Phase I/II study of stereotactic body radiotherapy boost in patients with cervical cancer ineligible for intracavitary brachytherapy.

PURPOSE: Stereotactic body radiotherapy (SBRT) boost is a promising treatment for cervical cancer patients who are ineligible for intracavitary brachytherapy (ICBT). The aim of this multicenter, single-arm, phase I/II study was to prospectively evaluate the efficacy and toxicity of SBRT boost. MATERIALS AND METHODS: ICBT-ineligible patients with untreated cervical cancer were enrolled. Patients underwent whole-pelvic radiotherapy (45 Gy in 25 fractions) with SBRT boost to the primary lesion. In the phase I dose-escalation cohort (3 + 3 design), patients were treated with SBRT boost of 21 or 22.5 Gy in three fractions. Although dose-limiting toxicity was not confirmed, a dose of 21 Gy was selected for the phase II cohort because it was difficult to reproduce the pelvic organs position in two patients during the phase I trial. The primary endpoint was 2-year progression-free survival. RESULTS: Twenty-one patients (phase I, n = 3; phase II, n = 18) were enrolled between April 2016 and October 2020; 17 (81%) had clinical stage III-IV (with para-aortic lymph node metastases) disease. The median (range) follow-up was 40 (10-84) months. The initial response was complete response in 20 patients and partial response in one patient. The 2-year locoregional control, progression-free survival, and overall survival rates were 84%, 67%, and 81%, respectively. Grade ≥ 3 toxicity was confirmed in one patient each in the acute (diarrhea) and late (urinary tract obstruction) phases. CONCLUSION: These findings suggested that a SBRT boost is more effective than the conventional EBRT boost and can be an important treatment option for ICBT-ineligible patients with cervical cancer. STUDY REGISTRATION: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000036845).

Clinical characteristics and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma confirmed by central pathologic review: A multi-institutional retrospective study from the Japanese Clinical Oncology Group.

OBJECTIVES: Low-grade and high-grade endometrial stromal sarcomas (LGESS and HGESS) and undifferentiated uterine sarcomas (UUS) are rare tumors whose pathological classification and staging system have changed recently. These tumors are reported to contain fusion genes. We aimed to clarify the genetic background, clinical features, prognostic factors, and optimal therapy of these tumors using a new classification and staging system. METHODS: We analyzed the clinical features and prognostic information of 72 patients with LGESS, 25 with HGESS, and 16 with UUS using central pathological review. Estrogen and progesterone receptors (PgRs) were examined by immunohistochemistry. JAZF1-SUZ12 and YWHAE-NUTM2A/B gene fusions were tested using real-time polymerase chain reaction. RESULTS: The 5-year overall survival (OS) rates of LGESS, HGESS, and UUS were 94%, 53%, and 25%, respectively. In LGESS, stage IV, incomplete surgery, and absence of PgR were associated with poor OS. The presence of JAZF1-SUZ12 fusion gene was not associated with OS. In HGESS, the relationship between stage and prognosis was unclear. None of the 3 patients with YWHAE-NUTM2A/B fusion gene died during follow-up. Adjuvant chemotherapy was associated with a favorable OS. Incomplete resection of UUS was associated with poor OS; however, residual tumors frequently occurred. Although most patients underwent adjuvant chemotherapy, their prognosis was extremely poor even in stage I disease. CONCLUSIONS: Prognosis of LGESS is generally good; however, stage IV, incomplete surgery, and PgR-negative tumors are associated with poor prognosis. Adjuvant chemotherapy may be useful for HGESS. Prognosis of UUS is extremely poor, even with adjuvant chemotherapy.

DNA methylation of the immediate upstream region of BRCA1 major transcription start sites is an independent favorable prognostic factor in patients with high-grade serous ovarian cancer.

