Therapeutic effects of the combined androgen blockade therapy versus luteinizing hormone-releasing hormone analog monotherapy in patients with hormone naïve metastatic prostate cancer: a multi-institutional comparative analysis

BackgroundThe clinical benefit of the combined androgen blockade (CAB) therapy over luteinizing hormone-releasing hormone analog (LH-RHa) monotherapy for hormone naïve metastatic prostate cancer (mHNPC) is unclear. Therefore, we retrospectively compare the effectiveness of CAB with the LH-RHa monotherapy on the prognosis of Japanese patients with mHNPC.MethodsWe retrospectively evaluated the prognosis of 517 patients diagnosed with mHNPC between August 2001 and May 2017. The patients’ data were obtained from the Michinoku Urological Cancer Research Group database and Hirosaki University-related hospitals. Patients were divided into the CAB and LH-RHa monotherapy groups based on primary androgen deprivation therapy (ADT). Overall survival (OS), cancer-specific survival (CSS), and castrate-resistant prostate cancer-free survival (CRPC-FS) were compared between the two groups using the Kaplan-Meier curve analysis. Inverse probability of treatment weighting (IPTW)-adjusted Cox hazard proportional analyses was performed to investigate the effect of primary ADT on oncological outcomes.ResultsThe median age was 73 years old. The numbers of patients in the CAB and LH-RHa monotherapy groups were 447 and 70, respectively. The Kaplan-Meier curve analysis showed no significant differences in either 5-year OS (56.7% vs. 52.5%, P=0.277), CSS (61.1% vs. 56.4%, P=0.400), and CRPC-FS (33.1% vs. 31.1%, P=0.529) between the groups. IPTW-adjusted multivariate Cox hazard proportional analyses showed no significant differences in OS, CSS, and CRPC-FS between the two groups.ConclusionsNo significant differences in oncological outcomes were observed between the CAB and LH-RHa monotherapy groups in patients with mHNPC.     

Results of definitive radiotherapy with concurrent chemotherapy for maxillary sinus carcinomas with neck lymph node metastasis

The purpose of this study was to describe the results of definitive radiotherapy (RT) with concurrent chemotherapy for maxillary sinus carcinomas (MSCs) with neck lymph node metastasis to clarify its limitation. Local control (LC), progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan–Meier method and were compared between subgroups using the log rank test. Toxicity was classified using common terminology criteria of adverse events version 5.0. Eighteen patients with inoperable MSC with neck lymph node metastasis including 12 men and 6 women with a median age of 67 years were analyzed. The histologic diagnoses were as follows: 16 patients had squamous cell carcinomas and 2 had other histology. Four patients had stage T3 MSC, 6 had T4a and 8 had T4b. Among 18 patients, 7 received concurrent systemic chemotherapy and 11 received selective arterial chemo-infusion. The median follow-up period was 17 months. The 2-year LC, PFS and OS rates for the entire cohort were 34, 31 and 46%, respectively. No significant differences were observed for LC, PFS and OS rates between systemic chemotherapy and selective arterial chemo-infusion cohorts. Grade 3 or higher acute toxicity, including both non-hematological and hematological, was observed in nine patients (50%), while no grade 3 or higher late toxicity was observed. In conclusion, we described the results of definitive RT for MSCs with neck lymph node metastasis. Local recurrence of primary tumor was a frequent pattern of failure and it should be addressed in future study.     

Quantitative analysis of distribution and fate of human lung cancer emboli labeled with 125I-5-iodo-2′-deoxyuridine in nude mice

The chemical and radio toxicity of ¹²⁵-5-iodo-2-deoxyuridine (¹²⁵IUDR) on 870127T human lung cancer (HLC) cells grown in tissue cultures and the quantitative analysis of the distribution and fate of ¹²⁵IUDR-labeled 870127T HLC cells in nude mice were evaluated. After 870127T HLC cells were plated and ¹²⁵IUDR was added to the dishes at levels ranging from 0.1 µCi/ml to 5.0 µCi/ml of media, the growth rate of the cells for 24h was similar to that of non-labeled cells. Nude mice were given intravenous injections of ¹²⁵IUDR labeled 870127T HLC cells and killed at various intervals ranging from 5 min to 24 h after injection. Organs were collected, processed, and monitored. The lung contained most of the tumor cells at all intervals and the number of tumor cells in the lung decreased gradually post-injection. The tumor cells died rapidly, and only about 1.5% of all cell survived after 24 h post-injection. This study confirmed that very few surviving tumor cells are needed to cause metastasis.     

Comprehensive genetic screening for vascular Ehlers–Danlos syndrome through an amplification-based next-generation sequencing system

Vascular Ehlers–Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys–Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.     

