Extended Treatment With Recombinant Human Parathyroid Hormone (1-84) in Adult Patients With Chronic Hypoparathyroidism.

OBJECTIVE: Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is efficacious in patients with hypoparathyroidism but additional data supporting its prolonged use are needed. We evaluated whether efficacy, safety, and tolerability are maintained during long-term rhPTH(1-84) treatment of patients with chronic hypoparathyroidism. METHODS: This was a phase 4, single-center, open-label, single-arm, 3-year extension (NCT02910466) of the phase 3 Hypo Extended (HEXT) study (NCT01199614). Patients self-administered rhPTH(1-84) once daily by subcutaneous injection, with doses individualized based on clinical parameters. Albumin-adjusted serum calcium levels (primary outcome measure), other disease biomarkers, health-related quality of life, and safety of rhPTH(1-84) were assessed using descriptive statistics. RESULTS: All patients (n = 39) had been exposed to rhPTH(1-84) (mean exposure [SD] 8.5 [3.5] years) before the start of the study, resulting in a mean exposure of 10.8 years including the present study. Mean patient age was 51.9 years, 79.5% were female, and 97.4% were White. Mean albumin-adjusted serum calcium concentrations were within the target range, and mean serum phosphate, serum calcium-phosphate product, and 24-hour urinary calcium excretion levels were within reference ranges at end of treatment. Mean doses of supplemental calcium and active vitamin D were maintained throughout the study. Bone turnover marker levels were maintained from baseline to end of treatment. No clinically relevant changes in bone mineral density were observed. Patient-reported health-related quality-of-life scores were generally maintained throughout the study. Four adverse events were considered treatment related and no new safety signals were identified. CONCLUSION: The effects of rhPTH(1-84) on biochemical, skeletal, and health-related quality-of-life parameters did not wane with extended use.

Hyperchloremic metabolic acidosis after plasma exchange in a patient with renal transplant rejection: A case report.

Therapeutic plasma exchange (TPE) is an effective treatment for several renal disorders, including renal transplant rejection. However, repeated plasma exchanges can result in various metabolic disturbances and complications. We present a 61-year old male with a medical history of type 2 diabetes, hypertension, successfully treated multiple myeloma, and a post-mortem kidney transplantation 7 months prior to presentation. The patient was hospitalized with an antibody-mediated transplant rejection for which treatment with methylprednisolone, TPE with a 40 g/L albumin solution as a replacement fluid, and intravenous immunoglobulins was initiated. After four TPE treatments, the patient developed gastrointestinal complaints and muscle weakness. Despite daily oral bicarbonate supplementation, laboratory tests revealed a hyperchloremic metabolic acidosis: bicarbonate 11.7 mmol/L, chloride 111 mmol/L, and sodium 138 mmol/L. Metabolic acidosis due to citrate accumulation was ruled out with a normal total-to-ionized calcium ratio. After treatment with intravenous bicarbonate supplementation, the symptoms disappeared. Analysis of the albumin solution showed a chloride concentration of 132 mmol/L. This is the first case that describes severe metabolic acidosis after multiple sessions of TPE with an albumin solution in a patient with impaired renal function. The hyperchloremic metabolic acidosis is the result of administration of large volumes of an albumin solution with high chloride concentrations. Special attention should be paid to the acid-base balance during TPE in patients with impaired renal function. Future research should investigate the incidence of hyperchloremic metabolic acidosis during TPE in patients with impaired renal function.

Drug Interactions Causing Warfarin Overdose in a Patient with Pancreatic Cancer: A Case Report.