OBJECTIVE: To establish a quantitative method to evaluate the DNA methylation level of an immediate upstream region of major BRCA1 transcriptional start sites (TSSs), and to investigate whether methylation of the region is a prognostic factor in high-grade serous ovarian cancer patients after neoadjuvant chemotherapy. METHODS: Ninety-two FFPE samples of advanced high-grade serous ovarian cancers after neoadjuvant chemotherapy between 2011 and 2018 were used for mutation and methylation analysis. DNA methylation levels were assessed by pyrosequencing and DNA methylation microarray. An association between methylation level (or a mutation) and progression-free survival was assessed by Kaplan-Meier analysis. RESULT: Major BRCA1 transcripts and CpG sites immediately upstream of their TSSs were identified, and a pyrosequencing method was developed. BRCA1 methylation, BRCA1/2 mutations, and a RAD51C mutation were detected in 17/79 (21.5%), 17/92 (18.5%), and 1/92 (1.1%) high-grade serious ovarian cancer samples. In univariate analysis, BRCA1 methylation and no residual tumor were associated with progression-free survival (BRCA1 methylation: P = 0.025, no residual tumor: P = 0.0026). Multivariate analysis showed that both BRCA1 methylation (P = 0.038, HR = 0.47, 95% CI: 0.21-0.96) and no residual tumor (P = 0.012, HR = 0.49, 95% CI: 0.28-0.85) were significant favorable prognostic factors. CONCLUSION: A quantitative method to estimate the methylation level of the immediate upstream region of major BRCA1 TSSs was established. Methylation of the region of was an independent favorable prognostic factor in high-grade serous ovarian cancer patients.

DNA methylation marker to estimate ovarian cancer cell fraction.

Evaluation of a cancer cell fraction is important for accurate molecular analysis, and pathological analysis is the gold standard for evaluation. Despite the potential convenience, no established molecular markers for evaluation are available. In this study, we aimed to identify ovarian cancer cell fraction markers using DNA methylation highly specific to ovarian cancer cells. Using genome-wide DNA methylation data, we screened candidate marker genes methylated in 30 ovarian cancer FFPE samples and 12 high-grade serous ovarian cancer cell lines, and unmethylated in two female leucocytes and two normal fallopian epithelial cell samples. Methylation levels of two genes, SIM1, and ZNF154, showed high correlation with pathological cancer cell fractions among the 30 ovarian cancer FFPE samples (R = 0.61 for SIM1, 0.71 for ZNF154). For cost-effective analysis of FFPE samples, pyrosequencing primers were designed, and successfully established for SIM1 and ZNF154. Correlation between a pathological cancer cell fraction and methylation levels obtained by pyrosequencing was confirmed to be high (R = 0.53 for SIM1, 0.64 for ZNF154). Finally, an independent validation cohort of 29 ovarian cancer FFPE samples was analyzed. ZNF154 methylation showed a high correlation with the pathological cancer cell fraction (R = 0.77, P < 0.0001). Therefore, the ZNF154 methylation level was considered to be useful for the estimation of ovarian cancer cell fraction, and is expected to help accurate molecular analysis.

High neutrophil-to-lymphocyte ratio is a predictor of short-term survival for patients with recurrent cervical cancer after radiation-based therapy.

AIM: Patients with recurrent cervical cancer after radiotherapy have poor prognoses because of the lack of effective treatment options. Biomarkers to predict survival outcomes for recurrent cervical cancer are warranted because patients with limited life expectancy sometimes benefit from less aggressive treatment in combination with early palliative care. Therefore, we aimed to explore a predictive biomarker for the outcomes of patients with recurrent cervical cancer. METHODS: We retrospectively investigated 231 patients initially treated with radiation-based therapy between January 2004 and December 2015. The associations between clinicopathological features at the time of relapse and overall survival after relapse were assessed. As factors which reflect patients' conditions, we particularly focused on C-reactive protein-to-albumin ratio (CAR) and neutrophil-to-lymphocyte ratio (NLR) at the time of relapse. Additionally, we investigated biomarkers predictive of short-term survival. RESULTS: Among 231 patients, 91 patients experienced relapse and 74 patients died during the follow-up period. Multivariate analysis revealed that treatment after relapse, CAR, and NLR was significantly associated with overall survival. Among them, treatment after relapse significantly affected survival outcomes, and patients who received definitive local treatment had a better 3-year survival rate than those who received other treatments. Conversely, NLR was the most influential biomarker for short-term survival, and the prognosis of patients with high NLRs was much worse than those with low NLRs. CONCLUSIONS: This study thus demonstrated that, for the patients with recurrent cervical cancer who received radiation-based therapy, definitive local treatment can provide long-term survival and extremely high NLRs are predictive of short-term survival.