Congener-specific data on polychlorinated biphenyls in tissues of common porpoise from Puck Bay,Baltic Sea

Individual congeners of polychlorinated biphenyls (PCBs), including the highly toxic non-ortho coplanar 3,3,4,4-tetrachlorobiphenyl (IUPAC No. 77), 3,3,4,4,5-pentachlorobiphenyl (IUPAC No. 126), and 3,3,4,4,5,5-hexachlorobiphenyl (IUPAC No. 169), and their mono- and di-ortho analogs, have been identified and quantified in the blubber, liver, and muscles of three female common porpoise Phocoena phocoena collected from the Puck Bay (inner Gulf of Gdask, Poland) in 1989–1990, to elucidate actual concentrations and toxic potential. The total 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalent for 13 coplanar PCBs in blubber was 1,500±470 pg/g wet wt. 2,3,4,4,5-Pentachlorobiphenyl (IUPAC No. 118) was the most contributing individual and occupied between 57 and 67% in total toxic equivalent of coplanar PCBs in blubber, while 2,2,4,4,5,5-hexachlorobiphenyl (IUPAC No. 153), 2,3,3,4,4-pentachlorobiphenyl (IUPAC No. 105) and 2,2,3,4,4,5-hexachlorobiphenyl (IUPAC No. 138) comprised between 9.5–14, 7.6–11.5, and 7.2–11.0%, respectively (totally 82–95%), and 2,3,3,4,4,5-hexachlorobiphenyl (IUPAC No. 156) was absent. A potentially most toxic non-ortho PCB members such as 3,3,4,4,5-pentachlorobiphenyl, 3,3,4,4,5,5-hexachlorobiphenyl and 3,3,4,4-tetrachlorobiphenyl were only minor contributors, altogether occupying between 1.0 and 14.5% in total TEQ of coplanar PCBs. Concentrations of total PCBs in lipids of the blubber ranged from 26 to 47 g/g and were comparable or lower than reported earlier for common porpoises from the Baltic Sea, North Sea, and North Atlantic by other authors.     

Hyposensitivity of peripheral α-adrenoceptors in respiratordependent amyotrophic lateral sclerosis assessed by intravenous norepinephrine infusion

Intravenous norepinephrine infusion test was performed in eight patients with amyotrophic lateral sclerosis (ALS) supported by respirators and nine control subjects, to examine -adrenoceptor function of peripheral resistant blood vessels. Baseline plasma norepinephrine concentrations in ALS patients were significantly higher than those in control subjects, indicating basal sympathetic hyperactivity (normal 218.2 ± 59.7 pg/ml; ALS 450.0 ± 288.4 pg/ml). The stimulus-response curves in the patients were similar to those in control subjects, and there were no significant differences between mean gains of the stimulus—response curves in both groups (normal 18.7 ± 5.5; ALS 15.2 ± 11.2). However, three ALS patients, two of whom had circulatory fluctuation and sympathetic hyperactivity, revealed lower gain levels than the mean minus 2 SD in control subjects (4.7, 1.1 and 3.7). This indicates hyposensitivity or down-regulation of the -adrenoceptor function of peripheral blood vessels in these ALS patients. For early detection of sympathetic hyperactivity and prediction of circulatory collapse, it would be useful to measure the plasma norepinephrine concentration and the gain of the norepinephrine infusion curve in respirator-dependent ALS patients.     

PCNA immunostaining combined with AgNOR staining in esophageal squamous cell carcinoma to identify patients with a poor prognosis

Immunostaining of the proliferating cell nuclear antigen (PCNA) provides important information about cell kinetics and is easily performed on routinely obtained formalin-fixed, paraffin-embedded materials. We report herein the results of a retrospective study on PCNA staining in esophageal cancer undertaken to determine its significance. As this study indicated that immunoreactivity was preserved in specimens fixed within 24 h, only 31 specimens from surgical patients were available for this investigation. The mean PCNA index of the patients without invasion to the adventitia (35.7±17.9) was significantly lower than that of those with invasion to the adventitia or neighboring structures (49.7±14.5), while the PCNA index did not correlate with other clinicopathologic parameters such as histologic type, lymph node metastases, or prognosis. However, when an analysis of PCNA staining was combined with an analysis of argyrophilic nucleolar organizer region (AgNOR) staining, a correlation with prognosis was found. In fact, seven patients with a high PCNA index (44) and AgNOR count (6) had a significantly poorer prognosis than the remaining 22 (P=0.0014), and six of these seven patients died within 2 years. These results indicate that this combined evaluation may be useful for the identification of patients with a poor prognosis among those undergoing surgery for esophageal squamous cell carcinoma.     