Mistletoe, Viscum album, is a medicinal plant used in complementary medicine in oncology. Patients do not necessarily mention to their oncologist this phytotherapeutic treatment which may be responsible for unsuspected drug interactions. Some patients are adept at taking medicinal plants, a practice often unknown to health professionals who take care of them. This case reports drug interactions leading to bleeding secondary to warfarin overdose. A patient over 75 years of age was treated with nab-paclitaxel and gemcitabine as a first course for metastatic pancreatic adenocarcinoma (day 0). He was also treated with warfarin for atrial fibrillation. At day 3, he reported faintness and melena. At day 5, the biological assessment revealed anemia with hemoglobinemia of 5.1 g/dL and an international normalized ratio of 7.3, indicating vitamin K antagonist (VKA) overdose. Warfarin was discontinued and the patient received vitamin K supplementation and transfusions. The final diagnosis was an anemic syndrome due to gastrointestinal bleeding secondary to VKA overdose. Based on the chronology, a drug interaction between chemotherapy and warfarin was first suspected. Then, the patient interview found out that he self-medicated with subcutaneous injections of mistletoe extracts: 10 mg on day 0 and on day 2. Nab-paclitaxel can displace warfarin from its albumin binding sites and increase the free and active concentration of warfarin. Mistletoe extracts (V. album) are used as complementary medicine in oncology. Warfarin is predominantly metabolized in the liver by 1A2, 2C9, and 3A4 cytochrome P450 (CYP) isoforms. An inhibitor of these cytochromes prevents the degradation of warfarin into inactive metabolites, leading to accumulation or even overdose of this narrow therapeutic index VKA. Nab-paclitaxel and gemcitabine do not act on these cytochromes. V. album is a cytochrome P450 3A4 inhibitor which therefore probably led to an increase in exposure to warfarin. Thus, there are two pharmacokinetic hypotheses that may explain warfarin overdose: the displacement of warfarin from its albumin binding sites or the inhibition of CYP3A4 by mistletoe. This adverse drug event was reported to the Regional Pharmacovigilance Center of Strasbourg on June 30, 2021, and registered under the number ST20212767.

Systematic Review of the Efficacy and Safety of Traditional Chinese Medicine Granules Associated with Hormone When Treating Primary Nephrotic Syndrome in Children.

Objective: To systematically evaluate the efficacy and safety of traditional Chinese medicine (TCM) granules associated with hormones when treating primary nephrotic syndrome (PNS) in children. Methods: Search online databases such as PubMed, EMBASE, ScienceDirect, Cochrane Library, China Knowledge Network Database (CNKI), China VIP Database, Wanfang Database, and China Biomedical Literature Database (CBM) to search for information on the use of hormone-related Chinese medicine granules in the treatment of children with PNS controlled trials. Retrieval time was limited to the period from the date the database was established to the present. Separately, two researchers gathered the data. Statistical software RevMan5.4 was adopted to estimate bias risk in accordance with the Cochrane Handbook 5.3 standard. Results: Finally, 7 articles were selected with a total sample size of 487 cases. The infection rate, recurrence rate, and adverse reaction rate after treatment were analyzed by meta-analysis. The infection rate and recurrence rate in the study group were notably lower, and the difference was statistically significant (P < 0.05). However, the incidence of adverse reactions exhibited not notably different (P > 0.05). The levels of albumin and blood cholesterol after treatment indicated no statistical difference between the levels (P > 0.05). Meta-analysis was performed on the time to negative urine protein and the time to edema subsidence after treatment. The urine protein negative time and edema subsidence time of the study group were shorter after treatment, but the difference exhibited not notable (P > 0.05). Meta-analysis was performed on the dosage of glucocorticoids after treatment. The dosage of glucocorticoid in the study group was notably lower, and the difference was statistically significant (P < 0.05). The levels of T lymphocytes after treatment were analyzed by meta. T lymphoid level in the study group was notably better after treatment, and the difference was statistically significant (P < 0.05). Further subgroup analysis indicated that the levels of CD3+ and CD4+ in the study group were higher after treatment (P < 0.05), and there exhibited no statistical difference in the levels of CD8+, CD4/CD8+, and CD19 (P > 0.05). Immunoglobulin levels in the study group after treatment were notably better, and the difference was statistically significant (P < 0.05). Further subgroup analysis indicated that the levels of IgA, IgM, and IgG in the study group were notably higher after treatment, and the difference was statistically significant (P < 0.05). Conclusion: Huai Qi Huang can reduce the recurrence rate of PNS children and the incidence of infection and the dosage of prednisone. A long-term application can improve the cellular and humoral immune function of children with PNS. It has high treatment safety and has no notable effect on plasma cholesterol levels, so it is suitable for clinical application.

Efficacy of Yishen Huashi Granules Combined with Linagliptin Tablets on Blood Glucose and Renal Function in Patients with Type 2 Diabetic Nephropathy.

