Identifying prognostic biomarkers for palbociclib add-on therapy in fulvestrant-resistant breast cancer using cell-free DNA sequencing.

BACKGROUND: The FUTURE trial (UMIN000029294) demonstrated the safety and efficacy of adding palbociclib after fulvestrant resistance in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced and metastatic breast cancer (ABC/MBC). In this planned sub-study, cancer panel sequencing of cell-free DNA (cfDNA) was utilized to explore prognostic and predictive biomarkers for further palbociclib treatment following fulvestrant resistance. MATERIALS AND METHODS: Herein, 149 cfDNA samples from 65 patients with fulvestrant-resistant disease were analysed at the time of palbociclib addition after fulvestrant resistance (baseline), on day 15 of cycle 1, and at the end of treatment using the assay for identifying diverse mutations in 34 cancer-related genes. RESULTS: During the course of treatment, mutations in ESR1, PIK3CA, FOXA1, RUNX1, TBX3, and TP53 were the most common genomic alterations observed. Analysis of genomic mutations revealed that before fulvestrant introduction, baseline PIK3CA mutations were marginally lower in metastatic aromatase inhibitor (AI)-treated patients compared to adjuvant AI-treated patients (P = 0.063). Baseline PIK3CA mutations were associated with poorer progression-free survival [hazard ratio: 1.62, P = 0.04]. Comparative analysis between baseline and early-changing gene mutations identified poor prognostic factors including early-changing MAP3K1 mutations (hazard ratio: 4.66, P = 0.04), baseline AR mutations (hazard ratio: 3.53, P = 0.04), and baseline PIK3CA mutations (hazard ratio: 3.41, P = 0.02). Notably, the relationship between ESR1 mutations and mutations in PIK3CA, MAP3K1, and TP53 weakened as treatment progressed. Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations. CONCLUSIONS: Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.

Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16.

BACKGROUND: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. PATIENTS AND METHODS: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. RESULTS: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036). CONCLUSIONS: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Blue-light hazard from CO2 arc welding of mild steel.

OBJECTIVES: The objective was to quantify the blue-light hazard from CO(2) arc welding of mild steel. METHODS: The spectral radiance of arcs in CO(2) arc welding of mild steel was measured for solid and flux-cored wires at welding currents of 120-480 A. Effective blue-light radiance and the maximum acceptable exposure duration were calculated from the spectral radiance using their definitions in American Conference of Governmental Industrial Hygienists guidelines. RESULTS: The effective blue-light radiance ranged from 22.9 to 213.1 Wcm(-2)sr(-1). The corresponding maximum acceptable exposure duration was only 0.47-4.36 s, meaning that the total daily exposure to the welding arc without eye protection should not exceed this duration. CONCLUSIONS: It is very hazardous to view the arcs in CO(2) arc welding of mild steel. Welders and their helpers should use appropriate eye protectors in these arc-welding operations. Also, they should avoid direct light exposure when starting an arc-welding operation.

Canine oocyte maturation in culture: significance of estrogen and EGF receptor gene expression in cumulus cells.

We examined the role of cumulus cells regarding in vitro maturation of canine oocytes, and investigated estrogen and epidermal growth factor (EGF) receptor gene expression and action on nuclear maturation. Canine cumulus-oocyte complexes (COC) were collected from anestrous and diestrous bitches; only COC with vitelline diameter >100 microm were used. In Experiment 1, expression of estrogen receptor (ER) alpha, ERbeta and EGF-receptor (EGF-R) were determined by reverse transcription-polymerase chain reaction (RT-PCR), using mRNA from the oocyte or cumulus cell. Transcripts for the ERbeta and EGF-R were detected in oocytes and cumulus cells, but no message was detected for ERalpha. In Experiment 2, intact COC and the denuded oocytes were cultured in TCM199 medium supplemented with various concentrations of estradiol-17beta (E(2); 0-10 microg/mL) or EGF (0-100 ng/mL) for 72 h; nuclear maturation was then evaluated. In oocytes cultured within intact COC, the rate of germinal vesicle breakdown (GVBD) was higher in the 1 microg/mL E(2) supplemented group (P<0.05), and the rate of metaphase I (MI) was higher in the 10 ng/mL EGF supplemented group, than in the non-supplemented group (P<0.05). However, supplementation of E(2) or EGF to denuded oocytes failed to promote nuclear maturation. In Experiment 3, intact COC were cultured in TCM199 supplemented with 1 microg/mL E(2), 10 ng/mL EGF, and 10% fetal bovine serum (FBS) for 72 h, and nuclear maturation was evaluated. There was no significant difference in the rate of metaphase II (MII) between the medium only, E(2)+EGF, and FBS supplement groups. When E(2) and EGF in combination with FBS were supplemented, the rate of MII was higher than in other groups (P<0.05). We inferred that cumulus cells were involved in mediating the stimulatory effects of E(2) and EGF on nuclear maturation of canine oocytes, and that E(2) and EGF in combination with FBS promoted the completion of oocyte meiotic maturation.

