Evidence of a Hardening in the Cosmic Ray Proton Spectrum at around 166 TeV Observed by the GRAPES-3 Experiment.

We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January 2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).

Effects of the time-of-day (morning vs. afternoon) of implementing a combined physical and cognitive exercise program on cognitive functions and mood of older adults: A randomized controlled study.

This study examined the effects of the time of conducting a combined physical and cognitive exercise program on cognitive functions and the mood of older adults. We randomly assigned 17 participants (8 men, 9 women, age 73,24±3,75) to the morning group (AM Group), 18 (8 men, 10 women, age 73,11±4,84) to the afternoon group (PM Group), and they completed a 12-week, dual-task exercise program in the morning or the afternoon, respectively. Moreover, the waiting-list control group consisted of 12 participants (6 men, 6 women, age 73,25±5,93). The cognitive functions and the mood of the participants were assessed before and after the program by using the Neurobehavioral Cognitive Status Examination, and the short version of the Profile of Mood States, respectively. As a result, the exercise program conducted in the afternoon had broader effects on cognitive functions (increased Repetition and Memory) than in the morning (increased Repetition), or the waiting-list control group (increased Judgment). Moreover, the program in the afternoon tended to reduce Anger-Hostility, and Fatigue. In conclusion, conducting the exercise program in the afternoon might be more effective for improving cognitive functions and the mood of older adults than in the morning. However, there was heterogeneity between the groups despite the randomization. Therefore, we suggest conducting a more rigorously controlled study using a larger sample to validate these findings.

Measurement of the Electrical Properties of a Thundercloud Through Muon Imaging by the GRAPES-3 Experiment.

The GRAPES-3 muon telescope located in Ooty, India records rapid (∼10 min) variations in the muon intensity during major thunderstorms. Out of a total of 184 thunderstorms recorded during the interval of April 2011-December 2014, the one on December 1, 2014 produced a massive potential of 1.3 GV. The electric field measured by four well-separated (up to 6 km) monitors on the ground was used to help estimate some of the properties of this thundercloud, including its altitude and area that were found to be 11.4 km above mean sea level and ≥380 km^{2}, respectively. A charging time of 6 min to reach 1.3 GV implied the delivery of a power of ≥2 GW by this thundercloud that was moving at a speed of ∼60 km h^{-1}. This work possibly provides the first direct evidence for the generation of gigavolt potentials in thunderclouds that could also possibly explain the production of highest-energy (100 MeV) gamma rays in the terrestrial gamma-ray flashes.

Safety and efficacy of guselkumab in Japanese patients with moderate-to-severe plaque psoriasis: a randomized, placebo-controlled, ascending-dose study.

BACKGROUND: The interleukin (IL)-23/IL-17 pathway is central in the pathogenesis of psoriasis. The favourable efficacy and safety of guselkumab, an IL-23-specific monoclonal antibody, has been demonstrated in global phase III studies of plaque psoriasis. OBJECTIVES: To evaluate the safety, efficacy and pharmacokinetics of single-dose subcutaneous guselkumab in Japanese patients with moderate-to-severe plaque psoriasis. METHODS: Patients with ≥ 10% of total body surface area involvement and a Psoriasis Area and Severity Index (PASI) ≥ 12 were randomized (5 : 1) to receive guselkumab or placebo in four cohorts of this double-blind, placebo-controlled, single ascending-dose, single-centre study. Safety, pharmacokinetics and clinical response were monitored at baseline and specific time points over a 24-week follow-up period. RESULTS: To week 24, 55% (11/20) of patients in the guselkumab group and 50% (2/4) in the placebo group experienced ≥1 adverse event (AE). No deaths, serious AEs or AEs leading to treatment discontinuation were reported. Maximum clinical response was seen at week 16 with PASI 75 (≥ 75% improvement from baseline PASI) response in two of five (10 mg), four of five (30 mg and 300 mg) and three of five (100 mg) patients; and PASI 90 (≥ 90% improvement from baseline PASI) in zero of five (10 mg), three of five (30 mg), two of five (100 mg) and three of five (300 mg) patients. Mean maximum serum concentration (Cmax ) and area under the curve from time zero to infinity values increased in a dose-proportional manner with a mean terminal half-life of 15·6-17·6 days and median time to reach Cmax of 4-6 days. CONCLUSIONS: Guselkumab was generally well-tolerated and exhibited sustained high levels of clinical response in Japanese patients with moderate-to-severe psoriasis.