Objective: To probe into the efficacy of Yishen Huashi granules combined with linagliptin tablets in the treatment of type 2 diabetic nephropathy (DN) and its effect on blood glucose and renal function in patients. Methods: 70 patients with type 2 DN at our hospital between May 2020 and May 2022 were chosen as the research objects and separated into the control group and the research group based on their treatments. With 35 cases in each group, the patients treated with initial therapy and linagliptin tablets were enrolled in the control group, and those who received the above treatments and also Yishen Huashi granules were included in the research group. Their clinical indexes such as blood glucose and renal function were compared with both groups after treatment. Results: After treatment, the research group had remarkably lower fasting blood glucose (FPG), 2 h-postprandial blood glucose (2 h-PBG), and glycosylated hemoglobin A1c (HbA1c) levels than those in the control group (P < 0.05). After treatment, the research group had remarkably lower levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) (P < 0.05) and higher high-density lipoprotein (HDL) levels (P < 0.05) than those in the control group. After treatment, the urinary microalbumin (u-mALB) level was remarkably lower in both groups (P < 0.05) and was distinctly lower in the research group than in the control group (P < 0.05). After treatment, the research group had remarkably lower renal function indexes such as serum creatinine (SCr), blood urea nitrogen (BUN), urinary protein (UPro), and urinary albumin excretion rate (UAER) (P < 0.05) and a higher estimated glomerular filtration rate (eGFR) level (P < 0.05) than those in the control group. The efficacy was evaluated by the traditional Chinese medicine (TCM) syndrome score after treatment. There were no patients in complete remission between both the groups, where slight differences were found in the proportion of significant remission (P > 0.05), with the total effective rate of the research group remarkably higher than that of the control group (P < 0.05). Conclusion: The combination of Yishen Huashi granules and linagliptin tablets can reduce the blood glucose and blood lipid levels in patients with type 2 DN and lower UPro and protect renal function at the same time, which provides a new idea and a method for clinical treatment of type 2 DN with integrated traditional Chinese and Western medicine.

Management of elderly patients with unresectable pancreatic cancer.

Systemic chemotherapy plays important role in pancreatic cancer not only for palliative treatment of unresectable disease, but also for neoadjuvant and adjuvant treatment of resectable disease. Most clinical trials of systemic chemotherapy have been conducted in non-elderly patients, and the results cannot always be extrapolated to elderly patients because of the uniqueness of this population. The number of elderly patients with pancreatic cancer has increased in an aging society; therefore, there is an urgent need to develop specific treatments for elderly patients with pancreatic cancer. Gemcitabine or S-1 monotherapy is generally considered appropriate even for vulnerable elderly patients. FOLFIRINOX is considered inapplicable based on its safety profile. Gemcitabine plus nab-paclitaxel and nanoliposomal irinotecan with fluorouracil plus folinic acid can be administered to elderly patients, because the phase III trials have shown the efficacy and safety for patients including those who were 75 years or older. However, the feasibility of these therapies for elderly patients is still under debate since the number of elderly populations was relatively small in these studies. To determine the indication for these regimens in the elderly, the background of each patient should be considered. Geriatric assessment such as the Geriatric 8 and the Geriatric Nutritional Risk Index can identify vulnerabilities and are therefore recommended in daily clinical practice as well as in clinical studies of elderly patients. It is expected that geriatric assessment will elucidate the eligibility criteria for those regimens in elderly individuals. Randomized clinical trials are ongoing to establish a standard treatment in the vulnerable elderly with advanced pancreatic cancer, who cannot tolerate the same regimen as in the non-elderly patients.

Results of a Phase II Study on the Use of Neoadjuvant Chemotherapy (FOLFIRINOX or GEM/nab-PTX) for Borderline-resectable Pancreatic Cancer (NUPAT-01).

