Utility of vaginal vault cytology in the local recurrence of cervical cancer.

BACKGROUND: In Japan, 8000 women were newly diagnosed with cervical cancer in 2018. The healthcare insurance policy in Japan allows physicians to utilize vaginal volt cytology tests and serum biomarker measurement at every visit and imaging analysis at an adequate interval with screening for recurrence after initial treatment. However, the major surveillance guidelines published in the United States and European countries recommend focusing on pelvic examinations and symptom reviews to avoid unnecessary tests. This study aimed to reassess the benefits of standard surveillance methods adopted in this study by retrospective analysis. METHODS: From January 2009 to December 2015, the medical records of patients with recurrence who were initially diagnosed with International Federation of Gynecology and Obstetrics stage I-III cervical cancer were collected for this study. Clinicopathological data were statistically analyzed to identify significant factors. In the first 2 years, the patients underwent regular surveillance, including pelvic examination, serum tumor marker tests, vaginal vault cytology every 1-3 months, and imaging analysis at 6- to 12-month intervals. In the following 2 years, the patients received a regular check with the same methods every 4 months and an annual imaging analysis. Afterward, the patients had regular screening every 6 to 12 months. RESULTS: In the study period, 84 of the 981 patients experienced recurrence, and 88.1% had an asymptomatic recurrence. The disease-free interval was not related to the recurrence site. In univariate analysis, primary treatment, recurrence site, and diagnostic method were significant factors for survival outcomes. In contrast, multivariate analysis indicated that only primary treatment was a significant factor. In patients with local recurrence, multivariate analysis demonstrated that radiation as salvage therapy was an independent predictive factor for overall survival after recurrence. CONCLUSIONS: In this retrospective study, routine imaging analysis and serum biomarker measurement did not contribute to patient prognosis after recurrence. In contrast, vaginal vault cytology can improve survival after recurrence in some patients. Tailored surveillance methods based on individual disease conditions and treatment modalities can improve post-recurrent survival outcomes.

Reassessment of intensive surveillance practices adopted for endometrial cancer survivors.

BACKGROUND: In Japan, 17,000 women are newly diagnosed with endometrial cancer in 2018. The healthcare insurance policy in Japan provides more intensive patient surveillance compared with the United States and European countries. The aim of this study was to retrospectively analyze data, including surveillance methods, recurrence sites, salvage therapy, and survival period after recurrence, to consider the benefits of surveillance for patients with endometrial cancer. METHODS: Between January 2009 and December 2015, the medical records of patients who were initially diagnosed with the International Federation of Gynecology and Obstetrics stage I-IV endometrial cancer and treated were enrolled in this retrospective study. Only patients with stage IV cancer with peritoneal dissemination were included. Within the first 2 years, the included patients underwent tumor marker tests, Papanicolaou smear test every 1-3-months, and imaging analysis at 6-12- month intervals. Until 4 years, the patients underwent regular surveys every 4 months and imaging analysis annually. Subsequently, the patients received regular surveys every 6 -to 12-months. RESULTS: Among 847 patients, 88 experienced recurrence, and their clinicopathological data were statistically analyzed. The recurrence site was not associated with the initial treatment method or histology. Among the patients with recurrence, 75% were asymptomatic. Univariate analysis demonstrated that time to recurrence and local recurrence were significant factors for survival outcomes, whereas multivariate analysis indicated that only local recurrence was a significant factor. In patients with distant metastasis, neither symptomatic nor asymptomatic recurrence showed a significant difference in survival. CONCLUSIONS: In this retrospective study, an intensive surveillance protocol did not benefit patients with endometrial cancer. Thus, we hypothesize that the characterization of tumors by emerging technologies that can precisely predict the nature of the tumor will help tailor individualized and efficient surveillance programs. In addition, the ideal salvage therapy needs to be developed to benefit patients after recurrence.

Treatment-related leukemia after taxane and platinum therapy in gynecological cancer patients (Gynecologic Oncology Trial and Investigation Consortium 011).

