Comparative Effectiveness of FOLFIRINOX Versus Gemcitabine and Nab-paclitaxel in Initially Unresectable Locally Advanced Pancreatic Cancer: A Population-based Study to Assess Subsequent Surgical Resection and Overall Survival.

AIMS: First-line FOLFIRINOX (FOLinic acid, Fluorouracil, IRINotecan, and OXaliplatin) and gemcitabine plus nab-paclitaxel (GnP) have been publicly funded for patients with unresectable locally advanced pancreatic cancer (uLAPC) in Ontario, Canada. We examined the overall survival and surgical resection rate after first-line FOLFIRINOX or GnP and determined the association between resection and overall survival in patients with uLAPC. MATERIALS AND METHODS: We conducted a retrospective population-based study including patients with uLAPC who received first-line treatment FOLFIRINOX or GnP from April 2015 to March 2019. The cohort was linked to administrative databases to ascertain demographic and clinical characteristics. Propensity score methods were used to balance differences between FOLFIRINOX and GnP. The Kaplan-Meier method was used to calculate overall survival. Cox regression was used to determine the association between receipt of treatment and overall survival, adjusting for time-dependent surgical resections. RESULTS: We identified 723 patients with uLAPC (mean age = 65.8, 43.5% female) who received FOLFIRINOX (55.2%) or GnP (44.8%). The median overall survival and 1-year overall survival probability were higher for FOLFIRINOX (13.7 months, 54.6%) than for GnP (8.7 months, 34.0%). Post-chemotherapy surgical resection occurred in 89 (12.3%) patients (FOLFIRINOX: 74 [18.5%] versus GnP: 15 [4.6%]), with no difference in survival since surgery between FOLFIRINOX and GnP (P = 0.29). After adjusting time-dependent post-treatment surgical resection, FOLFIRINOX (inverse probability treatment weighting hazard ratio 0.72, 95% confidence interval 0.61, 0.84) was independently associated with improved overall survival. CONCLUSIONS: In this real-world population-based study of patients with uLAPC, FOLFIRINOX was associated with improved survival and higher resection rates. FOLFIRINOX was associated with improved survival in patients with uLAPC after accounting for the effect of post-chemotherapy surgical resection, suggesting the benefit of FOLFIRINOX was not solely due to improving resectability.

Systemic therapies for recurrent or metastatic nasopharyngeal carcinoma: a systematic review.

BACKGROUND: The majority of published studies in recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) are single-arm trials. Reliable modelling of progression-free survival (PFS) and overall survival (OS) outcomes, therefore, is difficult. This study aim to analyse existent literature to estimate the relative efficacy of available systemic regimens in RM-NPC, as well as provide estimates of aggregate OS and PFS. METHODS: We conducted a systematic search of MEDLINE, EMBASE and the Cochrane Library to March 2015. Clinical trials (in English only) investigating cytotoxic and molecularly targeted agents in adult patients with RM-NPC were included. All relevant studies were assessed for quality using Downs and Blacks (DB) checklist (maximum quality score of 27). Aggregate data analysis and Student's t-test were performed for all identified studies (model A). For studies that published analysable Kaplan-Meier curves, survival data were extracted and marginal proportional hazards models were constructed (model B). RESULTS: A total of 56 studies were identified and included in model A, 26 of which had analysable Kaplan-Meier curves and were included in model B. The 26 studies in model B had significantly higher mean DB scores than the remaining 30 (17.3 vs 13.7, P=0.002). For patients receiving first line chemotherapy, the estimated median OS was 15.7 months by model A (95% CI, 12.3-19.1), and 19.3 months by model B (95% CI, 17.6-21.1). For patients undergoing second line or higher therapies (2nd+), the estimated median OS was 11.5 months by model A (95% CI 10.1-12.9), and 12.5 months by model B (95% CI 11.9-13.4). PFS estimates for patients undergoing first-line chemotherapy by model A was 7.6 months (95% CI, 6.2-9.0), and 8.0 months by model B (95% CI, 7.6-8.8). For patients undergoing therapy in the 2nd+ setting, the estimated PFS by model A was 5.4 months (95% CI, 3.8-7.0), and 5.2 months by model B (95% CI, 4.7-5.6). CONCLUSIONS: We present the first aggregate estimates of OS and PFS for RM-NPC patients receiving first and second-line or higher treatment settings, which could inform the design of future clinical trials in this disease setting.

Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge.

BACKGROUND: The most intriguing function attributed to interleukin-31 (IL-31) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis (AD). As of today, this feature of IL-31 was tested in vivo only in animal models. METHODS: Ten patients with AD and 10 healthy controls were challenged with IL-31 and NaCl (negative control) by skin prick testing. Twenty additional healthy controls were subjected to skin prick testing with histamine. Itch and local inflammatory responses of the skin were assessed for up to 72 h. RESULTS: All of the histamine-challenged subjects developed immediate pruritus (i.e. within the first 5 min). In contrast, only one IL-31- and two of the NaCl-challenged subjects reported immediate itch at the provocation site (short lasting, for 2-6 min). Nine subjects (five patients with AD) reported late itch responses to IL-31 challenges with a mean delay of 143 min. No subject reported late itch responses to histamine or NaCl testing. There was no significant difference in IL-31-induced itch start time, duration and intensity between patients with AD and healthy volunteers. CONCLUSION: IL-31 does not induce immediate itch responses in humans. The late onset of IL-31-induced itch supports the notion that IL-31 exerts its pruritic effect indirectly via keratinocytes and secondary mediators, rather than through its receptors on cutaneous nerves.