Synthesis of infectious in vitro transcripts from Cassia yellow blotch bromovirus cDNA clones and a reassortment analysis with other bromoviruses in protoplasts.

Cassia yellow blotch virus (CYBV), genus Bromovirus, was isolated from the Australian native legume, Cassia pleurocarpa, in western Queensland, and its host range was found to be distinct from other bromoviruses. In this study, CYBV was shown to infect systemically and efficiently a model plant species, Arabidopsis thaliana, as we recently reported for another bromovirus, Spring beauty latent virus (SBLV). We constructed full-length cDNA clones of CYBV genomic RNAs from which infectious in vitro transcripts can be transcribed, and determined their complete nucleotide sequences. CYBV RNA3 contains the box B motif in the intercistronic region, but lacks the subgenomic promoter-like sequence in the 5' noncoding region, as does Brome mosaic virus (BMV). To understand relationships among bromoviruses, we generated reassortants between CYBV and three other bromoviruses, BMV, SBLV and Cowpea chlorotic mottle virus. We found that all reassortants between BMV and CYBV accumulated viral RNAs to detectable levels in protoplasts of Nicotiana benthamiana, even when RNAs 1 and 2, which encode the replication proteins 1a and 2a, respectively, were heterologous. Sequence comparison and reassortment experiments of CYBV and other bromoviruses demonstrated that CYBV is closely related to BMV.

Chromoendoscopy using indigo carmine dye spraying with magnifying observation is the most reliable method for differential diagnosis between non-neoplastic and neoplastic colorectal lesions: a prospective study.

BACKGROUND AND AIMS: Differential diagnosis between non-neoplastic and neoplastic lesions is very important at colonoscopy, since removal or biopsy of non-neoplastic polyps wastes time and resources. We therefore conducted a prospective study to examine whether indigo carmine dye spraying with and without magnification is more reliable than the conventional method for differential diagnosis. PATIENTS AND METHODS: 122 patients with 206 lesions of 10 mm or smaller were recruited into this study. All lesions detected on colonoscopy were first diagnosed using the conventional view, then at chromoendoscopy using 0.2 % indigo carmine, and finally at chromoendoscopy with magnification. The diagnosis at each step were recorded consecutively. All lesions were finally categorized as neoplastic or non-neoplastic according to pit pattern; non-neoplastic lesions were biopsied for histological evaluation, and all the neoplastic ones were removed endoscopically. The accuracy rate of each type of endoscopic diagnosis was evaluated, using histological findings as reference. RESULTS: Histologically, 46 lesions (22 %) were non-neoplastic and 160 (78 %) were neoplastic. The overall diagnostic accuracies by conventional view, chromoendoscopy, and chromoendoscopy with magnification were 84.0 % (173/206), 89.3 % (184/206) and 95.6 % (197/206), respectively. CONCLUSION: Chromoendoscopy with magnification is the most reliable method for determining whether a colorectal lesion is non-neoplastic or neoplastic.

A neonatal form of glycogen storage disease type IV.

We report of an infant with neonatal glycogen storage disease type IV (GSD IV) who was examined for severe hypotonia and cardiomyopathy. On the muscle biopsy there were many fibers with diastase-resistant polyglucosan bodies. Glycogen branching enzyme (GBE1) activity in the muscle was markedly reduced. The infant had a homozygous single nucleotide deletion in the open reading frame of GBE1 gene.

[Surgically treated mucoepidermoid carcinoma in a 6-year-old boy; report of a case].

