Chemotherapy Plus Atezolizumab Pre- and Post-Resection in Localized Esophageal or Gastroesophageal Junction Adenocarcinomas: A Phase I/II Single-Arm Study.

Efforts to improve the prognosis for patients with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma have focused on neoadjuvant approaches to increase the pathological complete response (pathCR) rate, improve surgical resection, and prolong event-free and overall survival (OS). Building on the recent evidence that PD-1 inhibition plus chemotherapy improves the OS of patients with metastatic GEJ adenocarcinoma, we evaluated whether the application of this strategy in the neoadjuvant setting would improve the pathological response. This single-center phase I/II trial evaluated the safety, toxicity, and efficacy of neoadjuvant atezolizumab with oxaliplatin and 5-fluorouracil (modified FOLFOX) followed by esophagectomy followed by atezolizumab. The primary objective goal was to achieve 20% pathCR. From the twenty enrolled patients, eighteen underwent resection and two (10%, 95% CI: 1.24-31.7%) achieved pathCR. After a median follow-up duration of 40.7 months, 11 patients had disease recurrence and 10 had died. The median disease-free and OS were 28.8 (95% CI: 14.7, NA) and 38.6 months (95% CI: 30.5, NA), respectively. No treatment-related adverse events led to death. Although modified FOLFOX plus atezolizumab did not achieve the expected pathCR, an acceptable safety profile was observed. Our results support the continued development of a more refined strategy (neoadjuvant chemotherapy plus perioperative immunotherapy/targeted agents) with molecular/immune profiling in parallel.

Unsteady Magnetopause Reconnection Under Quasi-Steady Solar Wind Driving.

The intrinsic temporal nature of magnetic reconnection at the magnetopause has been an active area of research. Both temporally steady and intermittent reconnection have been reported. We examine the steadiness of reconnection using space-ground conjunctions under quasi-steady solar wind driving. The spacecraft suggests that reconnection is first inactive, and then activates. The radar further suggests that after activation, reconnection proceeds continuously but unsteadily. The reconnection electric field shows variations at frequencies below 10 mHz with peaks at 3 and 5 mHz. The variation amplitudes are ∼10-30 mV/m in the ionosphere, and 0.3-0.8 mV/m at the equatorial magnetopause. Such amplitudes represent 30%-60% of the peak reconnection electric field. The unsteadiness of reconnection can be plausibly explained by the fluctuating magnetic field in the turbulent magnetosheath. A comparison with a previous global hybrid simulation suggests that it is the foreshock waves that drive the magnetosheath fluctuations, and hence modulate the reconnection.

Effects of Subauroral Polarization Streams on the Upper Thermospheric Winds During Non-Storm Time.

Intense sunward (westward) plasma flows, named Subauroral Polarization Stream (SAPS), have been known to occur equatorward of the electron auroras for decades, yet their effect on the upper thermosphere has not been well understood. On the one hand, the large velocity of SAPS results in large momentum exchange upon each ion-neutral collision. On the other hand, the low plasma density associated with SAPS implies a low ion-neutral collision frequency. We investigate the SAPS effect during non-storm time by utilizing a Scanning Doppler Imager (SDI) for monitoring the upper thermosphere, SuperDARN radars for SAPS, all-sky imagers and DMSP Spectrographic Imager for the auroral oval, and GPS receivers for the total electron content. Our observations suggest that SAPS at times drives substantial (>50 m/s) westward winds at subauroral latitudes in the dusk-midnight sector, but not always. The occurrence of the westward winds varies with AE index, plasma content in the trough, and local time. The latitudinally averaged wind speed varies from 60 to 160 m/s, and is statistically 21% of the plasma. These westward winds also shift to lower latitude with increasing AE and increasing MLT. We do not observe SAPS driving poleward wind surges, neutral temperature enhancements, or acoustic-gravity waves, likely due to the somewhat weak forcing of SAPS during the non-storm time.

