Phase I Study of a Multivalent WT1 Peptide Vaccine (Galinpepimut-S) in Combination with Nivolumab in Patients with WT1-Expressing Ovarian Cancer in Second or Third Remission.

We examined the safety and immunogenicity of sequential administration of a tetravalent, non-HLA (human leukocyte antigen) restricted, heteroclitic Wilms' Tumor 1 (WT1) peptide vaccine (galinpepimut-S) with anti-PD-1 (programmed cell death protein 1) nivolumab. This open-label, non-randomized phase I study enrolled patients with WT1-expressing ovarian cancer in second or third remission from June 2016 to July 2017. Therapy included six (every two weeks) subcutaneous inoculations of galinpepimut-S vaccine adjuvanted with Montanide, low-dose subcutaneous sargramostim at the injection site, with intravenous nivolumab over 12 weeks, and up to six additional doses until disease progression or toxicity. One-year progression-free survival (PFS) was correlated to T-cell responses and WT1-specific immunoglobulin (Ig)G levels. Eleven patients were enrolled; seven experienced a grade 1 adverse event, and one experienced a grade ≥3 adverse event considered a dose-limiting toxicity. Ten (91%) of eleven patients had T-cell responses to WT1 peptides. Seven (88%) of eight evaluable patients had IgG against WT1 antigen and full-length protein. In evaluable patients who received >2 treatments of galinpepimut-S and nivolumab, the 1-year PFS rate was 70%. Coadministration of galinpepimut-S and nivolumab demonstrated a tolerable toxicity profile and induced immune responses, as indicated by immunophenotyping and WT1-specific IgG production. Exploratory analysis for efficacy yielded a promising 1-year PFS rate.

Earthquake Nowcasting: Retrospective Testing in Greece.

Earthquake nowcasting (EN) is a modern method of estimating seismic risk by evaluating the progress of the earthquake (EQ) cycle in fault systems. EN evaluation is based on a new concept of time, termed 'natural time'. EN employs natural time, and uniquely estimates seismic risk by means of the earthquake potential score (EPS), which has been found to have useful applications both regionally and globally. Amongst these applications, here we focused on Greece since 2019, for the estimation of the EPS for the largest-magnitude events, MW(USGS) ≥ 6, that occurred during our study period: for example, the MW= 6.0 WNW-of-Kissamos EQ on 27 November 2019, the MW= 6.5 off-shore Southern Crete EQ on 2 May 2020, the MW= 7.0 Samos EQ on 30 October 2020, the MW= 6.3 Tyrnavos EQ on 3 March 2021, the MW= 6.0 Arkalohorion Crete EQ on 27 September 2021, and the MW= 6.4 Sitia Crete EQ on 12 October 2021. The results are promising, and reveal that the EPS provides useful information on impending seismicity.

Estimating the Epicenter of a Future Strong Earthquake in Southern California, Mexico, and Central America by Means of Natural Time Analysis and Earthquake Nowcasting.

It has recently been shown in the Eastern Mediterranean that by combining natural time analysis of seismicity with earthquake networks based on similar activity patterns and earthquake nowcasting, an estimate of the epicenter location of a future strong earthquake can be obtained. This is based on the construction of average earthquake potential score maps. Here, we propose a method of obtaining such estimates for a highly seismically active area that includes Southern California, Mexico and part of Central America, i.e., the area N1035W80120. The study includes 28 strong earthquakes of magnitude M ≥7.0 that occurred during the time period from 1989 to 2020. The results indicate that there is a strong correlation between the epicenter of a future strong earthquake and the average earthquake potential score maps. Moreover, the method is also applied to the very recent 7 September 2021 Guerrero, Mexico, M7 earthquake as well as to the 22 September 2021 Jiquilillo, Nicaragua, M6.5 earthquake with successful results. We also show that in 28 out of the 29 strong M ≥7.0 EQs studied, their epicenters lie close to an estimated zone covering only 8.5% of the total area.

Natural Time Analysis: The Area under the Receiver Operating Characteristic Curve of the Order Parameter Fluctuations Minima Preceding Major Earthquakes.