Extreme skeletal muscle loss during induction chemotherapy is an independent predictor of poor survival in advanced epithelial ovarian cancer patients.

AIM: Skeletal muscle loss is often observed in advanced cancer patients. This study investigates whether skeletal muscle loss is associated with survival outcomes of advanced epithelial ovarian cancer (EOC) patients after induction chemotherapy (IC) in a Japanese cohort. Whether serum inflammatory markers are associated with skeletal muscle changes is also addressed. METHODS: We retrospectively reviewed 60 patients with stage III/IV EOC who underwent IC between 2010 and 2017. Skeletal muscle area (SMA) was measured at the third lumbar vertebrae level on a single axial computed tomography-scan image. Receiver operating curve analysis was used to determine cut-off values of pre- and post-IC SMA and SMA ratio (SMAR). Univariate and multivariate analyses of overall survival (OS) were conducted using the log-rank test and Cox proportional hazards regression model, respectively. RESULTS: The SMA decreased significantly after IC (P = 0.019). The cut-off value between low and high SMAR was 0.96. High or low SMAR was observed in 34 (57%) and 26 (43%) patients, respectively. Univariate analysis revealed that low SMAR was associated with poor OS (P = 0.025). Multivariate analysis showed that incomplete resection during interval debulking surgery (hazard ratio, 0.30; 95% CI, 0.11-0.80; P = 0.016) and a low SMAR (hazard ratio, 3.17; 95% CI, 1.18-9.06; P = 0.022) were independent predictors of poor OS. Of the serum inflammatory markers investigated, only post-IC absolute neutrophil count correlated significantly with SMAR (P = 0.012). CONCLUSION: Low SMAR can be used to predict poor prognosis in advanced EOC patients who have undergone IC.

Postradiotherapy persistent lymphopenia as a poor prognostic factor in patients with cervical cancer receiving radiotherapy: a single-center, retrospective study.

BACKGROUND: Radiotherapy (RT) is effective in cervical cancer; radiation-induced lymphopenia correlates with poor survival outcome in several cancer types. We investigated the association of total lymphocyte count (TLC) with survival outcomes in patients with cervical cancer. METHODS: We retrospectively reviewed 168 patients with cervical cancer initially treated with definitive RT. We obtained clinicopathological data and TLCs before RT and at the end and at 6 months after RT. Patient-, treatment-, and tumor-specific factors were evaluated to determine their predictive values for overall survival. The association of overall and progression-free survivals with lymphopenia at each point was evaluated. RESULTS: Median follow-up duration was 44 (interquartile range: 25-67) months. Median TLCs before RT and at the end and at 6 months after RT were 1625/mm3, 400/mm3, and 800/mm3 (interquartile range: 1270-1930/mm3, 290-550/mm3, and 600-1067/mm3), respectively. For overall survival, in addition to FIGO stage, body mass index, histology, treatment, and presence of para-aortic lymph node metastasis, lymphopenia at 6 months after RT was a poor prognostic factor in multivariate analysis (P = 0.0026; hazard ratio [HR], 3.06; 95% confidence interval [CI]: 1.48-6.33). For progression-free survival, TLCs before and at 6 months after RT were poor prognostic factors in univariate analysis (P = 0.0318 and 0.0081, respectively); however, the latter was the only independent prognostic factor in multivariate analysis (P = 0.0021; HR, 2.67; 95% CI: 1.43-4.99). CONCLUSION: Post-RT persistent lymphopenia could be a poor prognostic factor for patients with cervical cancer who receive RT.