A 6-year-old boy was admitted to our hospital with a history of recurrent obstructive pneumonia and hemoptysis. A chest computed tomography (CT) showed atelectasis in the left lower lobe. Angiograpy, which was performed for the suspicion of pulmonary sequestration, showed no feeding artery and revealed bleeding from the bronchial artery in the left lower lobe. As hemoptysis would not stop, an emergency left lower lobectomy was performed. Macroscopic examination of the resected specimen revealed a mass measuring 20 x 15 x 17 mm in the S8 proximal lung parenchyma, bronchiectasis, and an abscess in the distal lung parenchyma. Histopathologic examination determined the tumor was a mucoepidermoid carcinoma. Immunohistochemical staining revealed some tumor cells were positive for CA 19-9. The child has not had a recurrence 3 years postoperatively.

Malignant transformation in a mature testicular teratoma left untreated for more than 50 years since childhood.

Although testicular teratoma in childhood is regarded as a benign tumor, little is known about the consequences of pediatric teratoma being left untreated. We report herein a case of malignant transformation observed in a mature testicular teratoma that was presumed to have remained benign for >50 years.

Interleukin-1beta and tumor necrosis factor-alpha induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblasts.

BACKGROUND: Colonic subepithelial myofibroblasts may play a role in the inflammatory responses and in extracellular matrix (ECM) metabolism. In this study, we investigated the effects of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha on chemokine (IL-8 and monocyte chemoattractant protein (MCP)-1) and ECM turnover (proliferation of subepithelial myofibroblasts, and secretion of ECM and matrix metalloproteinases (MMPs)) in colonic subepithelial myofibroblasts. METHODS: Human colonic subepithelial myofibroblasts were isolated using the method described by Mahida et al. Chemokine and MMP expressions were determined by ELISA and Northern blotting. Nuclear factor (NF)-kappaB and NF-IL6 DNA binding activities were evaluated by electrophoretic gel mobility shift assays (EMSA). RESULTS: IL-1beta and TNF-alpha did not affect the proliferation of subepithelial myofibroblasts, but stimulated the secretion of types I and IV collagens weakly. Unstimulated subepithelial myofibroblasts secreted a large amount of MMP-2, but a small amount of IL-8, MCP-1 and MMP-1. IL-1beta and TNF-alpha both induced a dose- and time-dependent increase in IL-8, MCP-1 and MMP-1 secretion, and weakly stimulated MMP-2 secretion. IL-1beta and TNF-alpha both rapidly evoked NF-kappaB DNA-binding activity. The inhibition of NF-kappaB activation markedly blocked both IL-1beta- and TNF-alpha-induced IL-8 and MCP-1 mRNA expression, but did not affect MMP-1 mRNA expression. CONCLUSIONS: These observations indicate that chemokine secretion and ECM metabolism are collectively regulated by the proinflammatory cytokines, IL-1beta and TNF-alpha, in colonic subepithelial myofibroblasts. Thus, colonic subepithelial myofibroblasts may play an important role in the pathophysiology of inflammation in the colon.

Association of plasma free-3-methoxy-4-hydroxyphenyl (ethylene)glycol, natural killer cell activity and delirium in postoperative patients.

We measured and compared levels of plasma free 3-methoxy-4-hydroxyphenyl (ethylene)glycol (pMHPG), a major metabolite of noradrenaline, and natural killer (NK) cell activity in 26 patients prior to their undergoing an operation for cardiovascular diseases; 11 of whom expressed delirium and 15 who did not. In conclusion, we found that pMHPG levels before an operation were higher in patients with postoperative delirium than in the patients without, while NK cell activity showed no difference between the two groups. It is possible that hyperactivity of noradrenargic neurons is connected with the development of postoperative delirium. Furthermore, we considered that measurement of pMHPG level before operation might be a useful tool to predict the occurrence of postoperative delirium.

Rational design, discovery, and synthesis of a novel series of potent growth hormone secretagogues.

In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The 3D pharmacophore identified was then used to search 3D databases to explore chemical structures that could be novel GHSs. A number of these were chosen for synthesis and assessment of their ability to release growth hormone (GH) from rat pituitary cells. Among the compounds tested, those with a benzothiazepin scaffold were discovered with micromolar activity. To facilitate lead optimization, a second program, a site-dependent fragment QSAR procedure was developed. This program calculates a library of chemical and physical properties of "fragments" or chemical components in a known pharmacophore and determines which, if any, of these properties are important for the observed activity. The combined use of the 3D pharmacophore and the results of the site-dependent fragment QSAR analysis led to the discovery and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.