It has been reported that major earthquakes are preceded by Seismic Electric Signals (SES). Observations show that in the natural time analysis of an earthquake (EQ) catalog, an SES activity starts when the fluctuations of the order parameter of seismicity exhibit a minimum. Fifteen distinct minima-observed simultaneously at two different natural time scales and deeper than a certain threshold-are found on analyzing the seismicity of Japan from 1 January 1984 to 11 March 2011 (the time of the M9 Tohoku EQ occurrence) 1 to 3 months before large EQs. Six (out of 15) of these minima preceded all shallow EQs of magnitude 7.6 or larger, while nine are followed by smaller EQs. The latter false positives can be excluded by a proper procedure (J. Geophys. Res. Space Physics 2014, 119, 9192-9206) that considers aspects of EQ networks based on similar activity patterns. These results are studied here by means of the receiver operating characteristics (ROC) technique by focusing on the area under the ROC curve (AUC). If this area, which is currently considered an effective way to summarize the overall diagnostic accuracy of a test, has the value 1, it corresponds to a perfectly accurate test. Here, we find that the AUC is around 0.95 which is evaluated as outstanding.

Nowcasting Avalanches as Earthquakes and the Predictability of Strong Avalanches in the Olami-Feder-Christensen Model.

Nowcasting earthquakes, suggested recently as a method to estimate the state of a fault and hence the seismic risk, is based on the concept of natural time. Here, we generalize nowcasting to a prediction method the merits of which are evaluated by means of the receiver operating characteristics. This new prediction method is applied to a simple (toy) model for the waiting (natural) time of the stronger earthquakes, real seismicity, and the Olami-Feder-Christensen earthquake model with interesting results revealing acceptable to excellent or even outstanding performance.

Identifying the Occurrence Time of the Deadly Mexico M8.2 Earthquake on 7 September 2017.

It has been shown that some dynamic features hidden in the time series of complex systems can be unveiled if we analyze them in a time domain termed natural time. In this analysis, we can identify when a system approaches a critical point (dynamic phase transition). Here, based on natural time analysis, which enables the introduction of an order parameter for seismicity, we discuss a procedure through which we could achieve the identification of the occurrence time of the M8.2 earthquake that occurred on 7 September 2017 in Mexico in Chiapas region, which is the largest magnitude event recorded in Mexico in more than a century. In particular, we first investigated the order parameter fluctuations of seismicity in the entire Mexico and found that, during an almost 30-year period, i.e., from 1 January 1988 until the M8.2 earthquake occurrence, they were minimized around 27 July 2017. From this date, we started computing the variance of seismicity in Chiapas region and found that it approached the critical value 0.070 on 6 September 2017, almost one day before this M8.2 earthquake occurrence.

Micro-scale, mid-scale, and macro-scale in global seismicity identified by empirical mode decomposition and their multifractal characteristics.

The magnitude time-series of the global seismicity is analyzed by the empirical mode decomposition giving rise to 14 intrinsic mode functions (IMF) and a trend. Using Hurst analysis one can identify three different sums of these IMFs and the trend which exhibit distinct multifractal behaviour and correspond to micro-, mid- and macro-scales. Their multifractal detrended fluctuation analysis reveals that the micro-scale time-series exhibits anticorrelated behaviour in contrast to the mid-scale one which is long-range correlated. Concerning the mid-scale one, in the range of 30 to 300 consecutive events the maximum entropy method power spectra indicates that it exhibits an 1/f α behaviour with α close to 1/3 which is compatible with the long-range correlations identified by detrended fluctuation analysis during periods of stationary seismicity. The results have been also verified to hold regionally for the earthquakes in Japan and shed light on the significance of the mid-scale of 30 to 300 events in the natural time analysis of global (and regional) seismicity. It is shown that when using the mid-scale time-series only, we can obtain results similar to those obtained by the natural time analysis of global seismicity when focusing on the prediction of earthquakes with M ≥ 8.4.

Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia.