The effect of bolus volume on laryngeal closure and UES opening in swallowing: Kinematic analysis using 320-row area detector CT study.

This study investigated the effects of three different volumes of honey-thick liquid on the temporal characteristics of swallowing. Twenty-six healthy subjects (15 males, 11 females) underwent 320-row area detector CT scan while swallowing 3, 10 and 20 mL of honey-thick liquid barium. Three-dimensional images were created at 10 images/s. Kinematic events involving six structures (velopharynx, hyoid bone, epiglottis, laryngeal vestibule (LV), true vocal cords (TVC), upper esophageal sphincter (UES)) and timing of bolus movement were timed using frame by frame analysis. The overall sequence of events did not differ across three volumes; however, increasing bolus volume significantly changed the onset and termination of events. The bolus head reached to pharynx and esophagus earlier and the duration of bolus passing through UES was significantly longer in 10 and 20 mL compared to 3 mL (P < .05). Consequently, the onset of UES opening was significantly earlier with increased volume (P < .05). LV and TVC closure occurred later in 20 mL compared to 3 mL (P < .05). These changes in motion of pharynx and larynx appeared to promote swallow safety by preventing aspiration, suggesting that anatomical structure movements adapt in response to bolus volume. Our findings also suggest that the pharyngeal swallow behaviours may be modified by afferents in the oral cavity. The three-dimensional visualization and quantitative measurements provided by 320-ADCT provide essential benchmarks for understanding swallowing, both normal and abnormal.

A new insight into the fabella at knee: the foetal development and evolution.

Using longitudinal semiserial sections of 12 lower extremities from 8 human foetuses at 15-18 weeks, we compared foetal morphologies of the knee in specimens with and without fabellae. We also compared the fabella, if present, with the hallucal sesamoid in the same foetus. Cartilaginous fabella, positive for versican and tenascin by immunohistochemistry, was found in 5 of the 8 foetuses. This structure was embedded in a thick and tight lateral fibrous band, providing a common origin of the plantaris muscle and the lateral head of the gastrocnemius muscle. The plantaris was covered by the lateral head of the gastrocnemius, but these 2 muscles were separated by a distinct fascia or space. Notably, the foetal fabella did not attach to the joint capsule. In the 3 specimens without fabellae, the lateral fibrous band was thin, containing a fibrous mass, negative for versican and tenascin, in place of the fabella. The "medial" head of the gastrocnemius faced or covered the plantaris, while the lateral head was continuous with the plantaris. A hallucal cartilaginous sesamoid, positive for versican and tenascin, was present in all 8 specimens. It carried a flat surface facing the joint cavity and was covered by tendons of the short muscles of the foot. Because of the difference in topographical relation of muscles between specimens with or without fabella, rather than mechanical stress to the tendon, fabella development may require a distinct plantaris muscle independent of the gastrocnemius. We discussed about an evolutionary aspect of the fabella and plantaris muscle.

Transient Weakening of Earth's Magnetic Shield Probed by a Cosmic Ray Burst.