Interleukin-33 promotes the proliferation of mouse mast cells through ST2/MyD88 and p38 MAPK-dependent and Kit-independent pathways.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new modulator of immune and inflammatory responses. Although IL-33 and its associated receptor ST2 are reportedly expressed in mast cells (MCs), the precise role of IL-33 in modulating MC function has not been determined. In the present studies, we explored IL-33 effects on MCs in vivo and in vitro. IL-33 increased the number of peritoneal and skin MCs in vivo. IL-33 also resulted in increased proliferation of MCs in vitro, as explored by WST assay. Cell cycle analysis further confirmed this result by showing increased G2 cell populations in MCs stimulated with IL-33. We found that IL-33-mediated MC proliferation requires ST2 and MyD88, is independent of Kit, and is mediated through a p38 MAPK-dependent pathway. IL-33 did not induce degranulation and was not cytotoxic for MCs. This novel mechanism for increasing MC proliferation and numbers further defines the role of IL-33 in MC-dependent diseases including allergies and may help to develop novel approaches for the treatment of these disorders.

Role and relevance of mast cells in fungal infections.

In addition to their detrimental role in allergic diseases, mast cells (MCs) are well known to be important cells of the innate immune system. In the last decade, they have been shown to contribute significantly to optimal host defense against numerous pathogens including parasites, bacteria, and viruses. The contribution of MCs to the immune responses in fungal infections, however, is largely unknown. In this review, we first discuss key features of mast cell responses to pathogens in general and then summarize the current knowledge on the function of MCs in the defense against fungal pathogens. We especially focus on the potential and proven mechanisms by which MCs can detect fungal infections and on possible MC effector mechanisms in protecting from fungal infections.

Biochemical and molecular evaluation of neutrophil NOS in spontaneously hypertensive rats.

Resting neutrophils generate NO, while activation leads to the production of reactive oxygen and nitrogen species. Nowadays cardiovascular pathological conditions such as hypertension, cardiac ischemia, reperfusion and heart failure are associated with inflammation. This project explores the respiratory burst potential and NO generation status in the neutrophils, plasma, aorta, and kidneys from normotensive Wistar and spontaneously hypertensive rats (SHR). Total and protein associated nitrite content was quantitated using Griess reagent following cadmium reduction and mercuric chloride treatment respectively. NO and superoxide generation evaluated by Flowcytometry and peroxynitrite by spectrofluorimetric method. Expression of NOS isoforms was analyzed by RT-PCR. NO generation from SHR neutrophils was significantly augmented in comparison to normotensive counterparts. Neutrophils activated in response to arachidonic acid, PMA, fMLP or E. coli generated more superoxide radicals among SHR, and consequentially peroxynitrite. Expression of iNOS was significantly more in the SHR neutrophils, while that of nNOS remained unaffected. Results suggest that NO generated in SHR is utilized in scavenging superoxide radicals thereby limiting its bioavailability. Thus induction of NOS in neutrophils combined with augmented oxidative stress might influence its association with endothelium and contribute to inflammatory responses under hypertensive condition.

Nitric oxide synthase localization in the rat neutrophils: immunocytochemical, molecular, and biochemical studies.

Nitric oxide (NO) modulates diverse functions of polymorphonuclear neutrophils (PMNs), but localization of NO synthase (NOS) and identification of its interacting proteins remain the least defined. The present study discerns subcellular distribution of NOS and caveolin-1, a prominent NOS-interacting protein in rat PMNs. Localization of NOS was explored by confocal and immunogold electron microscopy, and its activity was assessed by L-[3H] arginine and 4,5-diaminofluorescein diacetate (DAF-2DA). Reverse transcriptase-polymerase chain reaction using NOS primers and Western blotting demonstrated the presence of neuronal NOS (nNOS) and inducible NOS (iNOS) in PMNs. Immunocytochemical studies exhibited distribution of nNOS and iNOS in cytoplasm and nucleus, and L-[3H] citrulline formation and DAF fluorescence confirmed NOS activity in both fractions. NOS activity correlated positively with calmodulin concentration in both of the fractions. nNOS and iNOS colocalized with caveolin-1, as evidenced by immunocytochemical and immunoprecipitation studies. The results thus provide first evidence of nNOS and iNOS in the nuclear compartment and suggest NOS interaction with caveolin-1 in rat PMNs.

Reconstruction of major column defects and pelvic discontinuity in revision total hip arthroplasty.

