A phase Ib/II dose expansion study of subcutaneous sasanlimab in patients with locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma.

BACKGROUND: Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS: Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS: Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS: Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries.

Pre-treatment 18F-FDG PET-based radiomics predict survival in resected non-small cell lung cancer.

AIM: To assess the prognostic value of 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-based radiomics using a machine learning approach in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Ninety-three patients with stage I-III NSCLC who underwent combined PET/computed tomography (CT) followed by curative resection. A total of 35 unique quantitative radiomic features was extracted from the PET images, which included imaging phenotypes such as pixel intensity, shape, and texture. Radiomic features were ranked based on score according to their correlation with disease recurrence status within a 3-year follow-up. The recurrence risk classification performances of machine learning algorithms (random forest, neural network, naive Bayes, logistic regression, and support vector machine) using the 20 best-ranked features were compared using the areas under the receiver operating characteristic curve (AUC) and validated by the random sampling method. RESULTS: Contrast and busyness texture features from neighbourhood grey-level difference matrix were found to be the two best predictors of disease recurrence. The random forest model obtained the best performance (AUC: 0.956, accuracy: 0.901, F1 score: 0.872, precision: 0.905, recall: 0.842), followed by the neural network model (AUC: 0.871, accuracy: 0.780, F1 score: 0.708, precision: 0.755, recall: 0.666). CONCLUSION: A PET-based radiomic model was developed and validated for risk classification in NSCLC. The machine learning approach with random forest classifier exhibited good performance in predicting the recurrence risk. Radiomic features may help clinicians to improve the risk stratification for clinical practice.

Development of a Screening Tool to Predict Chronic Kidney Disease Risk in Post-nephrectomy Living Kidney Donors.

Few studies have examined the long-term risks of kidney removal to donors despite the increase of frequency in kidney transplantation. This is the 1st study to develop prediction models of chronic kidney disease (CKD) for the 1-year period after donor nephrectomy in living donors. A prospective cohort of patients who underwent donor nephrectomy from March 1, 2006, to December 31, 2016, at the Severance Hospital, Seoul, South Korea, was used. CKD was defined as a glomerular filtration rate (GFR) <60 mL/min/1.73 m2. GFR was estimated with the use of the abbreviated Modification in Diet and Renal Disease Study equation. Patients with a previous CKD history or estimated GFR <60 mL/min/1.73 m2 were excluded, and those with 1-year post-nephrectomy follow-up were included. Among 440 patients who underwent donor nephrectomy, 144 (32.7%) developed a first-time onset of a GFR <60 mL/min/1.73 m2 by 1 year after surgery. Our logistic regression models derived from these 3 variables predicted CKD with an area under the receiver operating characteristic curve of 0.796, an accuracy of 70.9%, and a sensitivity of 66.2% and specificity of 80.6%. This model could assist with decision making about potential donors and for surveillance of those at risk of post-nephrectomy CKD.

Prognostic significance of cachexia score assessed by CT in male patients with small cell lung cancer.

To determine the prognostic significance of CT-determined cachexia scores (CSs) in 127 consecutive male small cell lung cancer (SCLC) patients, cross-sectional areas of muscle and fat tissues at the third lumbar vertebra (L3) were retrospectively measured on baseline CT images. CSs were determined based on the presence of sarcopenia and/or adipopenia. According to the presence of sarcopenia (L3 muscle index <55 cm2 /m2 , 86.8%) and adipopenia (L3 fat index <22 cm2 /m2 , 11.8%), CSs were defined as follows: CS2 (sarcopenia and adipopenia, 11.8%), CS1 (sarcopenia only, 74.8%) and CS0 (13.4%). CS2 was significantly related to lower body mass index (p < .001) and poor performance status (p = .002), and patients with CS2 had shorter OS than patients with CS1 or CS0 (median OS, 5.0 months vs. 8.9 months vs. 18.3 months; p = .007). Multivariable analysis revealed that CS was an independent prognostic factor of poor survival (HR, 1.99 for CS1 and 2.59 for CS2, p = .036 and .023, CS0 as a reference), along with extensive stage (p < .001), supportive care only (p < .001) and an elevated lactate dehydrogenase (p = .005). CT-determined CSs, based on the presence of sarcopenia and/or adipopenia, could be used to predict prognosis in male SCLC.