The GRAPES-3 tracking muon telescope in Ooty, India measures muon intensity at high cutoff rigidities (15-24 GV) along nine independent directions covering 2.3 sr. The arrival of a coronal mass ejection on 22 June 2015 18:40 UT had triggered a severe G4-class geomagnetic storm (storm). Starting 19:00 UT, the GRAPES-3 muon telescope recorded a 2 h high-energy (∼20 GeV) burst of galactic cosmic rays (GCRs) that was strongly correlated with a 40 nT surge in the interplanetary magnetic field (IMF). Simulations have shown that a large (17×) compression of the IMF to 680 nT, followed by reconnection with the geomagnetic field (GMF) leading to lower cutoff rigidities could generate this burst. Here, 680 nT represents a short-term change in GMF around Earth, averaged over 7 times its volume. The GCRs, due to lowering of cutoff rigidities, were deflected from Earth's day side by ∼210° in longitude, offering a natural explanation of its night-time detection by the GRAPES-3. The simultaneous occurrence of the burst in all nine directions suggests its origin close to Earth. It also indicates a transient weakening of Earth's magnetic shield, and may hold clues for a better understanding of future superstorms that could cripple modern technological infrastructure on Earth, and endanger the lives of the astronauts in space.

Serum IL-33 levels are increased in patients with psoriasis.

BACKGROUND: Interleukin (IL)-33 is a recently identified cytokine, which is a member of the IL-1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) and IL-1 receptor accessory protein. Serum levels of IL-33 have been reported to be upregulated in various T helper (Th)1/Th17-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL-33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied. AIM: To study serum IL-33 levels in patients with psoriasis, a Th1/Th17-mediated skin disease, before and after anti-tumour necrosis factor (TNF)-α therapy. METHODS: Serum IL-33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL-33 levels and serum TNF-α, IL-6, vascular endothelial growth factor and C-reactive protein levels were also studied. In addition, the effect of IL-33 stimulation on IL-6, IL-8, TNF-α and VEGF secretion by human keratinocyte was analysed. RESULTS: Serum IL-33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL-33 levels correlated with serum TNF-α levels in patients with psoriasis, and decreased after anti-TNF-α therapy. IL-33 stimulated IL-6 and IL-8 secretion by human keratinocytes. CONCLUSIONS: These results suggest that serum IL-33 levels generally reflect increased inflammation in patients with psoriasis.

Positional changes in tendon insertions from bone to fascia: development of the pes anserinus and semimembranosus muscle insertion in human foetuses.

Development of a long muscle belly in foetal extremities generally requires a definite bony insertion of the long tendon. However, in adults, the pes anserinus and the semimembranosus tendon (SMT) are inserted into fasciae. Development of fascial insertions in foetuses was investigated by examining serial histological sections obtained from 7 foetuses at 8-9 weeks and 8 foetuses at 14-16 weeks. The presence of matrix substances and macrophages was also examined by immunohistochemistry. At 8 weeks, the tendons of the semitendinosus, gracilis, sartorius and semimembranosus muscles were straight and inserted into the initial shaft-like proximal end of the tibia on the proximal side of the popliteus muscle. At 9 weeks, however, the medially extending popliteus muscle appeared to push the pes anserinus tendons superficially, with a loss of cartilage insertions. The SMT obtained an attachment to the popliteus muscle. At 14-16 weeks, the SMT divided into thick and thin bundles: the former contained abundant macrophages and inserted into the tenascin-positive perichondrium of the enlarged proximal tibia, while the later without macrophages ended at the joint capsule. The pes anserinus tendons, negative for both versican and tenascin-c, took highly tortuous courses toward the fascia cruris. Because the medial extension of the popliteus muscle was associated with the enlargement of the proximal tibia, the topographical relationship of the popliteus muscle with these 4 tendons changed drastically, resulting in a loss of cartilage insertion of the pes anserinus tendons as well as the division and reconstruction of the SMT.

The circadian clock functions as a potent regulator of allergic reaction.

Symptoms and laboratory parameters of allergic diseases exhibit prominent ~24-h variations. For instance, in most allergic rhinitis patients, symptoms worsen overnight or early in the morning. Accordingly, there are benefits to nighttime dosing of anti-allergy medications in such patients. Although the circadian pathophysiology of allergic diseases is well documented, the biological basis of this phenomenon remains poorly understood. Recent studies have begun to reveal that the internal timekeeping system termed the circadian clock plays a key role in temporal regulation of allergic reaction, and may therefore underlie the circadian pathophysiology of allergic diseases. Here, we review new knowledge that highlights the emerging role of the circadian clock as a potent regulator of allergic reactions. Given the strong influence of circadian rhythms on allergic diseases, we believe that research on how the time of day impacts allergic reaction which we may call 'chronoallergology' will provide new insight into previously unknown aspects of the biology of allergies. Such knowledge should facilitate novel strategies for prevention and treatment of these diseases.