OBJECTIVE: Given the frequent adverse events with multidrug chemotherapy, not only the survival benefit but also the feasibility of using neoadjuvant chemotherapy to treat pancreatic cancer need to be clarified. SUMMARY OF BACKGROUND DATA: Although the development of multidrug chemotherapy regimens has improved the survival outcomes of patients with unresectable pancreatic cancer, the benefits of these treatments in the neo-adjuvant setting remain controversial. METHODS: Patients with borderline-resectable pancreatic cancer were enrolled and randomly assigned to receive neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GEM/nab-PTX). After the completion of chemotherapy, patients underwent surgical resection when feasible. This study (NUPAT-01) was a randomized phase II trial, and the primary endpoint was the R0 resection rate. RESULTS: Fifty-one patients were enrolled in this study [FOLFIRINOX (n = 26) and GEM/nab-PTX (n = 25)]. A total of 84.3% (n = 43/51) of the patients eventually underwent surgery, and R0 resection was achieved in 67.4% (n = 33/ 51) of the patients. Adverse events (grade >3) due to neoadjuvant treatment were observed in 45.1% of the patients (n = 23/51), and major surgical complications occurred in 30.0% (n = 13/43), with no mortality noted. The intention-to-treat analysis showed that the 3-year overall survival rate was 54.7%, with a median survival time of 39.4 months, and a significant difference in overall survival was not observed between the FOLFIRINOX and GEM/nab-PTX groups. CONCLUSIONS: These results indicate that neoadjuvant chemotherapy with FOLFIRINOX or GEM/nab-PTX is feasible and well tolerated, achieving an R0 resection rate of 67.4%. The survival of patients was even found to be favorable in the intention-to-treat analysis.

Therapeutic Effect and Safety of Tripterygium Glycosides Combined With Western Medicine on Type 2 Diabetic Kidney Disease: A Meta-Analysis.

PURPOSE: Tripterygium glycosides (TG) are widely used for the treatment of kidney disease in China. However, the application of TG in clinical practice is limited, as the therapeutic window is narrow, and the therapeutic dose is close to the toxic dose. In addition, the therapeutic effect of TG combined with Western medicine has not been fully elucidated. This study sought to explore standardized treatment, efficacy, and safety of TG combined with Western medicine for patients with type 2 diabetic kidney disease (T2DKD). METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature, Chinese Scientific Journal, and Wan Fang databases were searched for randomized controlled trials of TG combined with Western medicine on T2DKD from their inception until May 4, 2021. A random effects model was used to explore heterogeneity of studies. FINDINGS: A total of 33 studies with 2034 patients were included in the current meta-analysis. The findings showed that TG combined with Western medicine effectively reduced urinary albumin excretion rates (standardized mean difference, -2.55; 95% CI, -4.70 to -0.40; P = 0.02), 24-hour urinary protein level (mean difference, -0.79; 95% CI, -1.22 to -0.36; P = 0.0003), and serum creatinine level (mean difference, -8.23; 95% CI, -14.48 to -1.99; P = 0.01) and increased albumin level (mean difference, 4.70; 95% CI, 3.27 to 6.13; P < 0.00001) in patients with T2DKD. No serious adverse reactions occurred, and the incidence of adverse events in the TG combined with Western medicine treatment group was slightly higher than in the control group (8.14% vs 2.65%). The results were stable, and a significant publication bias was not detected (P > 0.05). IMPLICATIONS: Based on our results, TG combined with Western medicine may be an effective and safe therapy for T2DKD; the best treatment duration may be 3 to 6 months. Nevertheless, larger, longer multicenter studies should be conducted for clinical application of the regimen to patients in more countries and regions. PROSPERO registration number: CRD42021259466.

Effects of Alpha-lipoic Acid Supplementation on Human Diabetic Nephropathy: A Systematic Review and Meta-analysis.

BACKGROUND: Diabetic nephropathy (DN) is kidney dysfunction, which occurs due to elevated urine albumin excretion rate and reduced glomerular filtration rate. Studies on animals have shown that alpha-lipoic acid (ALA) supplementation can reduce the development of DN. OBJECTIVES: We performed a systematic review and meta-analysis to examine the effects of ALA supplementation on biological indices (albumin, creatinine, etc.) indicative of human DN. METHODS: The search procedure included PubMed Central, Embase, Cochrane Library (trials), and Web of Science (protocol registration: INPLASY202060095). RESULTS: We found that ALA supplementation decreased 24h urine albumin excretion rate in patients with diabetes (standardized mean difference=-2.27; confidence interval (CI)=(-4.09)-(-0.45); I2=98%; Z=2.44; p=0.01). A subgroup analysis revealed that the results of studies examining only ALA did not differ from those examined ALA in combination with additional medicines (Chisquared= 0.19; p=0.66; I2=0%), while neither ALA nor ALA plus medication had an effect on 24h urine albumin excretion rate (p>0.05). Also, ALA supplementation decreased urine albumin mg/l (mean difference (MD)=-12.95; CI=(-23.88)-(-2.02); I2=44%; Z=2.32; p=0.02) and urine albumin to creatinine ratio (MD=-26.96; CI=(-35.25)-(-18.67); I2=0%; Z=6.37; p<0.01) in patients with diabetes. When the studies examining ALA plus medication were excluded, it was found that ALA supplementation had no effect on urine albumin mg/l (p>0.05) but did significantly decrease urine albumin to creatinine ratio (MD=-25.88, CI=(34.40-(-17.36), I2=0%, Z=5.95, p<0.00001). CONCLUSION: The available evidence suggests that ALA supplementation does not improve biological indices that reflect DN in humans. Overall, we identified limited evidence, and therefore, the outcomes should be considered with caution.