Studies on karyotype evolution in higher primates in relation to human chromosome 14 and 9 by comparative mapping of immunoglobulin C epsilon genes with fluorescence in situ hybridization

Karyotypic homologies in relation to human chromosome 14 and 9 were studied through comparative mapping of the immunoglobulin C epsilon genes in higher primates by fluorescence in situ hybridization (FISH) technique. The C epsilon genes will be suitable probes for the analysis of evolutionary rearrangements due to that the multiple recombinational events such as gene duplications and deletions have occurred repeatedly in the immunoglobulin CH gene family (IGH@) during the course of primate evolution. IGH@ locating on the terminal region of human chromosome 14 (HSA14), at band HSA14q32.33, has generated multiple pseudogenes and among subclasses of IGH@ the C epsilon genes have shown most dynamic changes with generating both truncated type (C epsilon 2) and processed type (C epsilon 3) pseudogenes. In this study, chromosomal homologies and rearrangements on HSA14 (C epsilon 1) and HSA9 (C epsilon 3) in relation to the evolutionary genesis of their primate homologous chromosomes in speciation were investigated by comparative mapping with FISH and chromosome painting (ZOO-FISH) techniques. Comparative mapping of the C epsilon 1 gene at HSA14q32.33 was carried out in seven species of nonhuman primates: common chimpanzee (PTR), pygmy chimpanzee (PPA), gorilla (GGO), orangutan (PPY), white-handed gibbon (HLA), agile gibbon (HAG), and Japanese macaque (MFU). The C epsilon 1 gene was assigned to the telomeric region of HSA14 homologues in each species, namely, PTR15q32, PPA15q32, GGO18q16, PPY15q32, HLA17qter, HAG17qter, and MFU7q29, respectively. These results suggested that HSA14 has high degree of syntenic organization with its primate homologues confirmed by ZOO-FISH. Concerning HSA9, comparative mapping of the C epsilon 3 gene at HSA9p24.2-->p24.1 was performed. The mapped positions indicated the HSA9 homologous regions detected by ZOO-FISH in each species, namely, PTR11q34, PPA11q34, GGO13q22, PPY13q16, HLA8qter, HAG8qter, and MFU14q22, respectively, suggesting that several dynamic chromosomal rearrangements including at least twice pericentric inversions have occurred during the course of hominoid evolution. The comparison of syntenic groups and painting results has provided a hypothesis of the evolutionary genesis of HSA9 and its homologues with defined breakpoints on the present chromosomes. Likewise, studies on karyotype evolution will be promoted by combining comparative mapping with ZOO-FISH that can more clearly define the chromosomal rearrangements among species.     

Polymorphisms of the human homologue of the Drosophila white gene are associated with mood and panic disorders

The Drosophila white gene is a member of the ATP-binding cassette (ABC) transporter superfamily and is involved in the cellular uptake of tryptophan. Its human homologue gene (hW) has been mapped to chromosome 21q22.3. Tryptophan is the precursor for the neurotransmitter serotonin, which has been implicated in the regulation of mood and anxiety. The locus 21q22.3 has also been reported to be associated with mood disorders. The 3'-untranslated region (3'-UTR) in the hW gene has been shown to contain a polymorphic poly(T) region. We have identified a new polymorphism G2457A in the 3'-UTR in the present study. We examined the relationship between these polymorphisms and mood and panic disorders, and a significant association between the poly(T) polymorphisms and mood disorders was detected (P=0.039 (allele frequency)). Associations were found between the polymorphisms and mood (poly(T) polymorphism: P=0.047 (allele frequency), G2457A: P=0.040 (allele frequency), P=0.044 (genotype frequency)) and panic disorders (G2457A: P=0.026 (allele frequency), P=0.011 (genotype frequency)) in males, but not in females. These findings suggest that the hW gene may be an important gene in the control of mood and anxiety as well as one of the genetic factors related to mood disorders and panic disorder in males. The statistical significance of the association remains relatively low and larger materials facilitating further dissection of the clinical phenotype will be needed to confirm and independently validate this finding and to evaluate its significance.     

Problems of intravenous lidocaine treatment in status epilepticus or clustering seizures in childhood

Lidocaine was administered intravenously as a substitute for diazepam, to 12 patients with status epilepticus or clustering seizures aged 26 days to 11 years. The medication was very effective in 3 cases with acute convulsions, which disappeared immediately after infusion of lidocaine without relapse. The medication was effective only temporarily in 4 patients; they experienced relapsing seizures during drip infusion of lidocaine intravenously for maintenance. All the relapsing seizures were secondarily generalized ones with diffuse ictal discharges. In 2 cases of localization-related epilepsy, complex partial seizures evolved to secondarily generalized seizures immediately after administration of lidocaine. It must be noticed that in a relatively large number of cases lidocaine is ineffective or even harmful.