Anatomy of the larynx and pharynx: effects of age, gender and height revealed by multidetector computed tomography.

Although oropharyngeal and laryngeal structures are essential for swallowing, the three-dimensional (3D) anatomy is not well understood, due in part to limitations of available measuring techniques. This study uses 3D images acquired by 320-row area detector computed tomography ('320-ADCT'), to measure the pharynx and larynx and to investigate the effects of age, gender and height. Fifty-four healthy volunteers (30 male, 24 female, 23-77 years) underwent one single-phase volume scan (0.35 s) with 320-ADCT during resting tidal breathing. Six measurements of the pharynx and two of larynx were performed. Bivariate statistical methods were used to analyse the effects of gender, age and height on these measurements. Length and volume were significantly larger for men than for women for every measurement (P < 0.05) and increased with height (P < 0.05). Multiple regression analysis was performed to understand the interactions of gender, height and age. Gender, height and age each had significant effects on certain values. The volume of the larynx and hypopharynx was significantly affected by height and age. The length of pharynx was associated with gender and age. Length of the vocal folds and distance from the valleculae to the vocal folds were significantly affected by gender (P < 0.05). These results suggest that age, gender and height have independent and interacting effects on the morphology of the pharynx and larynx. Three-dimensional imaging and morphometrics using 320-ADCT are powerful tools for efficiently and reliably observing and measuring the pharynx and larynx.

Genetic polymorphism in IFNL4 and response to pegylated interferon-α and ribavirin in Japanese chronic hepatitis C patients.

A genetic polymorphism of the newly discovered interferon-λ 4 (IFNL4) gene was associated with hepatitis C virus (HCV) clearance in individuals of African ancestry. To assess whether a dinucleotide variant of IFNL4 (ss469415590) also affected treatment outcome of antiviral therapy in Japan, we genotyped 213 patients with chronic genotype 1 HCV infection and 176 healthy subjects. The ΔG allele was associated with treatment failure [odds ratio (OR) 4.73, P = 0.019], as was the IFL3 rs8099917 single nucleotide polymorphism (SNP) (OR 5.06, P = 0.068). The correlation between ss469415590 and rs8099917 was high (r(2) = 0.92, D' = 0.98). Multivariate analysis revealed that the rs8099917 SNP was independently associated with treatment failure (OR 5.28, P = 0.009). Therefore, ss469415590 may be another predictive marker of antiviral therapy outcome in the Japanese population.

Prolactin induces the production of Th17 and Th1 cytokines/chemokines in murine Imiquimod-induced psoriasiform skin.

BACKGROUND: Prolactin (PRL) is a pituitary-derived neuropeptide hormone that has been suggested to promote the development of psoriasis, a Th17/Th1-mediated inflammatory dermatosis. PRL increases the expression of Th1 cytokines; however, its effects on Th17 responses are unknown. OBJECTIVE: This study aims to determine the in vivo effects of PRL on the expression of Th17 cytokines/chemokines in imiquimod-induced psoriasiform skin inflammation in mice. METHODS: BALB/c mice were intraperitoneally injected with PRL or phosphate-buffered saline, and imiquimod cream or Vaseline was applied to the shaved back skin for six consecutive days. RESULTS: Intraperitoneal PRL increased the mRNA levels of IL-17A, IL-17F, IL-22, IL-23p19, IL-12p40, CCL20 and STAT3 in imiquimod-treated skin. Mice treated with imiquimod plus PRL, but not those treated with imiquimod plus phosphate-buffered saline, showed significantly increased mRNA levels of TNF-α, IFN-γ, IL-12p35 and CXCL2 compared with controls. Intraperitoneal PRL increased the numbers of CD3(+) and GR-1(+) cells in the dermis of imiquimod-treated skin. CONCLUSIONS: These results suggest that intraperitoneal PRL enhances the expression of Th17 and Th1 cytokines/chemokines, and augments inflammation in imiquimod-induced psoriasiform skin. Prolactin may thus exacerbate psoriasis through the enhancement of Th17/Th1 responses.