Geospace Plume and Its Impact on Dayside Magnetopause Reconnection Rate.

The role a geospace plume in influencing the efficiency of magnetopause reconnection is an open question with two contrasting theories being debated. A local-control theory suggests that a plume decreases both local and global reconnection rates, whereas a global-control theory argues that the global reconnection rate is controlled by the solar wind rather than local physics. Observationally, limited numbers of point measurements from spacecraft cannot reveal whether a local change affects the global reconnection. A distributed observatory is hence needed to assess the validity of the two theories. We use THEMIS and Los Alamos National Laboratory spacecraft to identify the occurrence of a geospace plume and its contact with the magnetopause. Global evolution and morphology of the plume is traced using GPS measurements. SuperDARN is then used to monitor the distribution and the strength of dayside reconnection. Two storm-time geospace plume events are examined and show that as the plume contacts the magnetopause, the efficiency of reconnection decreases at the contact longitude. The amount of local decrease is 81% and 68% for the two events, and both values are consistent with the mass loading effect of the plume if the plume's atomic mass is ∼4 amu. Reconnection in the surrounding is enhanced, and when the solar wind driving is stable, little variation is seen in the cross polar cap potential. This study illuminates a pathway to resolve the role of cold dense plasma on solar wind-magnetosphere coupling, and the observations suggest that plumes redistribute magnetopause reconnection activity without changing the global strength substantially.

A space hurricane over the Earth's polar ionosphere.

In Earth's low atmosphere, hurricanes are destructive due to their great size, strong spiral winds with shears, and intense rain/precipitation. However, disturbances resembling hurricanes have not been detected in Earth's upper atmosphere. Here, we report a long-lasting space hurricane in the polar ionosphere and magnetosphere during low solar and otherwise low geomagnetic activity. This hurricane shows strong circular horizontal plasma flow with shears, a nearly zero-flow center, and a coincident cyclone-shaped aurora caused by strong electron precipitation associated with intense upward magnetic field-aligned currents. Near the center, precipitating electrons were substantially accelerated to ~10 keV. The hurricane imparted large energy and momentum deposition into the ionosphere despite otherwise extremely quiet conditions. The observations and simulations reveal that the space hurricane is generated by steady high-latitude lobe magnetic reconnection and current continuity during a several hour period of northward interplanetary magnetic field and very low solar wind density and speed.

Sensitivity of Upper Atmosphere to Different Characteristics of Flow Bursts in the Auroral Zone.

Meso-scale plasma convection and particle precipitation could be significant momentum and energy sources for the ionosphere-thermosphere (I-T) system. Following our previous work on the I-T response to a typical midnight flow burst, flow bursts with different characteristics (lifetime, size, and speed) have been examined systematically with Global Ionosphere-Thermosphere Model (GITM) simulations in this study. Differences between simulations with and without additional flow bursts are used to illustrate the impact of flow bursts on the I-T system. The neutral density perturbation due to a flow burst increases with the lifetime, size, and flow speed of the flow burst. It was found that the neutral density perturbation is most sensitive to the size of a flow burst, increasing from ∼0.3% to ∼1.3% when the size changes from 80 to 200 km. A westward-eastward asymmetry has been identified in neutral density, wind, and temperature perturbations, which may be due to the changing of the forcing location in geographic coordinates and the asymmetrical background state of the I-T system. In addition to midnight flow bursts, simulations with flow bursts centered at noon, dawn, and dusk have also been carried out. A flow burst centered at noon (12.0 Local Time [LT], 73°N) produces the weakest perturbation, and a flow burst centered at dusk (18.0 LT, 71°N) produces the strongest. Single-cell and two-cell flow bursts induce very similar neutral density perturbation patterns.

Multiple transpolar auroral arcs reveal insight about coupling processes in the Earth's magnetotail.