A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. We previously reported a pilot study of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia (AML) patients. We have now conducted a phase 2 study investigating this vaccine in adults with AML in first complete remission (CR1). Patients received 6 vaccinations administered over 10 weeks with the potential to receive 6 additional monthly doses if they remained in CR1. Immune responses (IRs) were evaluated after the 6th and 12th vaccinations by CD4+ T-cell proliferation, CD8+ T-cell interferon-γ secretion (enzyme-linked immunospot), or the CD8-relevant WT1 peptide major histocompatibility complex tetramer assay (HLA-A*02 patients only). Twenty-two patients (7 males; median age, 64 years) were treated. Fourteen patients (64%) completed ≥6 vaccinations, and 9 (41%) received all 12 vaccine doses. Fifteen patients (68%) relapsed, and 10 (46%) died. The vaccine was well tolerated, with the most common toxicities being grade 1/2 injection site reactions (46%), fatigue (32%), and skin induration (32%). Median disease-free survival from CR1 was 16.9 months, whereas the overall survival from diagnosis has not yet been reached but is estimated to be ≥67.6 months. Nine of 14 tested patients (64%) had an IR in ≥1 assay (CD4 or CD8). These results indicated that the WT1 vaccine was well tolerated, stimulated a specific IR, and was associated with survival in excess of 5 years in this cohort of patients. This trial was registered at www.clinicaltrials.gov as #NCT01266083.

The Complexity Measures Associated with the Fluctuations of the Entropy in Natural Time before the Deadly México M8.2 Earthquake on 7 September 2017.

We analyse seismicity during the 6-year period 2012-2017 in the new time domain termed natural time in the Chiapas region where the M8.2 earthquake occurred, Mexico's largest earthquake in more than a century, in order to study the complexity measures associated with fluctuations of entropy as well as with entropy change under time reversal. We find that almost three months before the M8.2 earthquake, i.e., on 14 June 2017, the complexity measure associated with the fluctuations of entropy change under time reversal shows an abrupt increase, which, however, does not hold for the complexity measure associated with the fluctuations of entropy in forward time. On the same date, the entropy change under time reversal has been previously found to exhibit a minimum [Physica A 506, 625-634 (2018)]; we thus find here that this minimum is also accompanied by increased fluctuations of the entropy change under time reversal. In addition, we find a simultaneous increase of the Tsallis entropic index q.

Statistical Significance of Earth's Electric and Magnetic Field Variations Preceding Earthquakes in Greece and Japan Revisited.

By analyzing the seismicity in a new time domain, termed natural time, we recently found that the change of the entropy under time reversal (Physica A2018, 506, 625-634) and the relevant complexity measures (Entropy2018, 20, 477) exhibit pronounced variations before the occurrence of the M8.2 earthquake in Mexico on 7 September 2017. Here, the statistical significance of precursory phenomena associated with other physical properties and in particular the anomalous variations observed in the Earth's electric and magnetic fields before earthquakes in different regions of the world and in particular in Greece since 1980s and Japan during 2001-2010 are revisited (the latter, i.e., the magnetic field variations are alternatively termed ultra low frequency (ULF) seismo-magnetic phenomena). Along these lines we employ modern statistical tools like the event coincidence analysis and the receiver operating characteristics technique. We find that these precursory variations are far beyond chance and in addition their lead times fully agree with the experimental findings in Greece since the 1980s.

Tsallis Entropy Index q and the Complexity Measure of Seismicity in Natural Time under Time Reversal before the M9 Tohoku Earthquake in 2011.

The observed earthquake scaling laws indicate the existence of phenomena closely associated with the proximity of the system to a critical point. Taking this view that earthquakes are critical phenomena (dynamic phase transitions), here we investigate whether in this case the Lifshitz-Slyozov-Wagner (LSW) theory for phase transitions showing that the characteristic size of the minority phase droplets grows with time as t 1 / 3 is applicable. To achieve this goal, we analyzed the Japanese seismic data in a new time domain termed natural time and find that an LSW behavior is actually obeyed by a precursory change of seismicity and in particular by the fluctuations of the entropy change of seismicity under time reversal before the Tohoku earthquake of magnitude 9.0 that occurred on 11 March 2011 in Japan. Furthermore, the Tsallis entropic index q is found to exhibit a precursory increase.

Study in Natural Time of Geoelectric Field and Seismicity Changes Preceding the Mw6.8 Earthquake on 25 October 2018 in Greece.