Longitudinal monitoring of CYP3A activity in patients receiving 3 cycles of itraconazole pulse therapy for onychomycosis.

WHAT IS KNOWN AND OBJECTIVE: Itraconazole, a CYP3A inhibitor, is used for the treatment for onychomycosis with a three-cycle pulse therapy over 3 months, but its effects on in vivo CYP3A activity during the entire course remain unknown. METHODS: Urinary 6ß-hydroxycortisol/cortisol ratios were determined in 19 patients with onychomycosis, before therapy, during three cycles of itraconazole pulse therapy (200 mg twice daily for a week in each monthly cycle) and at 3 month after completion of therapy. RESULTS AND DISCUSSION: The mean 6ß-hydroxycortisol/cortisol ratio was reduced by 68% from baseline (P < 0·05) after the 1st pulse dosing, but the inhibitory effect appeared to be resolved before the next pulse dosing and at 3 months post-treatment. The magnitude of inhibition appeared in proportion to the baseline CYP3A activity. WHAT IS NEW AND CONCLUSION: The inhibitory effect of itraconazole pulse therapy on the in vivo CYP3A activity appears clinically relevant at the end of each cycle, but the inhibition resolves, on average, within 3 weeks.

Interface between intramembranous and endochondral ossification in human foetuses.

In the head and neck of human mid-term foetuses, the interface between areas of endochondral ossification and adjacent membranous (intramembranous) ossification is extensive. Using 8 foetal heads at 15-16 weeks, we have demonstrated differences in the matrices and composite cells between these 2 ossification processes, especially in the occipital squama and pterygoid process. Aggrecan-positive cartilage was shown to be invaded by a primitive bony matrix that was negative for aggrecan. At the interface, the periosteum was continuous with the perichondrium without any clear demarcation, but tenascin-c expression was restricted to the periosteum. In contrast, the interface between the epiphysis and shaft of the femur showed no clear localisation of tenascin-c. Versican expression tended to be restricted to the perichondrium. In the pterygoid process, the density of CD34-positive vessels was much higher in endochondral than in membranous ossification. The membranous part of the occipital was considered most likely to contribute to growth of the skull to accommodate the increased volume of the brain, while the membranous part of the pterygoid process seemed to be suitable for extreme flattening under pressure from the pterygoid muscles.

Biological clock dysfunction exacerbates contact hypersensitivity in mice.

BACKGROUND: Immediate-type skin allergic reactions, such as passive cutaneous anaphylactic reaction, are associated with circadian rhythm, but the role of circadian mechanisms on delayed-type skin allergic reactions, such as contact hypersensitivity (CHS), remains uncertain. In mice, CHS, a T-cell-mediated immune response, is a classic model of human allergic contact dermatitis. OBJECTIVES: We investigated whether biological clock dysfunction affects CHS pathogenesis in CLOCK mutant mice compared with wild-type (WT) mice. METHODS: Mice were treated with 2,4,6-trinitro-1-chlorobenzene (TNCB) on the abdominal skin on day 0 (sensitization) and then treated with TNCB on the ears on day 5 (challenge). RESULTS: We found that biological clock dysfunction resulted in severe inflammation. Ear swelling, serum immunoglobulin E level and mast cell number were significantly increased in CLOCK mutant mice compared with WT mice. These results provide evidence that CLOCK mutation promotes the T-helper type 2 immune response and exacerbates CHS. Corticosterone has a protective effect on CHS. The serum corticosterone level lost rhythmicity and showed a decreased daily level in CLOCK mutant mice compared with WT mice, supporting the exacerbating effect of CLOCK mutation on CHS. Adrenalectomy markedly worsened TNCB-induced CHS in WT mice but not in CLOCK mutant mice. In addition, dramatic dexamethasone-induced protection of CHS was observed in CLOCK mutant mice compared with WT mice. CONCLUSIONS: The present results suggest that circadian rhythm might be an important factor in the regulation of CHS via corticosterone rhythmicity and/or level.

