated with a small increase in the risk of patients developing hypertension, arterial thrombotic events, thrombocytopenia, and bleeding. Previous studies overestimated the actual risk associated with VEGFR-TKIs by analyzing the outcome with the lower baseline risk.

Hematological toxicities associated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been found to prolong survival in selected patients with peritoneal disease, but the extent of cytoreduction and chemoperfusion can result in systemic toxicities. We evaluate the incidence of perioperative hematological complications and its associated risk factors. METHODS: Retrospective analysis of a prospectively collected database of CRS-HIPEC cases between April 2001 and October 2016 was performed. Patients were stratified based on the clinicopathological characteristics, perioperative incidence, grade, and duration of leukopenia (white blood cells < 4000/mm3 ), neutropenia (absolute neutrophils < 2000/mm3 ), and thrombocytopenia (platelets < 140 000/mm3 ). RESULTS: Two hundred and thirty-five CRS-HIPEC were performed in 220 patients with peritoneal metastasis of colorectal, ovarian, primary peritoneal, appendiceal, or mesothelioma origins. The incidences of leukopenia, neutropenia, and thrombocytopenia were 15.3%, 3.8%, and 37.9%, respectively. Median time to onset was 1 day (0-16 days), 0 day (0-2 days), and 1 day (1-2 days), respectively, after operation. Median duration of leukopenia, neutropenia, and thrombocytopenia was 1 day (1-3 days), 1 day (1-2days), and 3 days (range 0-16 days), respectively. Age > 60 (odds ratio [OR] 0.229 [95% CI: 0.105-0.502], P < .001) and the use of prior chemotherapy (OR 2.46 [95% CI: 1.24, 4.83], P = .010) were independent risk factors for thrombocytopenia on multivariable logistic regression. CONCLUSION: Hematological toxicities are common after hyperthermic intraperitoneal chemotherapy with thrombocytopenia being most common. Patients with age > 60, and who have undergone chemotherapy, are at risk of these toxicities and should be closely monitored post CRS-HIPEC.

Hematologic Manifestations of Nutritional Deficiencies: Early Recognition is Essential to Prevent Serious Complications.

Nutritional deficiencies, including deficiencies of vitamin B12, copper, and vitamin C, may result in cytopenias and hematologic symptoms. Early recognition of these deficiencies is imperative for prompt treatment and improvement in hematologic and other manifestations. We describe 5 cases which illustrate the hematologic manifestations of nutritional deficiencies and challenges to initial diagnosis and management. Supplementation of the deficient vitamin or micronutrient in all of these cases resulted in rapid resolution of cytopenias, hemorrhage, and other associated hematologic symptoms. We also review other nutritional deficiencies that manifest with hematologic symptoms and compile recommendations on treatment and expected time to response.

Splenectomy may have more complications than currently proven.

The spleen has been one of the least understood major organs for centuries. Its significance is relatively well-known today but it seems that all aspects of its activities are not fully understood. Persian medicine (PM) has special views on the function of spleen; many side effects were reported in PM due to spleen dysfunction. On the other hand nowadays splenectomy as a treatment strategy is recommended for some disorders and increasing risk of infections is considered as the most important long term side effect of that. In this study, we hypothesize that splenectomy may have more side effects than currently proven. According to PM, spleen is in close connection with liver, cardiovascular system, stomach, bone, brain and skin, and that is why any kind of spleen dysfunction leads to change in blood viscosity, appetite and bone strength, liver dysfunction, mood and skin disorders, cancer formation and fever. Considering this viewpoint it can be hypothesized such side effects may also occur after splenectomy. Proven complications of splenectomy include hypercoagulated state, cardiovascular events and infectious diseases but there is also some evidence about increased risk of cancer, skin disease like systemic lupus erythematosus, mood disorder such as depression, defective bone formation and impairment of immunity which can be considered as different levels of evidence to confirm the hypothesis. But for some others such as changes in appetite, there are no studies let alone convincing evidence. Future research about theses possible complications may lead to novel results.

Vitamin D in hematological disorders and malignancies.