Proper regulation of cyclic AMP-dependent protein kinase is required for growth, conidiation, and appressorium function in the anthracnose fungus Colletotrichum lagenarium.

Colletotrichum lagenarium, the casual agent of anthracnose of cucumber, forms specialized infection structures, called appressoria, during infection. To evaluate the role of cAMP signaling in C. lagenarium, we isolated and functionally characterized the regulatory subunit gene of the cAMP-dependent protein kinase (PKA). The RPK1 gene encoding the PKA regulatory subunit was isolated from C. lagenarium by polymerase chain reaction-based screening. rpk1 mutants, generated by gene replacement, exhibited high PKA activity during vegetative growth, whereas the wild-type strain had basal level activity. The rpk1 mutants showed significant reduction in vegetative growth and conidiation. Furthermore, the rpk1 mutants were nonpathogenic on cucumber plants, whereas they formed lesions when inoculated through wounds. A suppressor mutant showing restored growth and conidiation was isolated from a rpk1 mutant culture. The rpkl-suppressor mutant did not show high PKA activity, unlike the parental rpk1 mutant, suggesting that high PKA activity inhibits normal growth and conidiation. The suppressor mutant, however, was nonpathogenic on cucumber and failed to form lesions, even when inoculated through wounds. The rpk1 and suppressor mutants formed melanized appressoria on the host leaf surface but were unable to generate penetration hyphae. These results suggest that proper regulation of the PKA activity by the RPK1-encoded regulatory subunit is required for growth, conidiation, and appressorium function in C. lagenarium.

Ultraviolet radiation emitted by CO(2) arc welding.

The arcs associated with arc welding emit high levels of ultraviolet radiation (UVR), and this often causes acute injuries in the workplace, particularly photokeratoconjunctivitis. It is important to know the level of UVR emitted by arc welding under various conditions, as this information will help in evaluating potential UVR hazards in welding workplaces and taking protective measures against it. In this study, the ACGIH effective irradiance for UVR was measured experimentally for CO(2) arc welding in order to evaluate its UVR hazards. A welding robot was used in the experiment in order to realize reproducible and consistent welding operations. The effective irradiance at 1 m from the arc was in the range 0.28-7.85 W/m(2) (28-785 microW/cm(2)) under the study conditions. The corresponding permissible exposure time per day is only 4-100 s, suggesting that UVR from CO(2) arc welding is actually hazardous for the eye and skin. It was found that the effective irradiance is inversely proportional to the square of the distance from the arc, is strongly dependent on the direction of emission from the arc with a maximum at 50-60 degrees from the plate surface, and tends to increase with welding current.

Contribution of enzymic alpha, gamma-elimination reaction in detoxification pathway of selenomethionine in mouse liver.

The objective of this study was to clarify the detoxification pathways of selenomethionine (SeMet) in mouse liver. It has been postulated that SeMet may be metabolized to selenocysteine (SeCyH) via a pathway similar to methionine (Met). CySeH may be decomposed to H(2)Se, which is consequently methylated to CH(3)SeH, (CH(3))(2)Se, and (CH(3))(3)Se(+). In this study, we estimated that the median lethal single oral dose (LD(50)) was 67.0 mg/kg. We also found that (CH(3))(3)Se(+) was quickly produced in mouse liver after single oral administration of SeMet. This result suggested the existence of a quick alpha,gamma-elimination pathway. We measured the amounts of alpha-ketobutyrate, NH(3), and CH(3)SeH produced by enzymic alpha,gamma-elimination reaction of SeMet in the liver of periodate-oxidized adenosine (PAD) or D,L-propargylglycine (PPG)-treated mice in order to verify the existence of alpha,gamma-elimination enzyme. PAD is an inhibitor of S-adenosylhomocysteinase (EC 3.3.1.1), which is necessary for conversion of SeMet to SeCyH. PPG is an effective inhibitor of the pyridoxal 5'-phosphate (PLP)-containing enzyme bacterial L-methionine gamma-lyase (EC 4.4.1.11) contributing to the alpha,gamma-elimination reaction of SeMet and cystathionine gamma-lyase (EC 4.4.1.1) relating to conversion of SeMet to SeCyH. When SeMet was incubated with the S9 fraction from liver of PAD-treated mice, the formation of alpha-ketobutyrate was much the same as that from nontreated mouse liver. However, the amount of alpha-ketobutyrate formed significantly decreased in the reaction of SeMet with S9 fraction from the liver of PPG-treated mice. In an in vivo experiment using mice treated with PAD before a toxic dosage of SeMet, the amount of SeMet in the liver decreased and the amount of acid-volatile Se derived from CH(3)SeH increased gradually. This phenomenon was not observed in the PPG-pretreated group. Furthermore, the protein fraction that had the alpha,gamma-elimination enzyme activity was found in mouse liver cytosol by gel chromatographic technique. The results of this study indicated that SeMet was directly metabolized to CH(3)SeH by an alpha,gamma-elimination enzyme analogous to bacterial L-methionine gamma-lyase, in addition to the generally acceptable pathway via SeCyH.

