Ten cancer patients (Six renal cell carcinoma and four breast cancer patients) were treated in a phase I/II study with a vaccine composed of autologous dendritic cells (DCs) and IL-2 to evaluate the DC vaccine-related toxicity and antigen-specific immune alteration.
Cancer patients were treated twice with autologous CD34+ hematopoietic stem cell-derived, GM-CSF/IFN-γ-differentiated DCs pulsed with autologous tumor lysate and KLH, by 4-week interval. Following each subcutaneous injection of therapeutic DCs, low-dose (200 MIU) IL-2 was introduced for 14 consecutive days as an immune adjuvant. To determine the DC vaccine-induced immunological alterations, the KLH-specific lymphocyte proliferation, number of IFN-γ secreting T cells (ELISPOT assay), NK activity and the cytokine modulation were measured.
Cultured-DCs expressing HLA-DR, CD11c, CD83, and B7.1/B7.2 produced IL-12p70. After vaccination, the patients tolerated it. Clinical response was observed in one RCC patient as stable disease. However DC-vaccine related antigen-specific immune responses including peripheral blood lymphocyte proliferation and the number of IFN-r secreting cells were induced in six patients without clear correlation with clinical responses. Also NK activity was induced significantly in six patients after vaccination. DC vaccine-related decrease of TGF-β level or increase of IL-12p70 level and decline of CD4+CD25+ T cells were observed in three patients. However only in the RCC patient whose disease stabilized, combination of stimulatory as well as inhibitory immune alterations including induction of IFN-γ secreting T cell with reduction of CD4+ CD25+ T cell were correlated with clinical responses.
Data indicated that DC vaccine combined with IL-2 is well tolerated without major side effects. DC vaccine induced the specific immunity against introduced antigen. Combinatorial alterations of immunological parameters indicating antigen-specific immune induction along with reduction of inhibitory immunity were correlated with clinical responses in DC vaccine treated patients.
Dendritic cell vaccine; Renal cell carcinoma; Breast cancer; Phase I/II trial; Immune response
Regulatory T lymphocytes evoke the immune tolerance by suppressing and inactivating cytotoxic T lymphocytes. The objective of this study was to compare the proportion of regulatory T lymphocytes, precisely defined as CD4+CD25high+Foxp3+ T lymphocytes, in primary and recurrent ovarian carcinoma before and after ex vivo expansion of ascites with interleukin-2 (IL-2).
Ascitic fluid samples were obtained from 26 patients with ovarian carcinoma. Lymphocytes were isolated from ascites and cell markers were analyzed by flow cytometry using anti-CD3/CD4/CD8/CD16/CD56/CD25 and anti-Foxp3 antibodies. Lymphocytes were incubated for 2 to 3 weeks and expanded ex vivo by IL-2 stimulation and their phenotypes were analyzed by flow cytometry.
Following ex vivo expansion, ascitic fluid lymphocytes increased by a greater extent in the recurrent group than in the primary group. The proportion of ex vivo-expanded lymphocytes changed as follows; CD4+ T lymphocytes increased, CD8+ T lymphocytes decreased, and the proportion of CD3-CD16+56+ NK cells was unchanged. The proportion of CD4+CD25high+Foxp3+ regulatory T lymphocytes in CD4+ T lymphocytes increased after ex vivo expansion in both groups, but to a greater degree in the recurrent group.
This study showed that regulatory T lymphocytes, neither cytotoxic T lymphocytes nor NK cells, were extensively increased after ex vivo expansion, especially in recurrent ovarian carcinoma. These results may provide information that helps to guide the future development of adoptive immunotherapy against ovarian carcinoma.
Regulatory T lymphocyte; Foxp3; Ex vivo expansion; Ovarian carcinoma; Ascites
Basaloid squamous cell carcinoma of the uterine cervix is an extremely rare malignancy of the female genital tract with a poorer clinical outcome than squamous cell carcinoma of the uterine cervix. We report a case of pure basaloid squamous cell carcinoma of the uterine cervix. A 70-yr-old woman with vaginal bleeding was referred to our institute. A basaloid squamous cell carcinoma of the uterine cervix, of International Federation of Gynecology and Obstetrics (FIGO) stage Ib1, was diagnosed by a loop electrosurgical excision procedure cone biopsy. A radical hysterectomy was performed, along with bilateral salpingo-oophorectomy, pelvic lymph node dissection, and para-aortic lymph node sampling. Pathologic findings were consistent with a basaloid squamous cell carcinoma confined to the cervix without an extracervical tumor. No further treatment was administered and there was no clinical evidence of recurrence during the 12 months of follow-up. Follow-up for the patient is ongoing. Although basaloid squamous cell carcinoma of the uterine cervix is thought to behave aggressively, accumulation of data on these rare tumors is necessary to determine whether their behavior differs significantly from that of conventional cervical squamous cell carcinoma of similar clinical stage. These data would be useful for defining the best diagnosis and treatment for these rare tumors.
Basaloid; Carcinoma, Squamous Cell; Cervix Uteri
To compare survival outcomes and treatment-related morbidities between radical hysterectomy (RH) and primary chemoradiation therapy (CRT) in patients with bulky early-stage cervical cancer.