Commonly known for its critical role in calcium homeostasis and bone mineralization, more recently vitamin D has been implicated in hematological cancer pathogenesis and shows promise as an anti-cancer therapy. Serum levels of 25(OH)D3 , the precursor to the active form of vitamin D, calcitriol, are frequently lower in patients with hematological disease compared to healthy individuals. This often correlates with worse disease outcome. Furthermore, diseased cells typically highly express the vitamin D receptor, which is required for many of the anti-cancer effects observed in multiple in vivo and in vitro cancer models. In abnormal hematological cells, vitamin D supplementation promotes apoptosis, induces differentiation, inhibits proliferation, sensitizes tumor cells to other anti-cancer therapies, and reduces the production of pro-inflammatory cytokines. Although the dosage of vitamin D required to achieve these effects may induce hypercalcemia in humans, analogs and combinatorial treatments have been developed to circumvent this side effect. Vitamin D and its analogs are well tolerated in clinical trials, and thus, further investigation into the use of these agents in the clinic is warranted. Here, we review the current literature in this field.

Dosimetric predictors of acute hematologic toxicity during concurrent intensity-modulated radiotherapy and chemotherapy for anal cancer.

PURPOSE: This study aimed at investigating whether the irradiated volume of pelvic bone marrow (PBM) and specific subsites may predict the occurrence of acute hematologic toxicity (HT) in anal cancer patients undergoing concurrent chemo-radiation. METHODS: 50 patients, submitted to IMRT and concurrent chemotherapy, were analyzed. Several bony structures were defined on planning-CT: PBM and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood-cell-count (WBC), absolute-neutrophil-count (ANC), hemoglobin (Hb) and platelet nadirs and acute hematologic toxicity (HT) according to RTOG scoring scale. Generalized linear modeling was used to find correlations between dosimetric variables and blood cell nadirs, while logistic regression analysis was used to test correlation with ≥G3 HT. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the optimal cut-off points for predictive dosimetric variables with the Youden method. RESULTS: Maximum detected acute HT comprised 38 % of ≥G3 leukopenia and 32 % of ≥G3 neutropenia. Grade 2 anemia was observed in 4 % of patients and ≥G3 thrombocytopenia in 10 %. On multivariate analysis a higher PBM-V 20 was associated with lower WBC nadir. Increased LSBM-V 40 was correlated with a higher likelihood to develop ≥G3 HT. A cut-off point at 41 % for LSBM-V 40 was found. Patients with LSBM-V 40 ≥41 % were more likely to develop ≥G3 HT (55.3 vs. 32.4 %; p < 0.01). CONCLUSIONS: Increased low-dose to pelvic bony structures significantly predicted for WBC decrease. Medium-high dose to specific osseous subsites was associated with a higher probability of HT. LSBM-V 40 was a strong predictor of ≥G3 HT. A threshold at 41 % for LSBM-V 40 could be used to limit HT.

Protective effects of paeoniflorin and albiflorin on chemotherapy-induced myelosuppression in mice.

Paeonia lactiflora root (baishao in Chinese) is a commonly used herb in traditional Chinese medicines (TCM). Two isomers, paeoniflorin (PF) and albiflorin (AF), are isolated from P. lactiflora. The present study aimed to investigate the protective effects of PF and AF on myelosuppression induced by chemotherapy in mice and to explore the underlying mechanisms. The mouse myelosuppression model was established by intraperitoneal (i.p.) injection of cyclophosphamide (CP, 200 mg·kg(-1)). The blood cell counts were performed. The thymus index and spleen index were also determined and bone morrow histological examination was performed. The levels of tumor necrosis factor-α (TNF-α) in serum and colony-stimulating factor (G-CSF) in plasma were measured by Enzyme-Linked Immunosorbent Assays (ELISA) and the serum levels of interleukin-3 (IL-3), granulocyte-macrophagecolony-stimulatingfactor (GM-CSF), and interleukin-6 (IL-6) were measured by radioimmunoassay (RIA). The levels of mRNA expression protein of IL-3, GM-CSF and G-CSF in spleen and bone marrow cells were determined respectively. PF and AF significantly increased the white blood cell (WBC) counts and reversed the atrophy of thymus. They also increased the serum levels of GM-CSF and IL-3 and the plasma level of G-CSF and reduced the level of TNF-α in serum. PF enhanced the mRNA level of IL-3 and AF enhanced the mRNA levels of GM-CSF and G-CSF in the spleen. PF and AF both increased the protein levels of GM-CSF and G-CSF in bone marrow cells. In conclusion, our results demonstrated that PF and AF promoted the recovery of bone marrow hemopoietic function in the mouse myelosuppression model.

Hematological Practice in Hong Kong and China.