Successful treatment of metastatic adenocarcinoma of the urachus: report of 2 cases with more than 10-year survival.

Metastatic urachal cancer is often considered lethal. We report 2 cases of metastatic urachal carcinoma successfully treated with surgical excision followed by combinations of surgery, radiation, and chemotherapy against local recurrence and/or distant metastases, with a recurrence-free survival period of more than 10 years. These cases provide support for multimodal treatments of metastatic urachal cancer.

Peroxisomal metabolic function is required for appressorium-mediated plant infection by Colletotrichum lagenarium.

Peroxisomes are organelles that perform a wide range of metabolic functions in eukaryotic cells. However, their role in fungal pathogenesis is poorly understood. Here we report that ClaPEX6, an ortholog of PEX6, is required for the fungus Colletotrichum lagenarium to infect host plants. ClaPEX6 was identified in random insertional mutagenesis experiments aimed at elucidating genes involved in pathogenesis. Functional analysis, using a green fluorescent protein cassette containing the peroxisomal targeting signal1 (PTS1), revealed that import of PTS1-containing proteins is impaired in clapex6 mutants generated by targeted gene disruption. Failure of growth on fatty acids shows an inability of fatty acid beta-oxidation in these mutants. These results indicate that disruption of ClaPEX6 impairs peroxisomal metabolism, even though clapex6 mutants show normal growth and conidiation in nutrient-rich conditions. The clapex6 mutants formed small appressoria with severely reduced melanization that failed to form infectious hyphae. These data indicate that peroxisomes are necessary for appressorium-mediated penetration of host plants. The addition of glucose increased the pathogenicity of clapex6 mutants, suggesting that the glucose metabolic pathway can compensate partially for peroxisomes in phytopathogenicity.

Suppression of spermatogenesis in ipsilateral and contralateral testicular tissues in patients with seminoma by human chorionic gonadotropin beta subunit.

OBJECTIVES: The pathologic complexity of the testicular tumor makes it difficult to demonstrate exactly the relationship between the impaired spermatogenesis in patients with a testicular tumor and the serum level of the human chorionic gonadotropin beta subunit (beta-hCG). Therefore, we performed quantitative evaluation of spermatogenesis in ipsilateral and contralateral testicular tissues of seminoma to simplify the relation pathologically and endocrinologically and to demonstrate the exact correlation between spermatogenesis and serum beta-hCG levels. METHODS: Fifty-three biopsy specimens from ipsilateral and contralateral testicular tissues of seminoma were analyzed histologically. The quantitative evaluation of spermatogenesis was performed by the mean Johnsen's score count (MJSC). Beta-hCG expression in seminoma was examined immunohistochemically. Serum beta-hCG, testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels were analyzed before orchiectomy. RESULTS: A significant linear relationship (r = -0.82; P <0.005) was found between the serum level of beta-hCG and the MJSC in contralateral testicular tissues but not in ipsilateral ones, although the suppression of spermatogenesis was observed in both sides without suppression of luteinizing hormone and/or follicle-stimulating hormone production. CONCLUSIONS: A clearcut fall in the MJSC with an associated rise in the serum level of beta-hCG was demonstrated in the contralateral testicular tissues but not in the ipsilateral ones of seminoma. It seems most likely that serum beta-hCG suppresses spermatogenesis in both ipsilateral and contralateral testicular tissues without the suppression occurring through the hypothalamus-pituitary-gonadal system, and also that some less well recognized factors affect spermatogenesis, making the relation between serum beta-hCG and MJSC obscure in ipsilateral testicular tissues.