Determining the recommended dose of stereotactic body radiotherapy boost in patients with cervical cancer who are unsuitable for intracavitary brachytherapy: a phase I dose-escalation study.

OBJECTIVE: Some patients are ineligible for intracavitary brachytherapy (ICBT) for locally advanced cervical cancer. Stereotactic body radiotherapy (SBRT) could be a good treatment option for such patients. This phase I clinical trial aimed to determine the recommended SBRT boost dose for ICBT-ineligible cervical cancer patients. METHODS: Patients with untreated uterine cervical cancer (clinical stages IB1-IIIB) who were ineligible for ICBT were enrolled. Radiotherapy consisted of whole-pelvis radiotherapy (45 Gy in 25 fractions) followed by SBRT. Three dose levels of SBRT (19.5/21/22.5 Gy in three fractions) were set; the treatment protocol began at 21 Gy (level 2). The 'rolling-six' design study was used to establish the recommended dose of SBRT. Each dose level covered three or six patients. The primary endpoint included dose-limiting toxicity (DLT), defined as the occurrence of grade 3 (or worse) non-hematologic adverse effects within 6 months after SBRT. RESULTS: The median follow-up after registration was 17 (range, 8-32) months. Three patients were enrolled in study level 2 (SBRT of 21 Gy); none of the patients exhibited DLT within 6 months after treatment completion. In study level 3 (SBRT of 22.5 Gy), three patients did not exhibit DLT. Although all six patients achieved locoregional control during follow-up, one patient treated with level 2 SBRT experienced distant metastases 14 months after registration. CONCLUSIONS: The recommended dose of SBRT boost was 22.5 Gy in three fractions. We plan to conduct a phase II multi-center clinical trial using the methodology obtained from the current study.

A low albumin to globulin ratio with a high serum globulin level is a prognostic marker for poor survival in cervical cancer patients treated with radiation based therapy.

OBJECTIVE: We investigated whether the pretreatment albumin to globulin ratio, serum albumin level, and serum globulin level can be used to predict survival among cervical cancer patients treated with radiation based therapy and assessed globulin fractions. METHODS: We retrospectively enrolled 128 patients with cervical cancer treated with radiation based therapy at our institution between 2010 and 2015. The associations of the pretreatment albumin to globulin ratio, and serum albumin and globulin levels with overall survival were assessed. Additionally, the associations of the globulin fractions with the serum globulin levels and overall survival were evaluated. RESULTS: Median follow-up duration was 30 months (IQR 16-44 months). A low albumin to globulin ratio (< 1.53) was found to be an independent prognostic factor for overall survival (HR= 3.07; 95% CI, 1.03 to 13.3; P=0.044). On evaluating serum globulin and albumin separately, a high serum globulin level was significantly associated with overall survival (cut-off value 2.9 g/dL; HR=3.74; 95% CI 1.08 to 23.6; P=0.036) whereas a low serum albumin level was not associated with overall survival (cut-off value 3.6 g/dL; HR=1.77; 95% CI 0.57 to 4.54; P=0.29). Electrophoresis data of the serum proteins revealed that the γ-globulin fraction was most strongly correlated with the globulin levels (P<0.001). Furthermore, a high γ-globulin level (≥1.28 g/dL) was significantly associated with poor overall survival (log rank test, P=0.034). CONCLUSIONS: A pretreatment low albumin to globulin ratio, which might be attributable to a high serum globulin level, can be used to predict poor prognosis in cervical cancer patients treated with radiation based therapy.

Lymphopenia after induction chemotherapy correlates with incomplete surgical resection in patients with advanced ovarian cancer.