Thalassemias and hemophilias are the most important inherited hematological diseases in Hong Kong and China. Prenatal diagnosis has significantly decreased the burden of these diseases. For thalassemia major, adequate transfusion and iron chelation therapy have dramatically improved patient outlook. Hematopoietic stem cell transplantation is curative for thalassemia major and is increasingly adopted. The efficacy of arsenic trioxide in acute promyelocytic leukemia (APL) was discovered in China. An oral formulation of arsenic trioxide was developed in Hong Kong for newly diagnosed and relapsed APL patients. With combination chemotherapy containing non-P-glycoprotein-dependent drugs and L-asparaginase, durable remission can be achieved in the most patients.

Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Inflammatory Rheumatic Diseases.

OBJECTIVE: Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. METHODS: We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. RESULTS: Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively). CONCLUSIONS: Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.

Copper Deficiency after Gastric Bypass for Morbid Obesity: a Systematic Review.

A large number of patients undergoing bariatric surgery are deficient in copper, and Roux-en-Y gastric bypass can further aggravate it. Delays in diagnosis and treatment of copper deficiency can leave patients with residual neurological disability. This has led to recommendation from the British Obesity and Metabolic Surgery Society that copper levels should be monitored annually after gastric bypass. This review concludes that copper deficiency in adequately supplemented patients is rare and can be adequately treated if a related haematological or neurological disorder is diagnosed. The cost of routine monitoring may therefore not be justified for adequately supplemented, asymptomatic patients who have undergone Roux-en-Y gastric bypass. The screening may however be necessary for high-risk patient groups to prevent severe complications and permanent disability.

Hematopoietic effects and mechanisms of Fufang e׳jiao jiang on radiotherapy and chemotherapy-induced myelosuppressed mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang e׳jiao jiang (FEJ), which has been widely used in clinic to replenish qi (vital energy) and nourish blood, is a famous traditional Chinese medicine formula made up of Colla corii asini (donkey-hide gelatin prepared by stewing and concentrating from the hide of Equus asinus Linnaeus.), Radix codonopsis pilosulae (the root of Codonopsis pilosula (Franch.) Nannf.), Radix ginseng rubra (the steamed and dried root of Panax ginseng C.A. Mey.), Fructus crataegi (the fruit of Crataegus pinnatifida Bunge) and Radix rehmanniae preparata (the steamed and sun dried tuber of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & C.A. Mey.). The present study aimed to investigate the hematopoietic effects of FEJ on myelosuppressed mice induced by radiotherapy and chemotherapy systematically and to explore the underlying hematopoietic regulation mechanisms. METHODS: The myelosuppressed mouse model was induced by (60)Co radiation, cyclophosphamide and chloramphenicol. FEJ was then administered by i.g. at the dosages of 5, 10, or 20 mL/kg·d for 10d. The numbers of blood cells from peripheral blood and bone marrow nucleated cells (BMNC) were counted. Body weight and the thymus and spleen indices were also measured. The numbers of hemopoietic progenitor cells and colony-forming unit-fibroblast (CFU-F) were measured in vitro. The ratio of hematopoietic stem cells (HSC) in BMNC, cell cycle and apoptosis of BMNC were determined by flow cytometry. The histology of femoral bone was examined by H&E staining. The levels of transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α), erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-6 (IL-6) in serum were measured by ELISA. IL-1ß, IL-3, IL-6 mRNA levels in spleen were detected by real-time quantitative PCR (RT-qPCR). In addition, bone marrow stromal cells (BMSC) were cultured in vitro followed by treatment with different doses of FEJ (2.5, 5, 10 µL/mL) for 48 h. Then the levels of cytokines (IL-6, SCF, GM-CSF) in the conditioned media and their mRNA levels in BMSC were determined by ELISA and RT-qPCR, respectively. RESULTS: FEJ could significantly increase the numbers of peripheral blood cells and BMNC, and reverse the loss of body weight and the atrophy of thymus and spleen in a dose-dependent manner. The quantities of hemopoietic progenitor cells and CFU-F in bone marrow were also significantly increased in a dose-dependent manner after FEJ administration. A high-dose FEJ of 20 mL/kg·d could significantly increase the ratio of HSC in BMNC, promote bone marrow cells entering the proliferative cycle phase (S+G2/M) and prevent cells from proceeding to the apoptotic phase. FEJ could also improve the femoral bone marrow morphology. Furthermore, FEJ could increase the levels of GM-CSF and IL-3 and reduce the level of TGF-ß in serum, and enhance the expressions of IL-1ß and IL-3 mRNA in spleen. Lastly, the levels of cytokines (IL-6, SCF, GM-CSF) in the conditioned media and their mRNA levels in BMSC were elevated after treatment with FEJ. CONCLUSIONS: FEJ was clearly confirmed to promote the recovery of bone marrow hemopoietic function in a myelosuppressed mouse model, which may be attributed to (i) improving bone marrow hematopoietic microenvironment; (ii) facilitating the cell proliferation and preventing BMNC from apoptosis; (iii) stimulating the expressions of IL-1ß, IL-3, IL-6, SCF and GM-CSF and inhibiting the expression of TGF-ß.

