Total Synthesis of a TNBC-Selective Cytotoxic Bromo Nor-eremophilane, PC-A, and Its Preliminary Structure-Activity Relationships.

PC-A (1), a bromo nor-eremophilane, showed selective antiproliferative activity against a triple-negative breast cancer (TNBC) cell line. This unique activity prompted us to establish a total synthesis to facilitate a structure-activity relationship (SAR) study and selectivity optimization. An enantioselective first total synthesis of 1 was achieved starting from (R)-carvone through a side chain extension with a Mukaiyama aldol reaction and decalin construction. The synthesized decalin derivatives and debromo PC-A (2) were evaluated for antiproliferative activity against five human tumor cell lines, including TNBC, to assess preliminary SAR correlations.

Continuous Deep Sedation for Psycho-Existential Suffering: A Multicenter Nationwide Study.

Background: There is ongoing debate on whether continuous deep sedation (CDS) for psycho-existential suffering is appropriate. Objective: We aimed to (1) clarify clinical practice of CDS for psycho-existential suffering and (2) assess its impact on patients' survival. Methods: Advanced cancer patients admitted to 23 palliative care units in 2017 were consecutively enrolled. We compared patients' characteristics, CDS practices, and survival between those receiving CDS for psycho-existential suffering ± physical symptoms and only for physical symptoms. Results: Of 164 patients analyzed, 14 (8.5%) received CDS for psycho-existential suffering ± physical symptoms and only one of them (0.6%) solely for psycho-existential suffering. Patients receiving CDS for psycho-existential suffering, compared with those only for physical symptoms, were likely to have no specific religion (p = 0.025), and desired (78.6% vs. 22.0%, respectively; p < 0.001) and requested a hastened death more frequently (57.1% vs. 10.0%, respectively; p < 0.001). All of them had a poor physical condition with limited estimated survival, and mostly (71%) received intermittent sedation before CDS. CDS for psycho-existential suffering caused greater physicians' discomfort (p = 0.037), and lasted for longer (p = 0.029). Dependency, loss of autonomy, and hopelessness were common reasons for psycho-existential suffering that required CDS. The survival time after CDS initiation was longer in patients receiving it for psycho-existential suffering (log-rank, p = 0.021). Conclusion: CDS was applied to patients who suffered from psycho-existential suffering, which often associated with desire or request for a hastened death. Further studies and debate are warranted to develop feasible treatment strategies for psycho-existential suffering.

Cross-cultural comparison of continuous deep sedation for advanced cancer patients in East Asian countries: prospective cohort study.

OBJECTIVE: Cultural, social, and legal factors have been known to affect physicians' practice of continuous deep sedation. There have been few quantitative studies to compare continuous deep sedation practice in Asian countries. We aimed to describe and compare clinical characteristics of continuous deep sedation in Japan, Korea and Taiwan. METHODS: Patients with advanced cancer admitted to participating palliative care units were enrolled from January 2017 to September 2018. We evaluated and compared (i) the prevalence of continuous deep sedation, (ii) the characteristics of sedated and non-sedated groups in each country, and (iii) continuous deep sedation administration patterns among the three countries. RESULTS: A total of 2158 participants were included in our analysis, and 264 received continuous deep sedation. The continuous deep sedation prevalence was 10, 16 and 22% in Japan, Korea and Taiwan, respectively. Delirium was the most frequent target symptom in all countries, along with dyspnoea (in Japan) and psychological symptoms (in Korea). Midazolam was most frequently used in Japan and Taiwan, but not in Korea (P < 0.001). Among the patients receiving continuous deep sedation, the hydration amount on the final day was significantly different, with median volumes of 200, 500 and 0 mL in Japan, Korea and Taiwan, respectively (P < 0.001). In Korea, 33% of the continuous deep sedation administration caused a high degree of physicians' discomfort, but 3% in Japan and 5% in Taiwan (P < 0.001). CONCLUSIONS: Clinical practices of continuous deep sedation and physicians' discomfort related to continuous deep sedation initiation highly varied across countries. We need to develop optimal decision-making models of continuous deep sedation and hydration during continuous deep sedation in each country.

Novel cancer-specific epidermal growth factor receptor antibody obtained from the serum of esophageal cancer patients with long-term survival.