Metastasectomy for recurrent or metastatic biliary tract cancers: A single center experience.

PURPOSE: To assess efficacy or long-term result of metastasectomy for recurrent or metastatic biliary tract carcinoma (BTC), we conducted a retrospective review of the outcomes of metastasectomy for recurrent or metastatic BTCs, comprising intrahepatic cholangiocellular carcinoma (IHCCC), proximal and distal common bile duct cancer (pCBDC and dCBDC), gallbladder cancer (GBC), and ampulla of Vater cancer (AoVC). PATIENTS AND METHODS: The clinicopathological features and outcomes of BTC patients who underwent surgical resection for the primary and metastatic disease at the Gachon University Gil Medical Centre from 2003 to 2013 were reviewed retrospectively. RESULTS: We found 19 eligible patients. Primary sites were GBC (seven patients, 37%), IHCCC (five patients, 26%), dCBDC (three patients, 16%), pCBDC (two patients, 11%), and AoVC (two patients, 11%). Eight patients (42%) had synchronous metastasis whereas 11 (58%) had metachronous metastasis. The most common metastatic site was liver (nine patients, 47%), lymph node (nine patients, 47%), and peritoneum (three patients, 16%). Nine patients (47%) achieved R0 resection, whereas four (21%) and six (32%) patients had R1 and R2 resection, respectively. With a median follow-up period of 26.7 months, the estimated median overall survival (OS) was 18.2 months (95% confidence interval, 13.6-22.9 months). Lower Eastern Cooperative Oncology Group performance status (P = 0.023), metachronous metastasis (P = 0.04), absence of lymph node metastasis (P = 0.009), lower numbers of metastatic organs (P < 0.001), normal postoperative CA19-9 level (P = 0.034), and time from diagnosis to metastasectomy more than 1 year (P = 0.019) were identified as prognostic factors for a longer OS after metastasectomy. CONCLUSIONS: For recurrent or metastatic BTCs, metastasectomy can be a viable option for selected patients.

Genome-wide microRNA expression profiling in placentas of fetuses with Down syndrome.

INTRODUCTION: Down syndrome (DS) is the most common aneuploidy, caused by an extra copy of all or part of chromosome 21 (chr21). Differential microRNA (miRNA) expression is involved in many human diseases including DS. However, the genome-wide changes in miRNA expression in DS fetal placentas have yet to be determined, and the function of these changes is also unclear. METHODS: We profiled genome-wide miRNA expression in placenta samples from euploid or DS fetuses by using microarray technology and predicted the functions of differentially expressed miRNAs using bioinformatics tools. RESULTS: Thirty-four miRNAs were significantly differentially expressed in the DS placenta compared with the normal placenta (16 up-regulated and 18 down-regulated). However, expression of chr21-derived miRNAs did not change. Predicted target genes included 7434 genes targeted by up-regulated miRNAs and 6071 genes targeted by down-regulated miRNAs. Seventy-six of these target genes were located on chr21 (10 genes controlled by down-regulated miRNAs and 34 genes by up-regulated miRNAs, and 32 genes by both). Target genes on chr21 were significantly associated with DS and DS-related disorders, such as mental retardation, neurobehavioral manifestations, and congenital abnormalities. DISCUSSION: To our knowledge, this is the first genome-wide study to comprehensively survey placental miRNAs in DS fetuses. Our results provide new insight into miRNA expression in placentas of fetuses with DS. Additionally, our findings indicate that the differentially expressed miRNAs in the DS placenta may potentially affect various pathways related to DS pathogenesis.

Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours.

BACKGROUND: Treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs) are still limited. We investigated the antitumour activity and safety profile of pazopanib--a multitarget drug with anti-angiogenic activity in patients with metastatic GEP NETs. METHODS: This was a nonrandomised, open-labeled, single-center phase II study. Pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The primary end point was an objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety. An independent review of objective response was planned. The trial is registered with ClinicalTrials.gov, NCT number 01099540. Correlative biomarker analyses were performed. RESULTS: Between April 2010 and February 2012, a total of 37 patients were enrolled. Thirty-two percent of the enrolled patients had pancreatic primary and 22% of the patients had colorectal primary NETs. This phase II study demonstrated an objective response rate of 18.9% (7 of the 37, 95% CI 8.0-35.2) and a disease control rate (CR+confirmed PR+stable disease) of 75.7% (28 of the 37, 95% CI, 58.8-88.2) in metastatic GEP NETs. The independent review demonstrated a higher overall response rate of 24.3% (95% CI, 11.8-41.2%) with nine confirmed PRs. CONCLUSION: Pazopanib showed a comparable efficacy to other targeted agents not only in pancreatic NETs but also in NETs originating from gastrointestinal (GI) tract.