Ciclosporin A inhibits production of interleukin-12/23p40 and interleukin-23 by the human monocyte cell line, THP-1.

Ciclosporin (Cs)A is an effective treatment for psoriasis. However, to date, the effect of CsA on the production of interleukins (ILs) is unknown. We investigated how CsA affects production of IL-12/23p40 and IL-23 production by the human monocyte cell line, THP-1, which is able to differentiate into macrophage-like cells or normal human keratinocytes (NHKs). THP-1 cells were preincubated with CsA, then stimulated with lipopolysaccharide (LPS), polyinosinic:polycytidylic acid or adenosine triphosphate. The levels of IL-12/23p40 and IL-23 released into the supernatant were assayed by ELISA. CsA significantly reduced both IL-12/23p40 and IL-23 production by LPS-stimulated THP-1 cells, but not in LPS-stimulated macrophage-like differentiated THP-1 cells. None of the stimuli used significantly induced either IL-12/23p40 or IL-23 production in NHKs. CsA inhibits not only IL-12/23p40 and IL-12p70, but also heterodimeric IL-23 production by human monocytes, which may be one possible mechanism for the therapeutic efficacy of CsA in psoriasis.

Postoperative DAV-IFN-ß therapy does not improve survival rates of stage II and stage III melanoma patients significantly.

BACKGROUND: DAV-interferon (IFN)-ß therapy is a combination chemotherapy of dacarbazine (DTIC), nimustine (ACNU) and vincristine (VCR) with local subcutaneous injection of IFN-ß that is widely employed as postoperative adjuvant chemotherapy to treat malignant melanoma in Japan. However, the efficacy of DAV-IFN-ß therapy has not been confirmed by randomized controlled trials and the benefit of DAV-IFN-ß therapy has not been established yet. This study evaluated the contribution of DAV-IFN-ß therapy to improve survival of postoperative patients with cutaneous melanoma. Methods Patients with stage II or III cutaneous melanoma seen at Nagoya University Hospital from January 1998 to December 2009 were eligible for this study. Disease-free survival rates and melanoma-specific survival rates were evaluated. A propensity score was calculated to control for the effects of variables related to decisions regarding the application of DAV-IFN-ß therapy. RESULTS: Eighty-two stage II and 60 stage III melanoma patients were included. In the post-matched stage II patients (17 matched pairs), the mean (± SE) disease-free survival rates were 39.9 ± 13.7% for DAV-IFN-ß therapy and 73.1 ± 11.7% for non-use (hazard ratio for recurrence, 2.06; 95% CI, 0.63-6.69; P = 0.23), and the melanoma-specific survival rates were 66.2 ± 20.0% for DAV-IFN-ß therapy and 86.2 ± 9.1% for non-use (hazard ratio for death, 1.09; 95% CI, 0.17-6.82; P = 0.93). In the post-matched stage III patients (nine matched pairs), the disease-free survival rates were 29.6 ± 16.4% for DAV-IFN-ß therapy and 33.3 ± 15.7% for non-use (0.69; 95% CI, 0.22-2.17; P = 0.53), and the melanoma-specific survival rates were 55.6 ± 16.6% for DAV-IFN-ß therapy and 44.4 ± 16.6% for non-use (0.67; 95% CI, 0.18-2.50; P = 0.55). CONCLUSIONS: DAV-IFN-ß therapy brought no significant improvement in either disease-free survival rates or melanoma-specific survival rates of patients with stage II or III cutaneous melanoma. A randomized controlled trial would be required to further evaluate the efficacy of DAV-IFN-ß therapy as an adjuvant chemotherapy.

Long-term survival after high-dose chemotherapy followed by peripheral stem cell rescue for high-risk, locally advanced/inflammatory, and metastatic breast cancer.

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials.

A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer.

PURPOSE: Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. METHODS: Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). RESULTS: Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. CONCLUSIONS: Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.