Although esophageal cancer has a poor prognosis after recurrence, some patients have shown long-term survival despite recurrence. We hypothesized that induction of either antitumor Abs or antitumor-specific CTLs could play a role in long-term survival (5 years or longer) in patients with recurrence and/or distant metastases. Therefore, we aimed to obtain Abs that specifically bind to cancer cells by using serum samples from patients with a good prognosis. A phage library was prepared using PBMC mRNA of the patients, and cell panning was carried out using an esophageal cancer cell line. Results showed the presence of an epidermal growth factor receptor (EGFR) Ab, KT112, that specifically bound to the cancer cell line. Notably, KT112 bound to only EGFR-positive cancer cells but failed to bind to normal esophageal cells. Furthermore, KT112 was characterized by responses to EGFR expressed on cancer cells but not to the recombinant extracellular domain of EGFR. Immunohistochemical analysis showed that KT112 reacted with 17.4% of esophageal squamous cell carcinoma tissue but not with any other cancer or normal tissue, suggesting that the Ab recognizes cancer-specific forms of EGFR and might have contributed to tumor suppression in patients with esophageal cancer. Furthermore, because of its high cancer specificity, KT112 could be a promising therapeutic option (e.g., in Ab-drug conjugates) for esophageal cancer.

Bicyclic Chalcones as Mitotic Inhibitors for Overcoming Androgen Receptor-Independent and Multidrug-Resistant Prostate Cancer.

To improve the biological effects of the lead compound 5'-chloro-2,2'-dihydroxychalcone (Cl-DHC), bicyclic aromatic chalcones were designed, synthesized, and evaluated against androgen-independent prostate cancer (PCa) DU145 and PC-3 cell proliferation. Newly synthesized bi-naphthyl derivatives 2 and 3 suppressed the proliferation of these two cell lines and also taxane-resistant prostate cancer cell lines at a submicromolar level. The two compounds were 4-18 times more potent than the parent molecule Cl-DHC. A structure-activity relationship analysis revealed that the orientation of the 10π-electron ring-A naphthalene had a significant effect on the activity. Mode-of-action studies in KB-VIN cells demonstrated that 2 and 3 arrested cells in mitosis at prometaphase and metaphase followed by induction of sub-G1 accumulation. Thus, 2 and 3 have good potential as leads for continued development of treatments for cancers especially for not only androgen-independent PCa but also multidrug-resistant tumors.

Continuous deep sedation at the end of life in children with cancer: experience at a single center in Japan.

Continuous deep sedation (CDS) is used to alleviate unbearable and otherwise refractory symptoms in patients dying of cancer. No data are available concerning CDS in children from Japan to date. This study primarily aimed to describe experience in CDS in child cancer patients at Kyoto University Hospital. The secondary aims were to identify the characteristics of patients who received CDS, and to assess ability in daily living at the end of life. A retrospective chart review was performed for child cancer patients who died at the institute between 2008 and 2017. The data of 35 patients were analyzed. Nine (26%) patients had received CDS. Indications for CDS were dyspnea (56%), agitation (22%), seizures (22%), and pain (11%). Midazolam was used in all nine cases. In eight (89%) patients, opioids were also prescribed. In seven (78%) patients, CDS was performed for < 48 hours. In all nine cases, consent was obtained from the parent(s) but not from the children. CDS was more likely in patients with solid tumors (p = 0.018) and those who had received no respite sedation (p = 0.002). Patients without central nervous system symptoms tended to maintain their capacity for oral intake and verbal communication until a few days prior to death. This is the first report on CDS in child cancer patients from Japan. In the CDS literature, cross-study differences are evident for incidence, target symptoms, duration, and the decision-making process. Further international discussion is warranted concerning indications for CDS and the decision-making process.

Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients.

Peritonitis is a major and the most significant complication of peritoneal dialysis (PD). Although some predictors of peritonitis in PD patients are known, the association between proton pump inhibitor (PPI) use and peritonitis has not been characterized. Here, we examined whether PPI use is a risk factor for the development of peritonitis, based on a single-center retrospective analysis of 230 consecutive Japanese PD patients at Narita Memorial Hospital. We assessed the association between PPI use and subsequent first episode of peritonitis using multivariate Cox proportional hazards models, following adjustment for clinically relevant factors. The median follow-up period was 36 months (interquartile range, 19-57 months). In total, 86 patients (37.4%) developed peritonitis. Analysis with multivariate Cox proportional hazards models revealed the following significant predictors of peritonitis: PPI use (adjusted hazard ratio [HR] = 1.72, 95% confidence interval [CI]: 1.11-2.66; P = 0.016) and low serum albumin level (per g/dl adjusted HR = 0.59, 95% CI: 0.39-0.90; P = 0.014). Thus, PPI use was independently associated with PD-related peritonitis. The results suggest that nephrology physicians should exercise caution when prescribing PPIs for PD patients.