Acetabular reconstruction with severe bone loss after failed total hip arthroplasty is a difficult problem. Defects were defined as major segmental and cavitary loss (type III anterior or posterior) or pelvic discontinuity (type IV). Seventeen cases were treated, of which 7 were type III and 10 were type IV. Bulk allograft was used in 16 of 17 cases, of which 7 were whole acetabular grafts, 2 were posterior segmental acetabular grafts, and 7 were femoral heads. Fourteen of 17 patients were female. The extensile triradiate approach was used in 12 cases. Long pelvic bone plates were applied to the posterior column and anterior brim of the pelvis in most cases. Allografts united to host-bone in 15 cases. Average follow-up was 83 months. The overall revision rate was 47%, of which 3 of 7 press-fit and 2 of 10 cemented cups had failed. The dislocation rate for the extensile approach was 50%; 2 patients had excisional arthroplasty for infection, and 2 patients had exploration of the sciatic nerve for release from migrating pelvic plate screws. Because of the overall poor results, this approach cannot be recommended for general use.

Anti-diarrhoeal evaluation of Clerodendrum phlomidis Linn. leaf extract in rats.

A study was undertaken to evaluate the effect of methanolic extract of leaves of Clerodendrum phlomidis Linn. (MECP) (Family: Verbenaceae) for its anti-diarrhoeal potential against several experimental models of diarrhoea in Wistar albino rats. MECP showed significant inhibitory activity against castor oil induced diarrhoea and PGE2 induced enteropooling in rats. The extract also showed a significant reduction in gastrointestinal motility in charcoal meal test in rats. The results obtained establish the efficacy and substantiated the folklore claim as an anti-diarrhoeal agent.

Evaluation of the biomechanics of the hip following a triple osteotomy of the innominate bone.

The biomechanics of the hip joint were evaluated in seventeen patients (twenty-two hips), twelve to forty-one years old (mean, twenty-four years old), who had a triple osteotomy of the innominate bone for treatment of symptomatic dysplasia of the hip. The duration of follow-up ranged from 2.2 to 13.8 years (mean, 6.8 years). Hip load, the area of the weight-bearing surface, and stress were determined from measurements on pelvic radiographs that were made preoperatively, postoperatively, and at the time of the latest follow-up; the values were compared with those in twenty-one hips from control subjects. The Harris hip-rating system was used for clinical assessment. According to the biomechanical analysis, there was significantly less relative stress on the hip after the triple osteotomy and at the time of the latest follow-up (p < 0.001 for both) than there had been preoperatively. The decrease in stress was a direct result of a significant increase in the area of the weight-bearing surface of the hip (p < 0.001). The load on the hip was not altered significantly, with the numbers available. The functional outcome was improved substantially when the biomechanical goals were achieved. Through the application of basic biomechanical principles, we were able to demonstrate the biomechanical efficacy of a triple osteotomy of the innominate bone. We recommend the use of biomechanical analysis as an adjunct to the clinical decision-making process in the treatment of a dysplastic hip.

Anterior cruciate ligament tears in skeletally immature patients: meniscal pathology at presentation and after attempted conservative treatment.

We evaluated 12 skeletally immature patients with acute, intrasubstance tears of the anterior cruciate ligament (ACL) and open physes for meniscal pathology. Arthrograms were completed in 10 of 12 patients, and subsequent arthroscopy confirmed 8 meniscal tears (4 medial, 4 lateral) in 6 patients. Four patients with repairable menisci underwent arthroscopic meniscal repair and stabilization. Eight patients received quadriceps and hamstrings rehabilitation and returned to sports with a brace. After return to sports, all braced patients developed instability with multiple episodes of "giving way." Average time from initial injury to first episode of instability was 7 months. Seven patients sustained further meniscal damage an average of 15 months (range 7-27 months) after initial injury. We conclude that meniscal pathology is commonly associated with ACL tears in skeletally immature patients and we recommend arthrography or arthroscopy to evaluate patients with suspected ACL tears. Brace management did not prevent instability or new meniscal tears.

Phorbol esters and forskolin infused into midbrain central gray facilitate lordosis.

Several peptides, when infused into the MCG, facilitate lordosis in estrogen-primed female rats. Since these peptides can act through cAMP and/or protein kinase C, and these second messenger systems have been implicated in neuromodulation, this study examined if pharmacological agents which stimulate these systems would facilitate lordosis. Ovariectomized female Fisher rats were given bilateral cranial cannulae targeted to the MCG, or cortex dorsal to MCG, and allowed at least a week to recover. Forty-eight hours after injection of 1.25 micrograms estradiol benzoate (EB), 1 microliter of each of the following was infused into the MCG (n=8-12): 1) forskolin (5 micrograms/microliter 50% DMSO); 2) phorbol-20-oxo-20-deoxy-12,13-dibutyrate (PBu; 5 micrograms/microliter 50% DMSO); 3) both forskolin and PBu (2.5 micrograms of each/microliter); 4) vehicle (50% DMSO). In a separate study of identical design, 1 microliter of another phorbol ester (12-myristate 13-acetate) was infused into the MCG of EB-primed rats. Forskolin and phorbol esters each facilitated lordosis maximally at 60-90 minutes after infusion. Combining both agents also facilitated lordosis, and vehicle had no effect. These results suggest that infusing agents which stimulate cAMP and protein kinase C into the MCG can facilitate lordosis in estrogen-primed female rats.