A distinct class of aurora, called transpolar auroral arc (TPA) (in some cases called "theta" aurora), appears in the extremely high-latitude ionosphere of the Earth when interplanetary magnetic field (IMF) is northward. The formation and evolution of TPA offers clues about processes transferring energy and momentum from the solar wind to the magnetosphere and ionosphere during a northward IMF. However, their formation mechanisms remain poorly understood and controversial. We report a mechanism identified from multiple-instrument observations of unusually bright, multiple TPAs and simulations from a high-resolution three-dimensional (3D) global MagnetoHydroDynamics (MHD) model. The observations and simulations show an excellent agreement and reveal that these multiple TPAs are generated by precipitating energetic magnetospheric electrons within field-aligned current (FAC) sheets. These FAC sheets are generated by multiple-flow shear sheets in both the magnetospheric boundary produced by Kelvin-Helmholtz instability between supersonic solar wind flow and magnetosphere plasma, and the plasma sheet generated by the interactions between the enhanced earthward plasma flows from the distant tail (less than -100 RE) and the enhanced tailward flows from the near tail (about -20 RE). The study offers insight into the complex solar wind-magnetosphere-ionosphere coupling processes under a northward IMF condition, and it challenges existing paradigms of the dynamics of the Earth's magnetosphere.

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer.

PURPOSE: Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial. PATIENTS AND METHODS: Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc. RESULTS: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25-7.20 months)/9.9 (6.74-12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06-23.49 months)]. Overall response rate (95% CI) was 18% (8.6%-31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 <5%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67+ CD8+/CD4+ cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67+ CD8+ T-cell values were higher in responders than in nonresponders. CONCLUSIONS: The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.

Safety and Efficacy Results of a Phase I, Open-Label Study of Concurrent and Delayed Nivolumab in Combination With nab-Paclitaxel and Carboplatin in Advanced Non-small Cell Lung Cancer.

Introduction: Multicenter, phase I study of concurrent and delayed nivolumab plus nab-paclitaxel/carboplatin in advanced non-small cell lung cancer (NSCLC). Methods: Chemotherapy-naive patients with advanced NSCLC (ineligible for potentially curative radiation or surgery) received nab-paclitaxel 100 mg/m2 (days 1, 8, 15) and carboplatin area under the curve 6 (day 1) intravenously every 21 days (first 4 cycles); nivolumab 5 mg/kg was administered intravenously (day 15) beginning in cycle 1 (concurrent) or cycle 3 (delayed) in separate cohorts and continued beyond the 4 chemotherapy cycles. The primary objective was to assess safety. Secondary objectives were to assess tolerability and explore antitumor activity. Results: All 32 patients received chemotherapy; 20 of 22 and 6 of 10 patients also received concurrent or delayed nivolumab, respectively. No dose-limiting toxicities were reported in the concurrent cohort; 1 dose-limiting toxicity was reported in the delayed cohort. In the concurrent cohort, 20 patients (91%) had ≥1 grade 3/4 treatment-emergent adverse event (TEAE), and 7 (32%) discontinued treatment due to TEAEs. In the delayed cohort, all patients had ≥1 grade 3/4 TEAE, and 2 (20%) discontinued due to TEAEs. The median progression-free and overall survival, respectively, were 10.5 and 29.3 months in the concurrent cohort and 4.1 and 8.2 months in the delayed cohort. Conclusions: The safety profile of the combination was consistent with that of individual agents and generally similar in the 2 cohorts. Efficacy outcomes in the concurrent cohort, but not in the delayed cohort, were encouraging and support the rationale for concurrent administration of nivolumab with nab-paclitaxel/carboplatin for the treatment of advanced NSCLC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02309177.

Stormtime substorm onsets: occurrence and flow channel triggering.