A new technology for increasing therapeutic protein levels in the brain over extended periods.

Effective delivery of protein therapeutics into the brain remains challenging because of difficulties associated with crossing the blood-brain barrier (BBB). To overcome this problem, many researchers have focused on antibodies binding the transferrin receptor (TfR), which is expressed in endothelial cells, including those of the BBB, and is involved in receptor-mediated transcytosis (RMT). RMT and anti-TfR antibodies provide a useful means of delivering therapeutics into the brain, but the anti-TfR antibody has a short half-life in blood because of its broad expression throughout the body. As a result, anti-TfR antibodies are only maintained at high concentrations in the brain for a short time. To overcome this problem, we developed a different approach which slows down the export of therapeutic antibodies from the brain by binding them to a brain-specific antigen. Here we report a new technology, named AccumuBrain, that achieves both high antibody concentration in the brain and a long half-life in blood by binding to myelin oligodendrocyte glycoprotein (MOG), which is specifically expressed in oligodendrocytes. We report that, using our technology, anti-MOG antibody levels in the brains of mice (Mus musculus) and rats (Rattus norvegicus) were increased several tens of times for a period of one month. The mechanism of this technology is different from that of RMT technologies like TfR and would constitute a breakthrough for central nervous system disease therapeutics.

Changes in opinions on palliative sedation of palliative care specialists over 16 years and their effects on clinical practice.

PURPOSES: Despite extensive debate on palliative sedation over the last few decades, no studies have explored longitudinal changes in physicians' opinion. Moreover, little is known about how physicians' opinions affect their practice. This study aimed to clarify (1) changes in palliative care specialists' opinions on palliative sedation and (2) the effects of these opinions on clinical practice. METHODS: In 2000 and 2016, nationwide questionnaire surveys involving Japanese palliative care specialists were performed: measurement was based on agreement with opinions on palliative sedation. In 2016, the physicians reported their practice of continuous deep sedation (CDS) and answered their thoughts on what factors lead to a good death as factors potentially affecting their practice. RESULTS: Of the 695 physicians enrolled in the 2016 survey, 469 responded (67%) and 417 were analyzed (60%). Compared with 54 physicians in 2000, the present respondents were more likely to consider palliative sedation is difficult to perform based on appropriate indications (ES = 0.84, P < 0.001), is unnecessary if conventional palliative care is performed sufficiently (ES = 0.30, P = 0.013), and may result in legal action (ES = 0.35, P = 0.003). The physicians' opinions more strongly affected their practice than their characteristics or thoughts on good death components. CONCLUSIONS: Recently, palliative care specialists in Japan tend to encounter more difficulties determining what conventional palliative care is and what palliative sedation is. They also fear legal ramifications. It is necessary to standardize methods of alleviating patients' suffering, to make CDS criteria clearer, and to create a legal basis that respects patients' rights at their end of life.

Japanese physicians' experiences of terminally ill patients voluntarily stopping eating and drinking: a national survey.

OBJECTIVES: Voluntarily stopping eating and drinking (VSED) could be regarded as a patients' own non-treatment decision that hastens death, which involves patients voluntarily forgoing food and liquid until death. The aims of this study were to investigate the experience of home hospice physicians and palliative care specialists who care for patients during VSED in Japan, and their opinions on continuous deep sedation (CDS) as a means to relieve patient symptoms during VSED. METHODS: 219 home hospice physicians and 695 palliative care specialists across Japan were surveyed by mail questionnaire in 2016. RESULTS: A total of 571 (62%) responses were analysed. A total of 185 (32%) had experience of patients who selected VSED. In response to questions about CDS to provide relief to patients during VSED, the number of physicians who replied that CDS was acceptable was 88 (15%). CONCLUSIONS: In Japan, 32% of physicians surveyed replied that they had experience of caring for patients during VSED in a clinical setting and 15% considered CDS acceptable.