Effects of Helichrysum Psudoplicatum supplementation on pruritus intensity, fatigue, quality of life and anorexia in hemodialysis patients: a randomized, double-blind placebo-controlled trial.

OBJECTIVES: Anorexia, fatigue and pruritus are common complications of hemodialysis (HD) patients. Today, the use of medicinal plants is more than synthetic drugs due to their safety. Therefore, we designed a randomized controlled clinical trial to evaluate the effects of Helichrysum psudoplicatum (H. psudoplicatum) supplementation on biochemical parameters, pruritus intensity, fatigue, quality of life and anorexia in HD patients. METHODS: This randomized, double-blind, placebo-controlled trial was performed on 50 subjects with, aged 55-65 years old. HD patients were randomly divided into two groups. Intervention group received 250 mg/day of H. psudoplicatum supplement capsule for 6 weeks (n=25), and the placebo group was given placebo capsule for the same time duration and dosage (n=25). The serum concentrations of urea, creatinine, albumin and hemoglobin were measured enzymatically methods. Anorexia, pruritus intensity, quality of life the dialysis patients with pruritus and fatigue score was measured using a Simplified Nutritional Appetite Questionnaire (SNAQ), Numerical rating scale (NRS), Fatigue severity scale (FSS) and ItchyQoL questionnaire, respectively. Shapiro-Wilk and independent-samples t-test or Mann-Whitney test were used for the analysis of the data. RESULTS: The results showed that the H. psudoplicatum supplementation significantly improved the pruritus intensity, quality of life the dialysis patients with pruritus and fatigue in HD patients, for 6 weeks (p<0.001). However, it did not significantly effect on the anorexia, albumin, hemoglobin, urea, creatinine, arm circumference, and body mass index (p>0.05). CONCLUSIONS: According to the results of this study, H. psudoplicatum supplementation can be effective as an adjunct therapy to improve pruritus intensity, quality of life, fatigue and relative improvement of anorexia in HD patients.

Albumin Substitution in Decompensated Liver Cirrhosis: Don't Forget Zinc.

Decompensated liver cirrhosis has a dismal prognosis, with patients surviving on average for 2-4 years after the first diagnosis of ascites. Albumin is an important tool in the therapy of cirrhotic ascites. By virtue of its oncotic properties, it reduces the risk of cardiovascular dysfunction after paracentesis. Treatment with albumin also counteracts the development of hepatorenal syndrome and spontaneous bacterial peritonitis. More recently, the positive impact of long-term albumin supplementation in liver disease, based on its pleiotropic non-oncotic activities, has been recognized. These include transport of endo- and exogenous substances, anti-inflammatory, antioxidant and immunomodulatory activities, and stabilizing effects on the endothelium. Besides the growing recognition that effective albumin therapy requires adjustment of the plasma level to normal physiological values, the search for substances with adjuvant activities is becoming increasingly important. More than 75% of patients with decompensated liver cirrhosis do not only present with hypoalbuminemia but also with zinc deficiency. There is a close relationship between albumin and the essential trace element zinc. First and foremost, albumin is the main carrier of zinc in plasma, and is hence critical for systemic distribution of zinc. In this review, we discuss important functions of albumin in the context of metabolic, immunological, oxidative, transport, and distribution processes, alongside crucial functions and effects of zinc and their mutual dependencies. In particular, we focus on the major role of chronic inflammatory processes in pathogenesis and progression of liver cirrhosis and how albumin therapy and zinc supplementation may affect these processes.