BACKGROUND: Lymphopenia is associated with poor outcomes in patients with various cancers, but little is known about the prognostic impact of lymphopenia in patients with epithelial ovarian cancer (EOC) after induction chemotherapy (IC). This study investigated the prognostic significance of pre- and post-IC lymphopenia in patients with advanced EOC. METHODS: We reviewed medical records of 68 patients with stage III/IV ovarian, fallopian tube, or peritoneal cancer treated with IC at our institution between 2009 and 2017. We assessed the associations of pre- and post-IC inflammatory markers, including lymphocyte counts, with several oncological outcomes, such as the implementation of interval debulking surgery (IDS), complete resection, progression-free survival (PFS), and overall survival (OS). RESULTS: Lymphocyte counts increased significantly post-IC compared with the pre-IC values (P = 0.009). Pre-IC lymphopenia was observed in 27 patients (40%), whereas only 16 patients (24%) displayed lymphopenia post-IC (P = 0.020). Among several inflammatory markers, only post-IC lymphopenia was significantly associated with incomplete resection outcome during IDS (P = 0.012). Moreover, post-IC lymphopenia was significantly associated with poor PFS (log-rank test, P = 0.009), whereas pre-IC lymphopenia was associated with neither PFS nor OS. CONCLUSIONS: Post-IC lymphopenia may predict incomplete resection during IDS and poor prognosis in patients with advanced EOC.

A case of mature cystic teratoma with intestinal structures harboring intestinal-type low-grade mucinous neoplasm.

The formation of gastrointestinal-type epithelium is found in 7-13% of mature cystic teratomas, which are the most common germ cell tumors of the ovary. Few cases harboring organized gastrointestinal tract formation have been reported, and a mucinous neoplasm arising in them is further rare. Here, we report a case of an ovarian mature cystic teratoma with intestinal structures harboring intestinal-type mucinous neoplasm, mimicking low-grade appendiceal mucinous cystadenoma. A 66-year-old female, with remarkably increased serum carcinoembryonic antigen (CEA) level, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy due to the ovarian tumor. The immunoprofile of the tumor showed CK7-/CK20+. We review the past literatures, and then consider that the existence of mucinous neoplasm should be kept in mind if we find elevated level of serum CEA and the organized gastrointestinal development in an ovary. The immunoprofile of CK7/CK20 is useful to determine the origin of mucinous tumors associated with mature cystic teratomas.

Radical hysterectomy with or without para-aortic lymphadenectomy for patients with stage IB2, IIA2, and IIB cervical cancer: outcomes for a series of 308 patients.

BACKGROUND: Although many studies have already shown that lymph node metastasis is one of the major prognostic factors for cervical cancer, the therapeutic significance of para-aortic lymphadenectomy for the surgical treatment of cervical cancer remains controversial. METHODS: A total of 308 patients diagnosed with stage IB2, IIA2, or IIB cervical cancer and treated with radical hysterectomy were retrospectively investigated to assess the incidence of para-aortic lymph node metastasis and the clinicopathological factors linked to cervical cancer prognosis. RESULTS: Para-aortic lymph node metastases were pathologically confirmed in 13 of the 136 patients (9.6 %) who underwent para-aortic lymphadenectomy. The incidence of para-aortic lymph node metastasis was significantly higher in the patients who had common iliac lymph node metastases (odds ratio 31.5, p < 0.001) according to logistic regression analysis. Common iliac lymph node metastasis was related to risk of recurrence (hazard ratio 2.43, p = 0.003) and death (hazard ratio 2.62, p = 0.007) in Cox regression analysis. Kaplan-Meier analysis and Cox regression analysis showed that para-aortic lymphadenectomy did not have a positive impact on survival in 308 patients or 140 pN1 patients, but para-aortic lymphadenectomy was related to better overall survival with a marginal trend toward significance (p = 0.053) in 30 patients with common iliac lymph node metastasis. CONCLUSIONS: Indication for para-aortic lymphadenectomy in the surgical treatment of stage IB2, IIA2, or IIB cervical cancer needs to be individualized. Patients with common iliac lymph node metastasis are possible candidates, and a prospective study is needed to clarify this issue.