We selected 215 patients with stage IB2 and IIA2 cervical cancer (tumor diameter > 4 cm on magnetic resonance imaging) who underwent RH followed by tailored adjuvant therapy (n=147) or primary CRT (n=68) at two tertiary referral centers between 2001 and 2010.
About twenty nine percent of patients were cured by RH alone and these patients experienced the best survival outcomes with the lowest morbidity rates. After the median follow-up times of 40 months, 27 RH (18.4%) and 20 CRT (29.4%) patients had recurrence (p=0.068) and 23 (15.6%) and 17 (25%) patients died of disease (p=0.101). The 5-year progression-free survival were 77% and 66% (p=0.047), and the 5-year overall survival were 78% and 67% (p=0.048) after RH and primary CRT, respectively. In multivariate analysis, patients who received primary CRT was at higher risk for tumor recurrence (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.24 to 4.14; p=0.008) and death (OR, 3.02; 95% CI, 1.53 to 5.98; p=0.001) than those who received RH. Grade 3-4, early (17% vs. 30.9%, p=0.021) and late (1.4% vs. 8.8%, p=0.007) complications were significantly less frequent after RH than primary CRT.
Thirty percent of patients were cured by RH alone. A treatment outcome was better in this retrospective study in terms of morbidity and survival. Randomized trials are needed to confirm this result.
Bulky early-stage cervical cancer; Chemoradiation therapy; Radical hysterectomy; Stage IB2; Stage IIA2
Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized pathologically by intraneuronal inclusions called Lewy bodies (LBs) and Lewy neurites. A major component of these inclusions is the protein α-synuclein, which is natively unfolded but forms oligomers and insoluble fibrillar aggregates under pathological conditions. Although α-synuclein is known to undergo several posttranslational modifications, the contribution of SUMOylation to α-synuclein aggregation and the pathogenesis of α-synucleinopathies have not been elucidated. Here, we provide evidence that aggregates and inclusions formed as a result of impaired proteasome activity contain SUMOylated α-synuclein. Additionally, SUMO1 is present in the halo of LBs colocalizing with α-synuclein in the brains of PD and DLB patients. Interestingly, SUMOylation does not affect the ubiquitination of α-synuclein. These findings suggest that proteasomal dysfunction results in the accumulation of SUMOylated α-synuclein and subsequently its aggregation, pointing to the contribution of this posttranslational modification to the pathogenesis of inclusion formation in α-synucleinopathies.
Parkinson’s disease; Dementia with Lewy Bodies; α-Synuclein; SUMOylation; protein aggregation; proteasome
This study was conducted to examine recent trends in ovarian cancer incidence and mortality and secular trends in demographic factors in Korea.
With the data from Korea Central Cancer Registry, International Agency for Research on Cancer, Korean Death Registry, and World Health Organization's Statistical Information System, we calculated age-standardized incidence and mortality rates for ovarian cancer. Also we estimated future incidence of ovarian and cervical cancer using linear regression model. To assess the demographic trend, data from national surveys in Korea or results from published papers were searched.
Ovarian cancer incidence rate was similar to that in women worldwide but lower than those in Western countries, and the trend has been increased steadily. Ovarian cancer-related mortality rates have been increasing in Korea, even though those in western and some Asian countries, such as China, have been decreasing. Age-specific incidence rate and mortality rate showed steep increases with advancing age. The incidence rate of ovarian cancer was estimated to surpass that of uterine cervix cancer in 2015. Korea showed rapid changes in nutritional, reproductive, and anthropometric factors.
These recent trends in ovarian cancer incidence and mortality may be partly attributed to gradual westernizing of life styles and to changes in socio-demographic behavior factors. In particular, the increasing trend in ovarian cancer mortality in Korea may be attributed to a real rise in mortality as well as, in part, a decline in misclassification bias related to an increase in the proportion of deaths confirmed by physician diagnosis.
Ovarian neoplasms; Epidemiology; Incidence; Mortality
The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.
Altretamine; Consolidation Therapy; Advanced Epithelial Ovarian Cancer
To evaluate the efficacy of taxane and platinum-based chemotherapy guided by extreme drug resistance assay (EDRA) in patients with epithelial ovarian cancer.
Thirty-nine patients were enrolled, who were diagnosed as epithelial ovarian cancer, tubal cancer or primary peritoneal carcinoma and received both debulking surgery and EDRA in Asan Medical Center between August 2004 and August 2006. Another thirty-nine patients were enrolled, who did not receive EDRA as control. Paclitaxel 175 mg/m2 and carboplatin AUC 5 were administered as primary combination chemotherapy to both EDRA group and the control group. In the EDRA group, paclitaxel was replaced by docetaxel 75 mg/m2 if a patient showed extreme drug resistance (EDR) to paclitaxel and not to docetaxel. Carboplatin was replaced by cisplatin 75 mg/m2 if a patient showed EDR to carboplatin and not to cisplatin. If only one drug showed low drug resistance (LDR), it was allowed to add another drug which showed LDR such as gemcitabine 1,000 mg/m2. CT scan was performed every three cycles and CA-125 was checked at each cycle.