A strong earthquake of magnitude M w 6.8 struck Western Greece on 25 October 2018 with an epicenter at 37.515 ∘ N 20.564 ∘ E. It was preceded by an anomalous geolectric signal that was recorded on 2 October 2018 at a measuring station 70 km away from the epicenter. Upon analyzing this signal in natural time, we find that it conforms to the conditions suggested for its identification as precursory Seismic Electric Signal (SES) activity. Notably, the observed lead time of 23 days lies within the range of values that has been very recently identified as being statistically significant for the precursory variations of the electric field of the Earth. Moreover, the analysis in natural time of the seismicity subsequent to the SES activity in the area candidate to suffer this strong earthquake reveals that the criticality conditions were obeyed early in the morning of 18 October 2018, i.e., almost a week before the strong earthquake occurrence, in agreement with earlier findings. Finally, when employing the recent method of nowcasting earthquakes, which is based on natural time, we find an earthquake potential score around 80%.

Estimating the Compressibility of Osmium from Recent Measurements of Ir-Os Alloys under High Pressure.

Several fcc- and hcp-structured Ir-Os alloys have been recently studied up to 30 GPa at room temperature by means of synchrotron-based X-ray powder diffraction in diamond anvil cells. Using their bulk moduli, which increase with increasing osmium content, showing a deviation from linearity, and after employing a thermodynamical model, it was concluded that the bulk modulus for osmium is slightly smaller than that for diamond. Here, a similar conclusion is obtained upon employing an alternative model, thus strengthening the conclusion that osmium is the densest but not the most incompressible element. This is particularly interesting for Earth Sciences because it may be of key importance toward clarifying the anomalous elastic properties of the Earth's core.

Endothelial growth factor receptor inhibitors in recurrent metastatic cancer of the head and neck.

Targeted therapy has become an important new class of therapeutic agents used in squamous cell carcinoma of the head and neck (SCCHN). Among them epidermal growth factor receptor (EGFR) inhibitors have been studied the most. Today, two classes of EGFR inhibitors are routinely used in the clinic; anti-EGFR monoclonal antibodies and small-molecule inhibitors of the EGFR tyrosine kinase activity. These agents have been used clinically in the recurrent metastatic (R/M) settings but only cetuximab has reached a regulatory approval. Current research is focused on innovative compound design, predictive biomarker discovery, and combination strategies in order to overcome resistance. Efforts should also be focused on endpoints other than overall survival, which is the current gold standard, such as surrogate endpoints. This article summarizes the clinical evidence of the anticancer activity of EGFR inhibitors in patients with R/M SCCHN, and analyzes the current, controversial clinical issues with respect to their interpretation. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2221-E2228, 2016.

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).

Patterns of hydroxyurea use and clinical outcomes among patients with polycythemia vera in real-world clinical practice: a chart review.

BACKGROUND: Hydroxyurea (HU) is among the most commonly used cytoreductive treatments for polycythemia vera (PV), but previous research and clinical experience suggest that not all patients respond optimally, consistently, or durably to HU treatment. This study investigated patterns of HU use and impact on disease control among patients with PV in real-world clinical practice in the United States. METHODS: Oncologists and hematologists recruited between April and July 2014 reported data from patient charts. Treatment history and disease symptom comparisons between HU subgroups were performed using Chi square tests or one-way analyses of variance for categorical and continuous variables. Other analyses were performed using descriptive statistics. RESULTS: Overall, 329 physicians participated and provided data on 1309 patients with PV (62.3 % male; mean age = 62.5 years, mean time since diagnosis = 5.2 years). In the 229 (17.5 %) patients who had stopped HU, the most common reasons for HU discontinuation-as assessed by the treating clinician-were inadequate response (29.3 %), intolerance (27.5 %), and disease progression (12.7 %). Among patients currently on HU, a significant proportion had elevated blood cell counts: 34.4 % had hematocrit values ≥45 %, 59.4 % had platelet levels >400 × 10(9)/L, and 58.2 % had WBC counts > 10 × 10(9)/L. Two-thirds (66.3 %) of patients had ≥1 elevated count, 40.3 % had ≥2 elevated counts, and 19.8 % had all 3 counts elevated. The most common PV-related signs and symptoms among all patients were fatigue and splenomegaly. CONCLUSIONS: Although many patients with PV benefit from HU therapy, some continue to have suboptimal control of their disease, as evidenced by persistence of abnormally elevated blood cell counts and the continued experience of disease-related manifestations (signs and symptoms). These data further denote a significant medical need for some patients with PV currently or previously treated with HU.

