Universal Constraint for Relaxation Rates for Quantum Dynamical Semigroup.

A general property of relaxation rates in open quantum systems is discussed. We find an interesting constraint for relaxation rates that universally holds in fairly large classes of quantum dynamics, e.g., weak coupling regimes, as well as for entropy nondecreasing evolutions. We conjecture that this constraint is universal, i.e., it is valid for all quantum dynamical semigroups. The conjecture is supported by numerical analysis. Moreover, we show that the conjectured constraint is tight by providing a concrete model that saturates the bound. This universality marks an essential step toward the physical characterization of complete positivity as the constraint is directly verifiable in experiments. It provides, therefore, a physical manifestation of complete positivity. Our conjecture also has two important implications: it provides (i) a universal constraint for the spectra of quantum channels and (ii) a necessary condition to decide whether a given channel is consistent with Markovian evolution.

Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer. Cancer-associated thrombosis/thromboembolism (CAT), frequently observed in PDAC, is known as a poor prognostic factor. Here, we investigated the underlying mechanisms between PDAC and CAT, and performed a trial of therapeutic approach for PDAC using a genetically engineered mouse model, PKF (Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox ). DESIGN: Presence of CAT in PKF mice was detected by systemic autopsy. Plasma cytokines were screened by cytokine antibody array. Murine and human plasma atrial natriuretic peptide (ANP) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were determined by ELISA. Distribution of VCAM-1 in PKF mice and human autopsy samples was detected by immunohistochemistry. PKF mice were treated with anti-VCAM-1 antibody and the effects on survival, distribution of CAT and the tumour histology were analysed. RESULTS: We found spontaneous CAT with cardiomegaly in 68.4% PKF mice. Increase of plasma ANP and sVCAM-1 was observed in PKF mice and PDAC patients with CAT. VCAM-1 was detected in the activated endothelium and thrombi. Administration of anti-VCAM-1 antibody to PKF mice inhibited tumour growth, neutrophil/macrophage infiltration, tumour angiogenesis and progression of CAT; moreover, it dramatically extended survival (from 61 to 253 days, p<0.01). CONCLUSION: Blocking VCAM-1/sVCAM-1 might be a potent therapeutic approach for PDAC as well as CAT, which can contribute to the prognosis. Increase of plasma ANP and sVCAM-1 might be a diagnostic approach for CAT in PDAC.

Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer.

Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.

Chemotherapy-induced neutropenia as a prognostic factor in patients with pancreatic cancer treated with gemcitabine plus nab-paclitaxel: a retrospective cohort study.

OBJECTIVES: Chemotherapy-induced neutropenia (CIN) is a common adverse event of chemotherapy. Several reports have suggested that CIN could be an important prognostic factor in chemotherapy of various cancers. However, whether CIN is a prognostic factor in unresectable pancreatic cancer (PC) treated with gemcitabine plus nab-paclitaxel (GnP) is unknown. The primary endpoint of this study was to compare overall survival (OS) between patients with severe CIN (grade ≥ 3) and those with absent/mild CIN (grade ≤ 2) in unresectable PC cases treated with GnP as first-line chemotherapy. METHODS: A retrospective, cohort study was conducted using data from a computerized database. A total of 290 patients with pathologically confirmed PC treated with GnP as first-line chemotherapy were analyzed (severe CIN: ≥ grade 3, n = 174; absent/mild CIN: ≤ grade 2, n = 116). RESULTS: The median OS was longer in the severe CIN group than in the absent/mild CIN group (19.2 months vs 11.3 months, respectively; P < 0.001). After adjustment, severe CIN was an independent predictive factor for OS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.38-0.74; P < 0.001). After adjustment by time-varying covariates, severe CIN was still a significant prognostic factor for OS (HR, 0.79; 95% CI 0.69-0.91, P = 0.001). CONCLUSION: The present results show that severe CIN is an independent and useful prognostic factor in PC patients treated with GnP.

Alternate Endpoints for Phase II Trials in Advanced Neuroendocrine Tumors.