SEOM clinical guidelines for pancreatic and biliary tract cancer (2020).

Pancreatic cancer (PC) and biliary tract cancer (BTC) are both aggressive and highly fatal malignancies. Nowadays we have a profound knowledge about the molecular landscape of these neoplasms and this has allowed new therapeutic options. Surgery is the only potentially curative therapy in both cancers, but disease recurrence is frequent. In PC, adjuvant treatment with mFOLFIRINOX has improved overall survival (OS) and in BTC adjuvant treatment with capecitabine seems to improve OS and relapse-free survival. Concomitant radio-chemotherapy could also be considered following R1 surgery in both neoplasms. Neoadjuvant treatment represents the best option for achieving an R0 resection in borderline PC. Upfront systemic chemotherapy is the treatment of choice in unresectable locally advanced PC and BTC; then locoregional therapy could be considered after an initial period of at least 3-4 months of systemic chemotherapy. In metastatic PC, FOLFIRINOX or Gemcitabine plus nab-paclitaxel have improved OS compared with gemcitabine alone. In metastatic BTC, cisplatin plus gemcitabine constitute the standard treatment. Progress in the knowledge of molecular biology has enabled the identification of new targets for therapy with encouraging results that could in the future improve the survival and quality of life of patients with PC and BTC.

Surgical Outcome Results From SWOG S1505: A Randomized Clinical Trial of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for Perioperative Treatment of Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The optimal neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDA) and the impact on surgical outcomes remains unclear. METHODS: S1505 (NCT02562716) was a randomized phase II study of perioperative chemotherapy with mFOLFIRINOX (Arm 1) or gemcitabine/nab-paclitaxel (Arm 2). Measured parameters included resection rate, margin positivity, pathologic response, and toxicity. RESULTS: Between 2015 and 2018, 147 patients were randomized. Of these, 44 (30%) were deemed ineligible (43 by central review). Of the 103 eligible patients, 77 (76%) completed preoperative therapy and underwent surgery; reasons patients did not undergo surgery included toxicity related to preoperative therapy (n = 9), progression (n = 9), or other (n = 7). Of the 77, 73 (95%) underwent successful resection; 21 (29%) required vascular reconstruction, 62 (85%) had negative (R0) margins, and 24 (33%) had a complete or major pathologic response to therapy. The grade 3-5 postoperative complication rate was 16%. Of the 73 patients completing surgery, 57 (78%) started and 46 (63%) completed postoperative therapy. This study represents the first prospective trial evaluating modern systemic therapy delivered in a neoadjuvant/perioperative format for resectable PDA. CONCLUSIONS: We have demonstrated: (1) Based on the high percentage of enrolled, but ineligible patients, it is clear that adherence to strict definitions of resectable PDA is challenging; (2) Patients can tolerate modern systemic therapy and undergo successful surgical resection without prohibitive perioperative complications; (3) Completion of adjuvant therapy in the perioperative format is difficult; (4) Major pathologic response rate of 33% is encouraging.

Prolonged response to liposomal irinotecan in a patient with stage IV pancreatic/bile duct cancer previously treated with FOLFIRINOX and gemcitabine plus nab-paclitaxel.

At 9%, and 2% when diagnosed at advanced stage, the 5-year relative survival rate for pancreatic ductal adenocarcinoma (pdac) is the lowest of any cancer. The currently approved treatment options for metastatic pdac in the United States are folfirinox [irinotecan-fluorouracil (5fu)-leucovorin (lv)-oxaliplatin], gemcitabine-nab-paclitaxel, and liposomal irinotecan plus 5fu-lv. Liposomal irinotecan is a novel formulation of irinotecan encapsulated within a lipid bilayer, which favours local metabolic activation. The napoli-1 trial demonstrated the efficacy of liposomal irinotecan in combination with 5fu and lv for the treatment of advanced pdac after progression on gemcitabine-based chemotherapy. The 1-year survival in those patients was 25%; however, none had had irinotecan-refractory disease before treatment with liposomal irinotecan. Furthermore, the U.S. National Comprehensive Cancer Network guidelines recommend liposomal irinotecan plus 5fu-lv in patients who have received prior fluoropyrimidine-based therapy if no prior irinotecan therapy has been given. Here, we report a male patient with stage iv cancer of pancreas or bile duct (site unconfirmed) who experienced a prolonged (51 weeks) response to liposomal irinotecan plus 5fu-lv despite prior disease progression on irinotecan. Several factors have previously been associated with long-term survival in patients receiving liposomal irinotecan therapy: no prior irinotecan-based chemotherapy, high Karnofsky performance status score, age 65 years or less, serum carbohydrate antigen 19-9 less than 59 U/mL, neutrophil-to-lymphocyte ratio 5 or less, and absence of liver metastasis. The patient in the present report had none of those characteristics indicative of long-term survival, except his age at diagnosis-47 years.