Foetal and neonatal outcomes in first-trimester pregnant women exposed to abdominal or lumbar radiodiagnostic procedures without administration of radionucleotides.

BACKGROUND/AIM: Little is known about exposures to low radiation doses in the first trimester of pregnancy and deterministic adverse effects in the offspring, and risks are extrapolated from catastrophic events or from exposures to radiotherapy. The study aimed to assess the foetal and neonatal outcomes of pregnant women exposed to radiodiagnostic procedures with abdominal or lumbar irradiation. METHODS: In a prospective cohort design, we studied the foetal and neonatal outcomes in 115 singleton pregnant women who required abdominal or lumbar radiodiagnostic procedures without the administration of radionucleotides, and in 527 age-matched (± 2 years) control pregnant women. RESULTS: In the exposed group, lumbar spine radiography (33.9%), plain abdominal radiography (16.5%) and upper gastrointestinal tract radiography with abdominal irradiation (15.7%) were the most common radiodiagnostic procedures. Major congenital malformations were identified in two (1.9%) babies born in the exposed group and in two (0.4%) babies born in the control group (odds ratio = 4.7; 95% confidence interval 0.7-33.6; P = 0.15). The rest of the foetal and neonatal outcomes was similar in the two groups except by a marginally higher rate of admissions to the neonatal intensive care unit among babies born to exposed women (odds ratio = 2.9; 95% confidence interval 1.0-9.4; P = 0.06). CONCLUSION: Our results indicate that X-ray and computed tomography scan exposure involving abdominal irradiation without the administration of radionucleotides is not associated with adverse foetal and neonatal deterministic outcomes. Efforts are required to reduce the use of radiodiagnostic procedures for general check-ups in childbearing age women.

Association of fetal-derived hypermethylated RASSF1A concentration in placenta-mediated pregnancy complications.

OBJECTIVES: To assess whether fetal-derived hypermethylated RASSF1A concentrations in maternal plasma during pregnancy are altered in pregnancies associated with placental dysfunction manifested by intrauterine growth restriction (IUGR), preeclampsia (PE), or placental previa (PP) and whether this alteration can be detected in susceptible subjects before the onset of clinical disease. METHODS: We performed a real-time quantitative polymerase chain reaction to quantify RASSF1A concentrations before and after methylation-sensitive restriction digestion in maternal plasma at 7-41 gestational weeks of normal pregnancies (n = 161), IUGR (n = 43), PE (n = 22), PP (n = 14) and non-pregnant women (n = 20). RESULTS: A positive correlation was observed between fetal-derived hypermethylated RASSF1A concentration and gestational age for all study groups (r = 0.624, p < 0.001 for IUGR; r = 0.381, p = 0.042 for PE; r = 0.697, p < 0.001 for PP; r = 0.560, p < 0.001 for controls). The concentration of hypermethylated RASSF1A was relatively high at 7-14 gestational weeks in all patient groups. Hypermethylated RASSF1A concentration at 15-28 weeks was significantly higher in patients who subsequently developed IUGR (p = 0.002), PE (p < 0.001) or PP (p < 0.001) than in controls. CONCLUSION: We first demonstrated increased concentration of fetal-derived hypermethylated RASSF1A sequences according to advancing gestation and before the onset of the clinical manifestation of pregnancy complications secondary to placental dysfunction, such as IUGR, PE and PP. Hypermethylated RASSF1A in maternal plasma may be useful as a potential biomarker to detect placental-mediated pregnancy complications, regardless of fetal gender and polymorphism.

Expression of CCL1 and CCL18 in atopic dermatitis and psoriasis.