Spatiotemporal variations of seismicity before major earthquakes in the Japanese area and their relation with the epicentral locations.

Using the Japan Meteorological Agency earthquake catalog, we investigate the seismicity variations before major earthquakes in the Japanese region. We apply natural time, the new time frame, for calculating the fluctuations, termed ß, of a certain parameter of seismicity, termed κ1. In an earlier study, we found that ß calculated for the entire Japanese region showed a minimum a few months before the shallow major earthquakes (magnitude larger than 7.6) that occurred in the region during the period from 1 January 1984 to 11 March 2011. In this study, by dividing the Japanese region into small areas, we carry out the ß calculation on them. It was found that some small areas show ß minimum almost simultaneously with the large area and such small areas clustered within a few hundred kilometers from the actual epicenter of the related main shocks. These results suggest that the present approach may help estimation of the epicentral location of forthcoming major earthquakes.

Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes.

Myelofibrosis (MF) is a rare chronic BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homologue 1)-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of MF include splenomegaly, consequent to extramedullary hematopoiesis, cytopenias, and an array of potentially debilitating abdominal and constitutional symptoms. Dysregulated Janus kinase (JAK)-signal transducer and activator of transcription signaling underlies secondary disease-associated effects in MF, such as myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia. Common fatal complications of MF include transformation to acute leukemia, thrombohemorrhagic events, organ failure, and infections. Potential complications from hepatosplenomegaly include portal hypertension and variceal bleeding, whereas extramedullary hematopoiesis outside the spleen and liver - depending on the affected organ - may result in intracranial hypertension, spinal cord compression, pulmonary hypertension, pleural effusions, lymphadenopathy, skin lesions, and/or exacerbation of abdominal symptoms. Although allogeneic stem cell transplantation is the only potentially curative therapy, it is suitable for few patients. The JAK1/JAK2 inhibitor ruxolitinib is effective in improving splenomegaly, MF-related symptoms, and quality-of-life measures. Emerging evidence that ruxolitinib may be associated with a survival benefit in intermediate- or high-risk MF suggests the possibility of a disease-modifying effect. Consequently, ruxolitinib could provide a treatment backbone to which other (conventional and novel) therapies may be added for the prevention and effective management of specific MF-associated complications.

Acetylated tubulin (AT) as a prognostic marker in squamous cell carcinoma of the head and neck.

Acetylated tubulin (AT) expression has been proposed as a marker for sensitivity to taxane chemotherapy. We wanted to explore AT as a prognostic marker in squamous cell carcinoma of the head and neck (SCCHN). We assessed AT expression in archival tissue from our institutional tissue bank of primary SCCHN specimens. We also examined AT expression on pre-therapy tissues of patients with SCCHN receiving induction chemotherapy with docetaxel, cisplatin and 5FU (TPF IC). AT expression was assessed on archival cases of SCCHN with (N = 63) and without (N = 82) locoregional lymph node metastases (LNM). The predominant tumor site was oral cavity (52 %). Immunohistochemistry staining was based on staining intensity and percentage of tumor cells stained to create a weighted index (WI). A total of nine patients who received TPF IC were evaluable for response by RECIST and also had pre-therapy tissues available. A significant independent correlation between AT and tumor grade (p = 0.001) and primary location (p = 0.008) was noted. There was a trend of higher AT in patients with presence of LNM (p = 0.052) and a trend in improved OS for patients with an AT WI below the median compared to those above the median for patients with no LNM (p = 0.054). For patients treated with induction TPF, we observed an inverse correlation between AT expression and response to TPF IC (p = 0.0071). AT expression is correlated with tumor grade and primary site. There was an observed trend correlating AT with presence nodal metastases. The observed inverse correlation with response to taxane based chemotherapy needs validation in a larger sample size.

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes.

PURPOSE: Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures. PATIENTS AND METHODS: COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 10(9)/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100-200 × 10(9)/L and >200 × 10(9)/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24). RESULTS: The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8-12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses. CONCLUSION: This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.