BACKGROUND: In phase II trials for neuroendocrine tumors (NETs), the objective response rate (ORR) is traditionally used as a primary endpoint. However, the validity of the ORR as a primary endpoint has never been systematically examined. Therefore, a literature-based analysis of phase II trials for NETs was performed to identify valid alternative endpoints for predicting median progression-free survival (PFS) in clinical trials for NETs. MATERIALS AND METHODS: Phase II trials of medical treatment for advanced NETs were identified based on a systematic search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. RESULTS: A total of 22 trials were identified, and 1,310 patients and 27 treatment arms were included in the analysis. There was no significant relationship between the ORR and median PFS (r = .374; 95% confidence interval [CI], -0.051 to 0.800; p = .085). Conversely, 12-month PFS rates showed very strong correlations with median PFS (r = .929; 95% CI, 0.831-1.027; p < .001). CONCLUSION: The results of the present analysis indicate that the ORR is not significantly correlated with median PFS and suggest that 12-month PFS rates are good alternate endpoints for screening phase II trials for NETs. IMPLICATIONS FOR PRACTICE: Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development. Thus, earlier endpoints are preferable, and the objective response rate (ORR) has been traditionally used as a surrogate endpoint in phase II trials for neuroendocrine tumors (NETs). However, the present study showed that the ORR was not significantly correlated with median progression-free survival (PFS). On the other hand, the 12-month PFS rate showed very strong correlation with median PFS and is considered a good alternate endpoint for screening phase II trials for NETs.

Predictive factors of the treatment outcome in patients with advanced biliary tract cancer receiving gemcitabine plus cisplatin as first-line chemotherapy.

BACKGROUND: Few studies have clearly identified the prognostic factors in patients with advanced biliary tract cancer (BTC) receiving gemcitabine plus cisplatin (GC) which is acknowledged as standard chemotherapy regimen. OBJECTIVES: The aim of this study was to identify predictive factors of the overall survival (OS) in advanced BTC patients receiving GC therapy. METHODS: Data of 307 patients with advanced BTC who received GC therapy as the first-line chemotherapy at our institution from January 2007 to June 2017 were reviewed retrospectively. The patients were randomly assigned to the investigation or the validation dataset at the ratio of 2:1. Multivariate analysis was conducted to identify the prognostic factors, a prognostic index is proposed from the investigation dataset, and the usefulness of this index was confirmed in the validation dataset. RESULTS: Multivariate analysis identified poor performance status, elevated serum lactate dehydrogenase, and elevated neutrophil-to-lymphocyte ratio as independent unfavorable predictors. The patients could be classified into three groups according to these factors, and it was found that the outcomes differed significantly among the three groups (P = 0.0002, good- vs. intermediate-prognosis groups; P = 0.005, intermediate- vs. poor-prognosis groups). When this index was applied to the validation dataset, the OS was confirmed to differ significantly among the three groups (P = 0.04, good- vs. intermediate-prognosis groups, P < 0.0001, intermediate- vs. poor-prognosis groups). CONCLUSIONS: We identified three predictors of the OS in patients with advanced BTC receiving GC therapy in this study, based on which we could classify the patients into three risk groups.

Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (Edition 1.0).

In Japan, the social (medical) health-care system is on the way to being developed to advance personalized medicine through the implementation of cancer genomic medicine, known as "cancer clinical sequencing," which uses a next-generation sequencer. However, no Japanese guidance for cancer genomic testing exists. Gene panel testing can be carried out to help determine patient treatment, confirm diagnosis, and evaluate prognostic predictions of patients with mainly solid cancers for whom no standard treatment is available. This guidance describes how to utilize gene panel testing according to the type of cancer: childhood cancer, rare cancer, carcinoma of unknown primary, and other cancers. The level of evidence classification for unified use in Japan is also detailed. This guidance establishes the basic principles of the quality control of specimens, requirements of medical institutions, informed consent, handling of data during the postanalysis stage, and treatment options based on the evidence level. In Japan, gene panel testing for cancer treatment and diagnosis is recommended to comply with this guidance. This is a collaborative work of the Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and the Japanese Cancer Association.