Bright auroral emissions during geomagnetic storms provide a good opportunity for testing the proposal that substorm onset is frequently triggered by plasma sheet flow bursts that are manifested in the ionosphere as auroral streamers. We have used the broad coverage of the ionospheric mapping of the plasma sheet offered by the high-resolution THEMIS all-sky-imagers (ASIs) and chose the main phases of 9 coronal mass ejection (CME) related and 9 high-speed stream (HSS)-related geomagnetic storms, and identified substorm auroral onsets defined as brightening followed by poleward expansion. We found a detectable streamer heading to near the substorm onset location for all 60 onsets that we identified and were observed well by the ASIs. This indicates that substorm onsets are very often triggered by the intrusion of plasma with lower entropy than the surrounding plasma to the onset region, with the caveat that the ASIs do not give a direct measure of the intruding plasma. The majority of the triggering streamers are "tilted streamers," which extend eastward as their eastern tip tilts equatorward to near the substorm onset location. Fourteen of the 60 cases were identified as "Harang streamers," where the streamer discernibly turns toward the west poleward of reaching to near the onset latitude, indicating flow around the Harang reversal. Using the ASI observations, we observed substantially less substorm onsets for CME storms than for HSS storms, a result in disagreement with a recent finding of approximately equal substorm occurrences. We suggest that this difference is a result of strong non-substorm streamers that give substorm-like signatures in ground magnetic field observations but are not substorms based on their auroral signature. Our results from CME storms with steady, strong southward IMF are not consistent with the ~ 2-4 h repetition of substorms that has been suggested for moderate to strong southward IMF conditions. Instead, our results indicate substantially lower substorm occurrence during such steady driving conditions. Our results also show the much more frequent occurrence of substorms during HSS period, which is likely due to the highly fluctuating IMF.

Treatment of Waldenstrom's macroglobulinemia with clarithromycin, low-dose thalidomide, and dexamethasone.

Twelve patients with Waldenstrom's macroglobulinemia (WM) underwent treatment with the nonmyelosuppressive combination regimen BLT-D: clarithomycin (Biaxin [BXN], Abbott Laboratories, Abbott Park, IL) 500 mg orally twice daily, low-dose thalidomide (THAL) 50 mg orally escalated to 200 mg daily, and dexamethasone (DXM) 40 mg orally once weekly all with modification for toxicity. Omeprazole (correction of omepraxole) 20 mgm orally twice daily for 2 days with the DXM, and enteric-coated aspirin 81 mg orally daily were also administered. Twelve patients have been evaluated. All had previously received at least one purine analogue or alkylating agent. Five had a reduction in either leukocytes and/or platelets prior to treatment, of which three were disease-related. Median age was 62 years. All patients received a minimum of 6 weeks of therapy. Of the 12 patients, 10 had a significant response (83%) consisting of three near complete, three major, four partial, and two minor responses. Four of five had restoration of reduced blood counts. Two with minor responses did not receive sufficient dose escalation due to toxicity. Median time on therapy was 7 months (range, 3 to 28 months). Patients were removed from therapy primarily due to neurotoxicity. Drug resistance occurred in three patients, with one transformation to large cell lymphoma. Toxicity was as follows: gastrointestinal (primarily constipation), 42%; neurological, 100%; endocrine, 42%, and thrombotic, 8%. Most toxicities were World Health Organization (WHO) grade 1 or 2; however, neurological toxicity was more prominent and severe in WM patients than in myeloma. BLT-D is effective in WM. Because of its toxicity, predominantly neurological, BLT-D may best serve as an induction regimen or to "rescue" patients with refractory disease or disease-related low counts.

Extended survival in advanced-stage multiple myeloma patients treated with gallium nitrate.