BACKGROUND: Recent studies have shown that chemoattractive proteins play an important role in the organization of the innate and adaptive immune responses. There are some reports that chemokine (C-C motif) ligand (CCL)1 and CCL18, members of a family of chemoattractive proteins, have increased expression in atopic dermatitis (AD). AIM: To evaluate the quantity and pattern of CCL1 and CCL18 expression in lesions and blood of patients with AD, and compare them with those of patients with psoriasis. METHODS: Biopsy specimens were taken from atopic skin and normal-appearing skin of patients with AD and from the psoriatic skin only of patients with psoriasis. Quantitative real-time PCR analysis and immunohistochemistry of CCL1 and CCL18 expression were performed, and the quantities of expressed CCL1 and CCL18 in acute AD were compared with those of normal-appearing atopic skin and psoriatic skin. The serum level of CCL1 and CCL18 was assessed by ELISA. RESULTS: Expression of CCL1 mRNA and protein was significantly higher in the acute lesional skin of patients with AD than in their nonlesional skin or in the lesional skin of patients with psoriasis. Both CCL18 mRNA and protein were abundant in acute AD lesions and in psoriatic lesions, but were lower in the nonlesional skin of patients with AD. The serum levels of CCL1 and CCL18 were not different in patients with AD and patients with psoriasis. CONCLUSIONS: CCL1 is a chemokine that is associated with AD. Both CCL1 and CCL18 may play important roles in the initiation and progression of atopic skin inflammation.

Extranodal natural killer/T-cell lymphoma from skin or soft tissue: suggestion of treatment from multinational retrospective analysis.

BACKGROUND: Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. PATIENTS AND METHODS: This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. RESULTS: Patients with Ann Arbor stage I, T1-2N0M0 by International Society for Cutaneous Lymphomas-European Organization of Research and Treatment of Cancer TNM (tumour-node-metastasis) stage, International prognostic index score of 0-1, and a Korean prognostic index (KPI) score of 0-1 were associated with better survival. Four of five patients with T1-2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. CONCLUSION: In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour-node-metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.

Pile mixing increases greenhouse gas emissions during composting of dairy manure.

The effect of pile mixing on greenhouse gas (GHG) emissions during dairy manure composting was determined using large flux chambers designed to completely cover replicate pilot-scale compost piles. GHG emissions from compost piles that were mixed four times during the 80 day trial were approximately 20% higher than emissions from unmixed (static) piles. For both treatments, carbon dioxide (CO(2)), methane (CH(4)), and nitrous oxide (N(2)O) accounted for 75-80%, 18-21%, and 2-4% of GHG emissions, respectively. Seventy percent of CO(2) emissions and 95% of CH(4) emissions from all piles occurred within first 23 days. By contrast, 80-95% of N(2)O emissions occurred after this period. Mixed and static piles released 2 and 1.6 kg GHG (CO(2)-Eq.) for each kg of degraded volatile solids (VS), respectively. Our results suggest that to minimize GHG emissions, farmers should store manure in undisturbed piles or delay the first mixing of compost piles for approximately 4 weeks.

A prospective cohort study of pregnancy outcomes of women inadvertently exposed to methylephedrine in the 1st trimester of pregnancy.

No information is currently available on the safety of methylephedrine, a component of various cold medications available in South Korea. With previous approval by an Institutional Review Board, 349 women inadvertently exposed to methylephedrine during the 1st trimester of pregnancy and an age- and gravidity-matched control group, were enrolled in a prospective cohort study. Study outcomes, for example gestational age at birth, birth weight and major and minor malformations were evaluated in 282 cases and 280 controls. Exposure to methylephedrine was at a gestational age of 4.0 weeks (median), at doses ranging from 52.5 to 1,575 mg/day, for a median duration of 3 (range: 1-30) days. No differences were observed between cases and controls in any of the pregnancy outcomes studied. There were 4/265 (1.5%) babies born with major malformations in the case group and 4/260 (1.5%) in the control group. In conclusion, inadvertent exposure to methylephedrine as a component of over-the counter oral cold remedies in early pregnancy was not associated with an increased rate of adverse pregnancy outcomes. Co-exposure with acetaminophen, cigarette smoking or alcohol did not appear to modify the outcomes.

CM1, a possible novel activation molecule on human lymphocytes.