Rare case of endometrioid adenocarcinoma arising from cystic adenomyosis.

Few reports on malignant transformation of adenomyosis are available, and endometrioid adenocarcinoma arising from cystic adenomyosis is further rarely reported. We report a case of a 67-year-old asymptomatic woman who was referred to our hospital for evaluation of a cystic lesion in the pelvis, which had been diagnosed as cystic degeneration of leiomyoma for 3 years. Magnetic resonance imaging revealed a cystic mass measuring 11 cm in diameter, which was contiguous with uterine myometrium. The lesion contained solid areas enhanced on gadolinium-enhanced T1 -weighted imaging. Transabdominal simple total hysterectomy with bilateral salpingo-oophorectomy was performed. Pathological examination revealed endometrioid adenocarcinoma arising from cystic adenomyosis. The patient underwent six courses of adjuvant combination chemotherapy with paclitaxel and carboplatin. No metastasis or recurrence has been demonstrated for 16 months following surgery. Our case demonstrates that cystic adenomyoma possesses the risk of malignant transformation, indicating the importance of long-term follow-up with imaging examination.

[Primary peritoneal carcinoma - a clinicopathological study of 15 cases].

This is a retrospective study of fifteen cases of primary peritoneal carcinoma who were treated between 2001 and 2010 in our hospital. The median age at the time of diagnosis was 63 years(range, 40 to 79 years). Three patients had clinical stage II disease, eleven patients had stage III disease, and one patient was unstaged. The serum CA125 values at pretreatment were elevated in all patients, with a median value of 4,144. 8 U/mL(range, 102. 8 to 23, 611. 0 U/mL). Optimal debulking was possible in 9 of the 15 patients. All patients were treated with paclitaxel and carboplatin chemotherapy during the preoperative and/or postoperative period. All patients at stage II disease were alive without evidence of disease at the time of evaluation(2 patients>5 years, 1 patient>3 years). Four patients with stage III disease had died from the disease less than 3 years after the first treatment. The results of our study showed poor survival for the group with stage III disease, but good survival for the group with stage II disease.

Is a low dose of concomitant chemotherapy with extended-field radiotherapy acceptable as an efficient treatment for cervical cancer patients with metastases to the para-aortic lymph nodes?

INTRODUCTION: Extended-field radiotherapy (EFRT) with the concomitant administration of chemotherapy for patients with advanced cervical cancer has problems regarding its feasibility. The goal of the present study was to assess the tolerability and control rate of low-dose cisplatin with EFRT in patients with imaging-confirmed positive para-aortic lymph nodes (PALs). METHODS: Sixteen patients with cervical cancer metastatic to the PALs treated with EFRT were evaluated. The patients included those with stages I to III disease according to the International Federation of Gynecology and Obstetrics with positive PALs diagnosed by computed tomographic imaging. The patients were treated with 25 to 30 mg/m weekly of cisplatin concurrently with radiation therapy. Doses of 48.6 to 51.0 Gy were delivered in 1.8-Gy fractions to the pelvis and included the PALs field. In addition, boost doses for the involved nodes of PALs were delivered contiguously for a total dose of 54 to 60 Gy. All patients were treated with a high dose rate of intracavitary brachytherapy combined with external irradiation. RESULTS: All patients completed the radiation therapy. Grade 3 or 4 acute hematologic toxicity occurred in 7 patients, but there were no cases of grade 3 or 4 nonhematologic acute toxicity. As a late toxicity, 1 patient developed a grade 3 small bowel obstruction. No grade 4 or worse late toxicity occurred. The 4-year overall survival rate was 56.3%. The 4-year distant metastasis-free survival rate was 50%. Seven patients had no recurrence. Eight patients developed distant failures, and another had an isolated local intrapelvic recurrence. CONCLUSIONS: A dose greater than 54 Gy for positive PALs in EFRT, in combination with intracavitary irradiation and low-dose weekly cisplatin administration, was safely completed by all of our patients. However, half of the patients had distant failure. This study provided relatively favorable local control and survival. Further considering modifications of the treatment should therefore be encouraged.