Adjunctive anti-bone resorption therapy has become an important part of multiple myeloma (MM) treatment. Currently, no definite evidence exists that this therapy increases survival. We examined a cohort of 13 of 167 patients (8%) treated with the M-2 protocol who received adjuvant gallium nitrate (GN) treatment for osteolysis, and then compared the outcome of these patients to all individuals treated with the M-2 regimen. The stage at diagnosis was IA in two patients, IIIA in 10 patients and IIIB in one. Median age at diagnosis was 51 years (range 35-73). Median (range) of entry data were: paraprotein level: 6000mg/dl (3058-8675); beta2M: 2.7mg/l, (1.2-9.6); LDH: 166U/l (142-237); hemoglobin: 10.2 g/dl (8.3-12.6); albumin: 3.7 g/dl (2.5-5.0); calcium: 10.0 mg/dl (8.3-14.5); creatinine: 1.2 mg/dl (0.7-2.7). Median survival in these patients was 87+ months from time of diagnosis compared with 48 months for all other patients treated on the M-2 protocol. We identified a subgroup of patients with remarkably prolonged survival who had received M-2 chemotherapy and GN. Survival in this group markedly exceeds expectations for patients with advanced stage disease and poor prognostic features. The administration of GN may have a positive impact on survival either by decreasing skeletal complications or through a direct action of GN on the complex cytokine network involved in the proliferation of the malignant myeloma cell.

Impact of early response to sequential high-dose chemotherapy on outcome of patients with advanced myeloma and poor prognostic features.

We report the results of a dose-intense chemotherapy regimen designed to rapidly induce remissions in patients with advanced multiple myeloma (MM). Patients received VAD for 3-6 cycles depending on response kinetics. This was followed by three sequential cycles of cyclophosphamide (CTX) at 3 g/m2 every 15 days with G-CSF support. 71% of these patients had stage IIIa, 23% had renal failure. The median age was 58, median beta-2 microglobulin 4.6 and median albumin was 3.5, indicating poor prognosis. Of 35 patients, 66% achieved a complete response (CR) (SWOG). Six patients (18%) had a partial response. Fifty percent of the patients with renal failure recovered their kidney function. High-dose CTX contributed to tumor-mass reduction particularly in patients presenting with high-tumor burden. Tumor-mass reduction following three pulses of dexamethasone (4 days each) is significantly higher than with one pulse (p < 0.005). While high beta-2 microglobulin and LDH levels (p < 0.05) were associated with poor outcome, patients who responded faster to chemotherapy had a longer survival (p = 0.005). We conclude that this regimen is safe and effective. A rapid response may be useful in selecting patients who may benefit from further high dose chemotherapy and stem cell support.

BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Waldenström's macroglobulinemia.

Multiple myeloma remains incurable. Despite the pursuit of various chemotherapeutic approaches, little improvement in outcome has been made in the last 30 years. Thalidomide, dexamethasone, and clarithromycin are oral, nonmyelosuppressive agents, each with reported single agent activity against myeloma. We evaluated a regimen of clarithromycin (Biaxin), low-dose thalidomide and dexamethasone (BLT-D) in patients with previously untreated or treated multiple myeloma or Waldenström's macroglobulinemia. Patients were initially given clarithromycin 500 mg twice daily, thalidomide 50-200 mg daily, and dexamethasone 40 mg weekly until disease progression. Minimum response was defined as > 50% reduction in monoclonal immunoglobulin or light chain levels in serum or urine. Response, toxicity, and survival were determined on an evaluable and/or intent-to-treat basis. Of the 50 patients available for analysis, 92% remain alive and 64% remain on treatment with a median and mean duration of treatment of 7 and 8 months, respectively. Overall, 93% of evaluable patients responded to BLT-D, including 13% complete remissions, 40% near complete responses, 13% major responses, and 27% partial responses. Minimal drug resistance was initially encountered. Neurotoxicity, although usually mild to moderate, was the primary reason for treatment discontinuation. Only four patients died, including three sudden deaths in patients with severe cardiopulmonary disease. It appears that BLT-D is a highly effective, nonmyelosuppressive regimen for myeloma. Caution should be exercised when using thalidomide, alone or in combination, in patients with a preexisting tendency to thromboses, severe cardiopulmonary disease, or neurologic dysfunction.