There was no significant difference in overall response rate between EDRA group and the control group (84.5% vs. 71.8%, p=0.107). However, 93.8% of patients in EDRA group did not show EDR to at least one drug and its response rate was significantly higher than that of the control group (93.3% vs. 71.8%, p=0.023).
we could choose a combination of taxane and platinum which did not show EDR and could obtain a good response in the patients with ovarian cancer.
Ovarian neoplasms; Antineoplastic combined chemotherapy protocol; Drug resistance; neoplasm; Biologic assay
To assess the prevalence of KRAS, BRAF, and TP53 mutations in cases of low-grade and high-grade serous carcinomas and to evaluate the clinical outcomes of these morphologically distinct carcinomas.
Materials and Methods
Patients with primary invasive serous carcinomas were classified according to the universal grading system. Grade 2 serous tumors were excluded. A total of 100 patients were included for clinical evaluation. Thirty-seven patients, including 20 with low-grade and 17 with high-grade carcinomas, were selected for mutational analysis.
The low-grade carcinoma group was characterized by young age and premenopausal period compared with the high-grade carcinoma group, but there were no statistically significant differences in stage, metastasis of lymph node and residual disease. There were no statistically significant differences in survival rates, however, the low-grade carcinoma group showed a trend for improved progression-free survival compared with the high-grade carcinoma group of early stage (p = 0.064). Mutations in KRAS and BRAF were found in 6 (30%) and 2 (10%) patients in the low-grade carcinoma group, respectively, however, they were not found in the high-grade carcinoma group. KRAS and BRAF mutations were mutually exclusive, and both mutations were observed in 40% (8/20). The frequency of TP53 mutations in low-grade and high-grade carcinoma groups were found in 20% (4/20) and 70.6% (12/17), respectively (p = 0.009).
Low-grade serous carcinoma shows mutation pattern different from that with high-grade carcinoma. As there were no significant differences in stage distribution and survival, especially in advanced stage, we suggest that more studies are needed to segregate these patients into distinct disease entities.
Ovary; serous carcinoma; grade; mutation
To compare the efficacy of neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical hysterectomy with radical surgery alone in patients with stage IB2-IIA bulky cervical cancer.
From November 1999 to September 2007, stage IB2-IIA cervical cancers with tumor diameter >4 cm, as measured by MRI, were managed with two cycles of preoperative paclitaxel and platinum. As a control group, we selected 35 patients treated with radical surgery alone.
There were no significant between group differences in age, tumor size, FIGO stage, level of SCC Ag, histopathologic type and grade. Operating time, estimated blood loss, the number of lymph nodes yielded and the rate of complications were similar in the two groups. In surgical specimens, lymph-vascular space invasion (LVSI), nodal metastasis and parametrial involvement did not differ significantly between the two groups. In the neoadjuvant group, pathologic tumor size was significantly smaller and fewer patients had deep cervical invasion. Radiotherapy, alone and in the form of concurrent chemoradiation, was administered to more patients treated with radical surgery alone (82.9% vs. 52.9%, p=0.006). No recurrence was observed in patients who could avoid adjuvant radiotherapy owing to improved risk factors after neoadjuvant chemotherapy. There were no significant differences in 5-year disease free and overall survival.
As neoadjuvant chemotherapy would improve pathologic prognostic factors, adjuvant radiotherapy can be avoided, without worsening the prognosis, in patients with locally advanced bulky cervical cancer. Neoadjuvant chemotherapy would be improving the quality of life after radical hysterectomy in patients with bulky cervical cancer.
Locally advanced cervical cancer; Neoadjuvant chemotherapy; Radical hysterectomy
To verify whether it can be justified to classify patients to stage IIIC epithelial ovarian cancer based on nodal involvement only.
This study included all consecutive patients with stage IIIC epithelial ovarian cancer who underwent upfront cytoreductive surgery according to the FIGO guideline followed by platinum based chemotherapy from September 1989 to September 2006 at Asan Medical Center.
During the study period, a total of 272 patients met the inclusion criteria. Optimal cytoreduction was achieved in 213 patients, and complete cytoreduction was achieved in 85 patients. Median follow-up time was 37 months (range, 6-181 months). The 5-year disease free survival (DFS) and overall survival (OS) rate of all patients were 23% and 57%, respectively. Forty-one patients were allocated to stage IIIC by positive nodes only. Patients with stage IIIC disease due to positive nodes only had significantly longer DFS and OS compared to other stage IIIC patients (p<0.001 and p<0.001). The DFS and OS of these patients was significantly better than those of other stage IIIC patients who achieved complete or optimal cytoreduction (p<0.001 and p<0.001). The outcome was even better than that of stage IIIA and IIIB patients (p<0.05 and p<0.05).
Patients with stage IIIC epithelial ovarian cancer due to positive nodes only had a more favorable prognosis compared to other stage IIIC patients. Therefore, reevaluation of the current FIGO staging system for stage IIIC epithelial ovarian cancer is required.
Epithelial ovarian cancer; Stage IIIC; Lymph node metastasis; Prognosis