A randomized control trial of phototherapy and 20% albumin versus phototherapy and saline in Kilifi, Kenya.

OBJECTIVE: The study evaluated the efficacy of phototherapy and 20% albumin infusion to reduce total serum bilirubin (TSB) in neonates with severe hyperbilirubinemia. The primary outcome was a reduction of TSB at the end of treatment. The secondary outcomes were the need for exchange transfusion, inpatient mortality, neurological outcomes at discharge, and development outcomes at 12-months follow-up. RESULTS: One hundred and eighteen neonates were randomly assigned to phototherapy and 20% albumin (n = 59) and phototherapy and saline (n = 69). The median age at admission was 5 (interquartile range (IQR) 3-6) days, and the median gestation was 36 (IQR 36-38) weeks. No significant differences were found in the change in TSB (Mann-Whitney U =609, p = 0.98) and rate of change in TSB per hour after treatment (Mann-Whitney U = 540, p = 0.39) between the two groups. There were no significant differences between the two groups in the proportion of participants who required exchange transfusion (χ2 (2) = 0.36, p = 0.546); repeat phototherapy (χ2 (2) = 2.37, p = 0.123); and those who died (χ2 (2) = 0.92, p = 0.337). Trial registration The trial was registered in the International Standardized Randomized Controlled Trial Number (ISRCTN); trial registration number ISRCTN89732754.

Selecting chemotherapy for pancreatic cancer: Far away or so close?

Pancreatic cancer is a lethal disease with a very poor prognosis. In contrast to treatments for many other tumor types, cytotoxic agents are still the first-line drugs for pancreatic cancer in both the palliative and adjuvant settings. Some progress has been made in recent years, but most large phase 3 studies have not shown significant improvements in survival. Because the available drugs and regimens are limited in both type and effect, the selection of chemotherapy based on clinicopathologic characteristics may be consequential for pancreatic cancer. In the present report, we focused on 7 landmark clinical trials for pancreatic cancer. We observed that FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) and NG (nab-paclitaxel and gemcitabine), 2 first-line regimens, exerted opposite effects on metastatic pancreatic cancer patients with different baseline carbohydrate antigen 19-9 (CA19-9) levels. This suggested that not only the performance status but possibly also CA19-9 levels should be considered when making a therapeutic choice for patients with advanced pancreatic cancer. Moreover, we found that patients with a diagnosis of pancreatic cancer who have undergone a surgical resection with a negative margin (R0) may benefit more from fluorouracil and/or oral prodrugs of fluorouracil-based adjuvant therapy than from gemcitabine. Conversely, gemcitabine or gemcitabine-based regimens may be more effective for patients with a positive resection margin (R1). Based on these findings, we propose flowcharts for selecting chemotherapy for both advanced and resected pancreatic cancer. Furthermore, we present possible mechanisms and interpretations underlying the selection of chemotherapy for pancreatic cancer and propose the tumor burden as a key variable in this process. Regardless of the possible bias and exact treatment selection process, this study offers an opportunity to improve patient outcomes by using agents currently used in the therapy of pancreatic cancer. Although these conclusions are based on indirect evidence, we provide insights and possibilities to drive the selection of chemotherapy for pancreatic cancer.

Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer: Results of the PANOVA phase 2 study.