Pup exposure facilitates retrieving behavior via the oxytocin neural system in female mice.

Parental behavior in mammals is innate, but it is also facilitated by social experience, specifically social interactions between the parent and infant. Social interactions with infants also induce the alloparental behavior of virgin animals. Oxytocin (OT) plays an important role in mediating alloparental behavior. Although parental behavior is modulated by the medial preoptic area (MPOA) and adjacent regions, it is unclear how OT acts in these regions as a control mechanism of alloparental behavior promoted by adult-pup interaction. The aim of this study was to investigate the role of OT for facilitating effects of adult-pup interactions on alloparental behavior via neural activity of preoptic area (POA), including MPOA and adjacent area. For this purpose, we conducted behavioral tests and examined the neural activity of the OT system in POA. Virgin female mice that were repeatedly exposed to pups showed shorter retrieving latencies and higher number of c-Fos expressing neurons in POA, particular in lateral preoptic area (LPO) compared to control animals that were exposed to pups only one time. In addition, repeated pup exposure increased the proportion of OT neurons and OTR neurons expressing c-Fos in POA. The concentration of OT also significantly increased in the POA. Finally, infusion of an OT antagonist into the POA area blocked the facilitating effects of repeated pup exposure on retrieving behavior. These results demonstrated that the facilitating effects of repeated pup exposure on alloparental behavior occurred via an organizational role of the OT system.

Development of CMV retinitis in an antigenemia-negative infant after cord blood transplantation.

A five-month-old male infant with familial hemophagocytic lymphohistiocytosis underwent cord blood transplantation using reduced-intensity conditioning. Methylprednisolone (mPSL) pulse administration was performed for marked pulmonary edema during the early phase of transplantation, followed by GVHD treatment with mPSL until day 100. CMV antigenemia was detected on days 27 and 55, but serum became negative with 2- to 3-week ganciclovir (GCV) treatment on both occasions. On day 120, ophthalmological findings included multiple bilateral white spots and a positive PCR study using anterior chamber fluid confirmed the diagnosis of CMV retinitis affecting both eyes, although CMV antigenemia was negative. Re-treatment with GCV had a minimal effect on the ophthalmological findings, while foscarnet administration markedly improved the retinitis and decreased the CMV-DNA level. Considering that a substantial proportion of patients develop CMV retinitis even when CMV antigenemia is not present, routine monitoring involving ophthalmological examinations should be conducted for hematopoietic transplant patients, especially infants, who cannot complain of ocular symptoms.

Munc13-4 deficiency with CD5 downregulation on activated CD8+ T cells.

Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by uncontrolled activation of T cells and macrophages and hypercytokinemia. We have recently described a significant increase in a subpopulation of CD8(+) T cells with downregulation of CD5 during the acute phase of FHL type2 (FHL2; perforin deficiency), which declines after successful treatment, with a concomitant reduction in serum cytokine level. This unusual subset of CD8(+) T cells, however, has not been characterized in patients with other subtypes of FHL. Herein, we describe a patient with FHL3 (Munc13-4 deficiency) carrying compound heterozygous mutations in the UNC13D gene. He had high serum levels of pro-inflammatory cytokines and significantly increased activated CD8(+) T cells with downregulation of CD5 during the acute phase, similar to that found in FHL2. This immunophenotypic feature may serve as a useful marker of immune dysregulation in FHL3 in addition to FHL2.

Acute lymphoblastic leukemia in a girl with Wilson's disease.

Wilson's disease (WD) is an autosomal recessive defect in cellular copper transportation. Although acute lymphoblastic leukemia (ALL) is the most common form of childhood malignancy, only two cases of ALL associated with WD have been reported to date. One patient died of relapse and infection, and the other died of neutropenic sepsis during the treatment. We here describe the case of a 10-year-old girl with WD and ALL. Adverse events of chemotherapy, including liver toxicity and severe myelosuppression, necessitated adjustments in the chemotherapy doses. After completion of the treatment, the patient has remained in remission from ALL without progression of liver damage for 2 years. Severe treatment-related toxicity should be considered in chemotherapy for patients with WD.

Sulforaphane inhibits advanced glycation end product-induced pericyte damage by reducing expression of receptor for advanced glycation end products.