CM1 (centrocyte/-blast marker 1) defined by a mAb developed against concanavalin-A activated PBMC, is expressed specifically on some tonsillar germinal center (GC) B cells. In single flow cytometric analysis, the bone marrow did not express these molecules nor did the PBMC or the thymocytes. The peripheral B lymphocytes showed more than 90% positive, while the peripheral T lymphocytes showed approximately 60% positive at 48 h after activation by PMA/ionomycin, respectively. A western blot analysis and an immunoprecipitation for CM1 showed a band at 70 kDa. Cross-linking of CM1 with anti-CM1 mAb induced apoptosis of the GC B cells (CD38(+)IgD(-)). Immunohistochemical staining revealed that the CM1 molecule is distributed over the entire area except the proximal dark zone of the tonsillar germinal centers. These results suggest that the CM1 molecule might be involved in differentiation of the germinal center B cells as one of the novel centrocyte markers.

C-terminal region of hTPO is important for secretion and expression in insect cells.

Human thrombopoietin (hTPO) variant cDNAs truncated in the C-terminal regions of wild-type hTPO (332 amino acids) were constructed by PCR and expressed in Trichoplusia ni (Tn5) insect cells using a baculovirus expression system. Each variant, hTPO163 (amino acids 1-163), hTPO198 (1-198) and hTPO245 (1-245), was produced in insect cells with very low efficiency in comparison with wild-type hTPO. Immunoblot analysis showed that the predicted 20, 25 and 34 kDa molecular sizes corresponding to hTPO163, hTPO198 and hTPO245, respectively, were barely detected in culture medium and most of the proteins remained within the cell. These results suggest that C-terminal regions containing potential N-glycosylation sites of hTPO are required for the secretion of hTPO into culture medium as well as expression in insect cells.

HPV-16-related proteins as the serologic markers in cervical neoplasia.

OBJECTIVE: Recently, a variety of HPV-related proteins have been synthesized and their utility as diagnostic and prognostic markers in cervical cancers needs to be assessed. The ability to generate preparative amounts of HPV-16 L1/L2 VLPs and E6, E7 proteins may have implications for the development of a serologic assay to detect anti-HPV-16 virion immune responses. The purpose of the study is to improve the way of proper management of the cervical cancer by investigating the utility of the recently developed HPV-16 L1/L2 VLPs, HPV-16 E6, E7 proteins as the clinical serologic markers through antibody reactions by comparison with those of SCCA and CEA which have been used as tumor markers for cervical cancer. METHODS: The serologic responses in Korean women with cervical neoplasia by ELISA using HPV-16 L1/L2 VLPs and radioimmunoprecipitation assay (RIPA) using in vitro translated HPV-16 E6, E7 proteins were investigated. PCR using E6 type-specific primers for HPV-16/18 was used to determine the presence and type of HPV infection (normal controls, 15 cases; preinvasive lesions, 28 cases; invasive cervical cancers, 124 cases). RESULTS: The sera of 34% (42/124) of cervical cancers were positive for SCCA and the sera of 18% (22/124) of cervical cancers were positive for CEA. The positivity of SCCA was increased with advancing clinical stages, but the antibody levels were not correlated with clinical stage of disease. The sera of 7% (1/15) of normal controls, 39% (11/28) of preinvasive lesions, and 56% (70/124) of patients with cervical cancer were ELISA positive for HPV-16 L1/L2 VLPs (P < 0.05). The sera of 7% (2/28) of preinvasive lesions and 51% (63/124) of cervical cancers were positive for in vitro translated HPV-16 E6 protein (P < 0.05) and the sera of 11% (3/28) of preinvasive lesions and 33% (41/124) of cervical cancers were positive for in vitro translated HPV-16 E7 protein (P < 0.05). The antibody levels to HPV-16 E7 protein were correlated to clinical stage and tumor burden in a significant number of cervical cancers. CONCLUSIONS: These data suggest that a considerable number of patients with cervical neoplasia generated positive antibody response to L1/L2 VLPs and in vitro translated E6, E7 proteins of HPV-16. These HPV-16-associated proteins might be disease-specific markers which could be useful in an adjunctive diagnostic assay and a seroepidemiologic study of HPV-related cervical neoplasia. In particular, the monitoring of antibody to HPV-16 E7 protein seems to be valuable in the proper management of cervical cancers for specific tumor markers.