BACKGROUND: Tumor Treating Fields (TTFields), low intensity alternating electric fields with antimitotic activity, have demonstrated survival benefit in patients with glioblastoma. This phase 2 PANOVA study was conducted to examine the combination of TTFields plus chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Forty patients with newly-diagnosed, locally advanced or metastatic PDAC received continuous TTFields (150 KHz for ≥18 h/day) plus gemcitabine (1000 mg/m2), or gemcitabine plus nab-paclitaxel (125 mg/m2). The primary endpoint was safety and secondary endpoints included compliance to TTFields, progression-free survival (PFS), and overall survival (OS). RESULTS: Seventeen patients (85%) in each cohort reported Grade ≥3 adverse events (AEs). No increase in serious AEs (SAEs) was observed compared to that anticipated with systemic chemotherapy alone. Twenty-one patients reported TTFields-related skin toxicity, of which 7 were Grade 3; all resolved following temporary reduction of daily TTFields usage. No TTFields-related SAEs were reported. Compliance to TTFields was 68-78% of the recommended average daily use in both cohorts. Median PFS was 8.3 months (95% CI 4.3, 10.3) and median OS was 14.9 months (95% CI 6.2, NA) in the TTFields + gemcitabine cohort. In the TTFields + gemcitabine + nab-paclitaxel cohort, the median PFS was 12.7 months (95% CI 5.4, NA); median OS has not been reached. CONCLUSION: The PANOVA trial demonstrated that the combination of TTFields and systemic chemotherapy is safe and tolerable in patients with advanced PDAC. Based on the safety and preliminary efficacy results of this phase 2 study, a randomized phase 3 study (PANOVA-3) is underway.

Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group.

BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.

Lumbrokinase/paclitaxel nanoparticle complex: potential therapeutic applications in bladder cancer.

BACKGROUND: Lumbrokinase (LK) is an enzyme complex with antithrombotic, antioxidant, antitumor, and immunomodulatory effects. It has been extensively studied and used in clinical anti-tumor therapy. However, its half-life is short, its bioavailability is low, and its toxicity and side effects are great, which greatly limit its clinical application. Therefore, LK is often combined with other drugs (such as immune agents, hormones, or Chinese herbal medicine) to reduce its dosage and side effects and to improve its anti-tumor effects. METHODS AND RESULTS: Here, we described an LK/paclitaxel (PTX) nanocarrier based on poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(ε-benzyoxycarbonyl-l-lysine)-r-poly(l-lysine)) (PEG-b-(PELG-g-(PZLL-r-PLL))). In the present study, LK and PTX were loaded by electrostatic and/or hydrophobic effects under mild conditions, thereby increasing the half-life and bioavailability of the drugs via the sustained release and enhancement of tumor site enrichment by the LK/PTX/PEG-b-(PELG-g-(PZLL-r-PLL)) complex through passive targeting. In this study, using bladder cancer cells (J82 cells) and rat bladder cancer model as the object, the structure of the nanocarrier, the relationship between drugs composition and antitumor properties were systematically studied. CONCLUSION: We propose that the block copolymer PEG-b-(PELG-g-(PZLL-r-PLL)) may function as a potent nanocarrier for augmenting anti-bladder cancer pharmacotherapy, with unprecedented clinical benefits.

Hyperbilirubinemia in preterm infants in Japan: New treatment criteria.

In 1992, Kobe University proposed treatment criteria for hyperbilirubinemia in newborns using total serum bilirubin and serum unbound bilirubin reference values. In the last decade, chronic bilirubin encephalopathy has been found to develop in preterm infants in Japan because it can now be clinically diagnosed based on an abnormal signal of the globus pallidus on T2-weighted magnetic resonance imaging and abnormal auditory brainstem response with or without apparent hearing loss, along with physical findings of kinetic disorders with athetosis. We therefore revised the Kobe University treatment criteria for preterm hyperbilirubinemic infants in 2017. The three revised points are as follows: (i) newborns are classified under gestational age at birth or corrected gestational age, not birthweight; (ii) three treatment options were created: standard phototherapy, intensive phototherapy, and albumin therapy and/or exchange blood transfusion; and (iii) initiation of standard phototherapy, intensive phototherapy, and albumin therapy and/or exchange blood transfusion is decided based on the total serum bilirubin and serum unbound bilirubin reference values for gestational weeks at birth at <7 days of age, and on the reference values for corrected gestational age at ≥7 days of age. Studies are needed to establish whether chronic bilirubin encephalopathy can be prevented using the 2017 revised Kobe University treatment criteria for preterm infants in Japan.