Advanced glycation end products (AGEs) not only inhibit DNA synthesis but also play a role in diabetic retinopathy by evoking apoptosis and inflammation in retinal pericytes via interaction with a receptor for AGE (RAGE). Similarly, sulforaphane, which is a naturally occurring isothiocyanate that is found in widely consumed cruciferous vegetables, protects against oxidative stress-induced tissue damage. Therefore, we hypothesized that sulforaphane could inhibit AGE-induced pericytes injury through its antioxidative properties. Advanced glycation end product stimulated superoxide generation as well as RAGE gene and protein expression in bovine-cultured retinal pericytes, and these effects were prevented by the treatment with sulforaphane. Antibodies directed against RAGE also blocked AGE-evoked reactive oxygen species generation in pericytes. Sulforaphane and antibodies directed against RAGE significantly inhibited the AGE-induced decrease in DNA synthesis, apoptotic cell death, and up-regulation of monocyte chemoattractant protein 1 messenger RNA levels in pericytes. For the first time, the present study demonstrates that sulforaphane could inhibit DNA synthesis, apoptotic cell death, and inflammatory reactions in AGE-exposed pericytes, partly by suppressing RAGE expression via its antioxidative properties. Blockade of the AGE-RAGE axis in pericytes by sulforaphane might be a novel therapeutic target for the treatment of diabetic retinopathy.

An endobronchial inflammatory myofibroblastic tumor in a 10-yr-old child after allogeneic hematopoietic cell transplantation.

IMTs belong to the group of soft tissue tumor and could occur at any anatomical site; however, the causes and growth feature remain unclear. This case report documents a 10-yr-old male suffering from slowly developing dyspnea on exertion and cough around seven months post-HCT. He was diagnosed with an endobronchial tumor based on imaging, and histology confirmed ALK-positive submucosal spindle-shaped cells with infiltrative cells, compatible with IMT. We should be aware that IMT is a potential complication of pediatric allogeneic HCT and can cause sudden airway obstruction.

Switching to multiple daily injection therapy with glulisine improves glycaemic control, vascular damage and treatment satisfaction in basal insulin glargine-injected diabetic patients.

BACKGROUND: Basal and bolus insulin therapy is required for strict blood control in diabetic patients, which could lead to prevention of vascular complications in diabetes. However, the optimal combination regimen is not well established. METHODS: Fifty-nine diabetic patients (49 type 1 and 10 type 2; 52.9 ± 13.3 years old) whose blood glucose levels were uncontrolled (HbA1c > 6.2%) by combination treatment of basal insulin glargine with multiple daily pre-meal injections of bolus short-acting insulin [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] for at least 8 weeks were enrolled in this study. We examined whether glycaemic control and vascular injury were improved by replacement of short-acting insulin with glulisine. Patient satisfaction was assessed with Diabetes Treatment Satisfaction Questionnaire. RESULTS: Although bolus and basal insulin doses were almost unchanged before and after replacement therapy, switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c , advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), monocyte chemoattractant protein-1 (MCP-1) and urinary albumin excretion. In multiple stepwise regression analysis, change in MCP-1 values from baseline (ΔMCP-1) was a sole determinant of log urinary albumin excretion. ΔAGEs and ΔsRAGE were independently correlated with each other. The relationship between ΔMCP-1 and ΔsRAGE was marginally significant (p = 0.05). Replacement of short-acting insulin by glulisine significantly increased Diabetes Treatment Satisfaction Questionnaire scores. CONCLUSIONS: Our present study suggests that combination therapy of glargine with multiple daily pre-meal injections of glulisine might show superior efficacy in controlling blood glucose, preventing vascular damage and improving treatment satisfaction in diabetic patients.

Fat embolism syndrome: an autopsy-proven case involving a patient on dialysis and systemic scleroderma.

A 66-year-old woman receiving continuous ambulatory peritoneal dialysis developed acute respiratory distress 12 hours after a fall. Blood gas analysis revealed hypoxia (PaO2 67.7 torr) and metabolic acidosis with an increased anion gap, consistent with lactic acidosis (lactate, 86.5 mg/dL; normal range, 4.0-16.0). Magnetic resonance imaging showed a lumbar vertebral body fracture. On the fourth hospital day, the patient died of multiorgan failure and disseminated intravascular coagulation. Postmortem studies revealed fat emboli in the systemic circulation, ie, fat embolism syndrome. Diagnosing fat embolism syndrome can be difficult in patients on dialysis or in those with collagen vascular or pulmonary diseases.