Physical status and expression of HPV genes in cervical cancers.

It is known that E2 protein of oncogenic human papillomavirus (HPV) inhibits the expression of E6 and E7 genes from their major promoters in vitro and suppresses the proliferation of cervical cancer cells. This suggests that the loss of functional E2 gene may provide selective advantages in the development of cervical cancer. Investigation of the relationship between the disruption of HPV-16/18 E2 genes by DNA integration and clinical outcome of cervical cancer may not only help to understand the mechanism of HPV-related cervical carcinogenesis, but may also provide novel management of cervical cancer. It was noted that integrated HPV-16/18 DNA was predominant in most patients with cervical cancers, marking 51 of a total of 68 cases (75%); episomal HPV DNAs were found in 5 cases (7.4%), and finally mixed forms of HPV DNAs with episome and integration were found in 12 cases (17.6%). Whole portions of E2 DNA of HPV-16 could be amplified by PCR in 19 (36.5%) of 52 cases of cervical intraepithelial neoplasia. It was shown that there was not statistically significant association with the different stages, but integrated HPV DNAs were detectable only in the patients with far-advanced stage of cervical cancers, which also means no episomal forms were detected. Episomal forms of HPV DNA were detectable in 14 (25.9%) of 54 squamous cell carcinomas (4 pure episomal forms and 10 mixed forms), whereas only 1 (8.3%) of 12 adenocarcinomas and adenosquamous cell carcinomas contained episomal viral DNA. When HPV DNA forms were compared with initial tumor size, lymphovascular space involvement, and frequency of nodal metastasis, statistically significant relationships were not found. The association of DNA integration with invasive cervical cancers was seen regardless of HPV type; however, there were differences between the integration profiles of HPV-16 and HPV-18 DNA. Of the 51 HPV-16-containing cancers, 36 (70.6%) revealed purely integrated HPV DNA, and another 10 cases (19.6%) displayed both integrated and episomal HPV DNAs. However, 5 (9.8%) cases showed only episomal copies of the HPV-16 genome. In contrast, all 17 HPV-18-containing cancers (5 cases positive for HPV-18 and 12 cases positive for both HPV-16 and -18) revealed only the integrated form of HPV-18 DNA. The expression of E6 and E7 transcripts of HPV-16/18 is uniformly correlated with the physical status of HPV DNAs. HPV E2 mRNAs were constantly expressed in the presence of the intact virus in cases with episome and mixed forms of HPV DNA. In general, amplified signals from HPV E2 RT-PCR are more intensive than those from DNA-PCR in the same patients. It is suggested that RT-PCR is a valuable method to evaluate dynamic expression of the specific gene and seems to be more sensitive than the DNA-PCR method in detecting intact E2 gene because of the gene copy numbers.

Expression of bFGF and VEGF in brain astrocytoma.

Neovascularization is an important factor in the prognosis of brain tumor and many angiogenetic factors have been evaluated for prognostic significance. Among them, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are known as potent angiogentic factors and mitogens. We evaluated seven cases of grade II brain astrocytoma. Four, group A, was diagnosed as anaplastic progression at their second operation, and three, group B, did not. Using monoclonal antibodies to bFGF and VEGF in paraffin embedded tissue from first operation, their immunoreactivity and differences between two groups were examined. The growth fractions of these tumor were also measured by Ki-67 monoclonal antibodies (MIB1). Immunostaining for bFGF in tumor cells were observed in both nuclei and cytoplasm, and for VEGF, mainly observed in the cytoplasm. Mean cell count number +/- standard deviation per high power field in each were as follows: 1) for bFGF, 20.08 +/- 6.38 in group A and 0.87 +/- 0.90 in group B (P < 0.01), 2) for VEGF, 43.75 +/- 17.09 in group A, and 0.8 +/- 1.06 in group B (P < 0.05) and 3) for the proliferation index with Ki-67 antibodies, 3.20 +/- 0.81 in group A and 0.77 +/- 1.03 in group B (P < 0.05). This data supports the assertion that angiogenetic factor such as bFGF and VEGF may contribute to progressive change of astrocytoma by tumor angiogenesis.