Hematological disorders following gastric bypass surgery: emerging concepts of the interplay between nutritional deficiency and inflammation.

Obesity and the associated metabolic syndrome are among the most common and detrimental metabolic diseases of the modern era, affecting over 50% of the adult population in the United States. Surgeries designed to promote weight loss, known as bariatric surgery, typically involve a gastric bypass procedure and have shown high success rates for treating morbid obesity. However, following gastric bypass surgery, many patients develop chronic anemia, most commonly due to iron deficiency. Deficiencies of vitamins B1, B12, folate, A, K, D, and E and copper have also been reported after surgery. Copper deficiency can cause hematological abnormalities with or without neurological complications. Despite oral supplementation and normal serum concentrations of iron, copper, folate, and vitamin B12, some patients present with persistent anemia after surgery. The evaluation of hematologic disorders after gastric bypass surgery must take into account issues unique to the postsurgery setting that influence the development of anemia and other cytopenias. In this paper, the clinical characteristics and differential diagnosis of the hematological disorders associated with gastric bypass surgery are reviewed, and the underlying molecular mechanisms are discussed.

Safety and efficacy of modified FOLFOX6 plus high-dose bevacizumab in second-line or later treatment of patients with metastatic colorectal cancer.

AIM: The aim of this retrospective study was to show the efficacy and safety of modified FOLFOX6 plus high-dose bevacizumab (10 mg/kg/2 weeks) in the second-line or later treatment of metastatic colorectal cancer. METHODS: A total of 24 consecutive patients treated between August 2007 and August 2009 were included in this retrospective study. None of the patients had received bevacizumab as part of prior treatment. RESULTS: All 24 patients received modified FOLFOX6 plus high-dose bevacizumab and were followed for a median of 36.9 months. Overall response rate was 29%. Median progression-free survival was 7.5 months, and median overall survival was 17.3 months. Grade 3/4 adverse events were: neutropenia (54.2%), leukopenia (25.0%), neuropathy (12.5%), hypertension (12.5%), thrombocytopenia (8.3%), and decreased haemoglobin, gastrointestinal haemorrhage, wound complications, nausea, diarrhoea, mucositis and fatigue (each 4.2%). CONCLUSION: Modified FOLFOX6 plus high-dose bevacizumab may be useful in the second-line treatment of patients with metastatic colorectal cancer who have not received bevacizumab.

Garlic oil suppressed the hematological disorders induced by chemotherapy and radiotherapy in tumor-bearing mice.

Although the anticancer effects of garlic and its products have been demonstrated by a variety of studies; however, few studies were conducted to investigate the effects of garlic on the adverse effects of chemo/radiotherapy. In order to clarify the above question and make a more comprehensive understanding of the anticancer effects of garlic, tumor xenograft mice model was established by subcutaneous injection of H22 tumor cells, and was used for the investigation of effects of garlic oil (GO) on the chemo/radiotherapy. In the chemotherapy test, tumor-bearing mice were treated with cyclophosphamide (CTX) or CTX plus GO (25 or 50 mg/kg bw) for 14 d, while the mice received a single 5 Gy total body radiation or radiation plus GO (25 or 50 mg/kg bw) in radiotherapy test. The results showed that GO did not increase the tumor inhibitory rate of CTX/radiation, which indicated that GO could not enhance the chemo/radiosensitivity of cancer cells. However, the decrease of the peripheral total white blood cells (WBCs) count induced by CTX/radiation was significantly suppressed by GO cotreatment. Furthermore, GO cotreatment significantly inhibited the decrease of the DNA contents and the micronuclei ratio of the bone marrow. Lastly, the reduction of the endogenous spleen colonies induced by CTX/radiation was significantly suppressed by GO cotreatment. These findings support the idea that GO consumption may benefit for the cancer patients receiving chemotherapy or radiotherapy.