Endoscopic Ultrasound-Guided Gallbladder Drainage for Aberrant Right Posterior Duct Obstruction Developing after Placement of a Covered Self-Expandable Metallic Stent in a Patient with Distal Biliary Obstruction.

Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has been utilized as an alternative endoscopic technique for patients with acute cholecystitis. In addition to EUS-guided hepaticogastrostomy and EUS-guided cystogastrostomy, EUS-GBD has been reported as being useful for biliary drainage in cases with distal malignant biliary obstruction instead of conventional endoscopic retrograde cholangiopancreatography. We present a case of successful EUS-GBD for malignant obstruction of an aberrant hepatic duct draining directly into the cystic duct.

Progression-free survival as a surrogate endpoint in advanced neuroendocrine neoplasms.

In oncology clinical trials, overall survival (OS) is considered the gold standard outcome measure. In phase III trials for neuroendocrine neoplasms (NENs), however, progression-free survival (PFS) is more frequently used, as NENs are relatively rare and indolent neoplasms. But this surrogacy of PFS for OS has never been systematically validated. We, therefore, performed a literature-based analysis of phase II and III trials for NENs to evaluate the correlation between PFS and OS in NENs treated with medical treatment. We identified phase II and III clinical trials of medical treatment for advanced NENs based on a systematic electronic search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. A total of 20 trials were identified, and 2530 patients and 30 treatment arms were included in the analysis. There was a statistically significant relationship between PFS and OS (rs , 0.587; 95% confidence interval, 0.249-0.925). Conversely, the objective response rate was not significantly correlated with OS. The results of subgroup analyses indicated that the correlation between PFS and OS was higher for study arms that prohibited concomitant therapy with somatostatin analogues than for those that permitted it. The results of the present analysis indicate that PFS is significantly correlated with OS, and suggest that PFS is an acceptable surrogate for OS in clinical trials for NENs.

[Resection of Adrenal Metastasis after Chemotherapy and Radiation Therapy for a Patient with Stage IV B Hepatocellular Carcinoma].

In the treatment of hepatocellular carcinoma, atypical, off guideline multidisciplinary approaches are sometimes effective. A 70-year-old man was diagnosed with multiple hepatocellular carcinomas, multiple bone metastases, and a right adrenal metastasis. Sunitinib was started and the primary hepatic lesions and bone metastases disappeared. However, his adrenal metastasis worsened. Sorafenib, radiotherapy, and some investigational agents were administered, but the adrenal metastasis did not respond. There were no other new lesions except the adrenal lesion 4 years after the initial treatment, so we decided to perform a resection. In the left half lateral decubitus position, the adrenal mass was removed with right thoracolaparotomy. After the surgery, his tumor markers quickly returned to normal. Seven years after the initial treatment(2 years and 4 months after the last surgery), he is alive without any recurrence. Multidisciplinary treatment with chemotherapy, radiotherapy, and surgery may result in long term survival even for patients with advanced hepatocellular carcinoma with multiple extra-hepatic lesions.

Sufficient and necessary condition for zero quantum entropy rates under any coupling to the environment.

We find the necessary and sufficient conditions for the entropy rate of the system to be zero under any system-environment Hamiltonian interaction. We call the class of system-environment states that satisfy this condition lazy states. They are a generalization of classically correlated states defined by quantum discord, but based on projective measurements of any rank. The concept of lazy states permits the construction of a protocol for detecting global quantum correlations using only local dynamical information. We show how quantum correlations to the environment provide bounds to the entropy rate, and how to estimate dissipation rates for general non-Markovian open quantum systems.

Bifurcation phenomenon in spin relaxation.

Spin relaxation in a strong-coupling regime (with respect to the spin system) is investigated in detail based on the spin-boson model in a stochastic limit. We find a bifurcation phenomenon in temperature dependence of relaxation constants, which is never observed in the weak-coupling regime. We also discuss inequalities among the relaxation constants in our model and show the well-known relation 2gamma(T)>or=gamma(L), for example, for a wider parameter region than before.