Clinical significance of UDP-glucuronosyltransferase 1A1*6 for toxicities of combination chemotherapy with irinotecan and cisplatin in gynecologic cancers: a prospective multi-institutional study.

BACKGROUND: To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin. METHODS: Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m(2) of irinotecan on days 1, 8 and 15, and 60 mg/m(2) of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed. RESULTS: From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6. CONCLUSION: In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.

Late recurrence of invasive cervical cancer: twenty years' experience in a single cancer institute.

AIM: To estimate the characteristics of, and prognosis for, late recurrence of cervical cancer. METHOD: Between 1977 and 1996, of 1721 patients with invasive cervical cancer, 1157 survived more than 5 years. Twenty-eight patients whose cancer recurred after a disease-free interval of 5 years were retrospectively investigated. For 22 patients the cancer recurred after less than 10 years, for five patients it recurred between 10 and 20 years after the original occurrence, and in one patient the cancer recurred after more than 20 years. RESULTS: The histologic subtypes included 20 squamous cell carcinomas and eight adenocarcinomas. The initial therapies were surgery alone (on one patient), surgery and adjuvant radiotherapy (on 20 of the patients) and radiotherapy alone (on seven of the patients). Recurrence was initially diagnosed by internal or external examination (11 patients), chest X-ray (six patients) and computed tomography (11 patients). Rates of lymphogenous metastases were 19% of patients with primary surgery and 57% of patients without primary surgery, while those of hematogenous metastases were 48% of patients with primary surgery and none of patients without primary surgery (P = 0.023). The overall survival rate after recurrence was 50.5% after 2 years and 22.3% after 5 years, respectively. Four of the patients survived for more than 3 years without evidence of disease; these patients all had recurrence outside the irradiated field and achieved complete remission with radiotherapy. CONCLUSIONS: Late recurrence of cervical cancer was frequently observed in patients with initial treatment, including radiotherapy. Some had very long disease-free intervals, but many were diagnosed by ordinary internal or external examination or chest X-ray. Patients with primary surgery experienced recurrence less frequently in the case of lymph node metastasis than was the case for hematogenous metastasis. Radiotherapy was effective and improved prognosis, especially for recurrence of cancer outside the irradiated field.

Safety and immunogenicity of a peptide containing the cross-neutralization epitope of HPV16 L2 administered nasally in healthy volunteers.

Amino acid (aa) 108-120 of L2 protein of human papillomavirus (HPV) type 16 contains a cross-neutralization epitope against genital HPV. We designed a placebo-controlled trial in healthy adults to evaluate the safety and immunogenicity of a synthetic peptide consisting of the aa 108-120 of HPV16 L2 (L2-108/120) region. A total of 13 volunteers were given nasal inoculations with 0.1 (n=5) or 0.5mg (n=5) doses of the peptides or placebo (n=3) without adjuvant at weeks 0, 4, and 12. Sera were collected before inoculation and at 6, 16 and 36 weeks. The inoculation caused no serious local and systemic complications. The inoculation generated anti-L2 antibodies binding to both HPV16 and 52 L1/L2-capsids in four of the five recipients in the 0.5mg group. Sera of the four recipients showed neutralizing activities against HPV16 and 52. Serological responses to the peptides were not found in the 0.1mg group and the placebo group recipients. This study suggests the L2-108/120 peptide is tolerable in humans and has the potential as a broad-spectrum prophylactic vaccine against genital HPV.