Complications and toxicities after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: The purpose of our study was to evaluate the perioperative complications, toxicity, mortality rates after cytoreductive surgery (CRS), and effects of hyperthermic intraperitoneal chemotherapy (HIPEC) used in the treatment of peritoneal surface malignancies. METHODS: Between September 2007 and March 2012, we performed 118 CRS and HIPEC with the closed abdominal technique on 115 patients with peritoneal carcinomatosis (PC). Systemic toxicities were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria and were analyzed from a prospectively collected database. RESULTS: The mean age of patients was 53.4 (range, 20-82) years; 76.3 % were female. PC was synchronous to primary cancer in 53.4 % of patients, metachronous in 41.5 %, and recurrent in 5.1 % of the patients. PCI was ≥15 in 53.4 % of the patients, and CC-0 cytoreduction was achieved in 68.5 % of the patients. Perioperative mortality was observed in 9 (7.6 %) patients. A total of 98 complications were observed in 46 (39.0 %) patients, and 4 patients underwent 6 reoperations for perioperative surgical complications. We observed toxicity in 25.4 % of the patients, nephrotoxicity in 18.6 %, and hematological toxicity in 13.6 % of patients. No significant difference was observed among age, gender, PCI and CC scores, origin of the primary tumor, and occurrence of toxicity and surgical complications. Prolonged operation times resulted in higher complication and/or toxicity rates (P < 0.01). CONCLUSIONS: Cytoreductive surgery and HIPEC is a combined treatment strategy for peritoneal surface malignancies with acceptable complication and toxicity rates.

Studies on silver nanoparticle-glycyrrhizic acid complex as a radioprotector and an adjuvant in radiotherapy under in vivo conditions.

Silver nanoparticles (SN) of particle size of less than 50 nm were dispersed in an aqueous solution of Pluronic F127 and complexed with the phytoceutical, glyzyrrhizic acid (GLY). Radioprotecting ability of the obtained nanoparticle-glyzyrrhizic acid complex (SN-GLY) was evaluated in an in vivo model using Swiss albino mice. The potential of the complex as an adjuvant during radiotherapy was also analyzed in tumor-bearing mice. The administration of SN-GLY, SN, and GLY protected the hemopoetic and gastrointestinal system against radiation-induced damages as revealed by the total white blood cell count, bone marrow cellularity, endogenous spleen colony formation, levels of cellular antioxidants, and histopathologcal examination of gastrointestinal tract. Oral administration of SN-GLY, SN, and GLY 1 hour before a sublethal dose of radiation exposure reduced the radiation-induced depletion of cellular antioxidants and lipid peroxidation in various tissues of mice. Survival of animals following exposure to a lethal dose of gamma radiation was also improved. It was also found that the oral administration of the complex to tumor-bearing mice before 4 Gy gamma irradiation resulted in a faster tumor regression.

Toxicity of hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric patients with sarcomatosis/carcinomatosis: early experience and phase 1 results.

BACKGROUND: Intra-abdominal metastasis is a rare form of tumor dissemination in children. Complete surgical resection is usually deemed impossible. Children are frequently offered palliative care only. We adopted an aggressive approach for these cases which includes removal of dozens to hundreds of tumor nodules followed by perfusion of the abdominal cavity with hyperthermic chemotherapy (HIPEC) with a curative intent. METHODS: We evaluated toxicity in 23 children and young adults undergoing 27 HIPEC procedures using cisplatin. Disease diagnoses included rhabdomyosarcoma (RMS), non-RMS soft tissue sarcoma, (NRSTS), desmoplastic small round cell tumor, (DSRCT), mesothelioma, Wilms tumor, melanomatosis, and adenocarcinoma. Patients underwent cytoreductive surgery followed by cisplatin at 40.5-41 °C, for 90 minutes. A subset of these patients was enrolled on our phase 1 study and as part of dose escalation cohort received 150 mg/m(2) of cisplatin. All toxicities were recorded. RESULTS: Maximum tolerated dose was 100 mg/m(2). Dose limiting toxicity was grade 3 renal failure. In five of 27, 18% had grade 3 or higher renal failure. One patient developed a subclinical decrease in hearing and there were 2 grade 3 hematologic toxicities, 2 grade 3 hepatic toxicities, and one grade 3 ileus. One patient suffered grade3 cardiotoxicity. There were no operative/perioperative mortalities. Surgical complications occurred in 5/27 (18%) of patients. With a follow-up of 6-60 months, seven patients (26%) had no recurrence. CONCLUSIONS: HIPEC is reasonably tolerated in pediatric patients with extensive abdominal metastasis. More study is needed to determine for which histologies HIPEC is most efficacious.