AIM: To clarify incidence and clinical features of treatment-related leukemia (TRL) due to taxane/platinum therapy in gynecological cancer patients. METHODS: We conducted a retrospective study of gynecological cancer patients who were diagnosed at facilities participating in the Gynecologic Oncology Trial and Investigation Consortium and started only taxane/platinum therapy as chemotherapy between 2002 and 2006. RESULTS: The site of the primary lesion was the ovary in 124, endometrium in 37, and uterine cervix in 4. The regimen of chemotherapy was paclitaxel (T) + carboplatin (C) therapy in 134 and others in 31 patients. The cumulative incidence was 2.4% (4/165), and the incidence was 2.9/1,000 person-years. All four cases were acute myeloid leukemia. The average total doses of T and C in patients without TRL were 1,693 (SD 1,050) and 4,170 (SD 2,423) mg. For TRL patients, the total T and C doses were, respectively, 1,555 and 3,540 mg, 1,620 and 4,200 mg, 2,130 and 4,700 mg, 3,220 mg and 8,310 mg. The fourth patient received additional 2,415 mg of docetaxel and 2,155 mg of nedaplatin. The intervals from the primary chemotherapy to the onset of TRL were 27, 34, 67, and 114 months. Three patients had no evidence of ovarian cancer. Three patients died of TRL at 4 days, 5 months, and 11 months, one patient remained in remission at 25 months after diagnosis of TRL. CONCLUSION: Patients receiving taxane/platinum therapy should undergo long-term follow-up with attention to the development of TRL, even if the gynecologic malignant cancer is in remission.

Nadir CA-125 serum levels during neoadjuvant chemotherapy and no residual tumor at interval debulking surgery predict prognosis in advanced stage ovarian cancer.

BACKGROUND: Recent phase III randomized trials have suggested that neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) is a treatment option for patients with advanced epithelial ovarian cancer. This study aimed to use CA-125 and computed tomography (CT) scanning to generate a simple and clinically applicable model of predicting complete cytoreduction by interval debulking surgery (IDS) and the overall survival in patients who receive taxane/platinum-based chemotherapy as neoadjuvant chemotherapy (NACT). METHODS: Patients with stage IIIc or IV epithelial ovarian cancer who underwent taxane/platinum-based NACT followed by IDS in Gunma Prefectural Cancer Center, Takasaki General Medical Center, and Gunma University from April 2009 to March 2015 were included. Patients underwent a CT scan to confirm confirm tumors unresectable by standard surgery before NACT. CA-125 levels were measured pre-NACT, after each cycle of NACT, and before IDS. CT was also performed before IDS to evaluate tumor metastasis. Data were collected retrospectively and analyzed to determine the predictive factors of complete resection and overall survival. RESULTS: Among 63 patients who received NACT-IDS, 43 and 20 patients had stages IIIc and IV epithelial ovarian cancer at diagnosis, respectively. CT predictors of residual tumors after IDS such as extra-ovarian implants (P = 0.009) and omental cakes (P = 0.038) were not present. Univariate analysis revealed that the independent factors for overall survival were no residual tumor by IDS (P = 0.0016) and CA125 ≤ 20 U/ml before IDS (P = 0.0011). CONCLUSIONS: Although this study had a small sample size, NACT-IDS used to completely remove macroscopic disease which significantly improved the prognosis of patients with preoperative CA-125 ≤ 20 U/ml. Results from this study provide useful information for future studies on the management of patients with advanced epithelial ovarian cancer.

Phase I Study of Carbon Ion Radiotherapy and Image-Guided Brachytherapy for Locally Advanced Cervical Cancer.

A phase I study was performed to determine the recommended dose of carbon ion radiotherapy and 3D image-guided brachytherapy for histologically confirmed stage II (≥4 cm), III, or IVA cervical cancer. Dose-limiting toxicities (treatment-related toxicities occurring within three months from the start of carbon ion radiotherapy) included Grade 3 non-hematological toxicity, Grade 4 hematological toxicity, or interruption of treatment for more than two weeks due to treatment-related toxicities. Carbon ion radiotherapy consisted of whole-pelvic irradiation with 36.0 Gy (relative biological effectiveness) in 12 fractions and local boost with 19.2 Gy in four fractions for the primary site, and for positive lymph nodes. Three sessions of three-dimensional (3D) image-guided brachytherapy were administered after completion of carbon ion radiotherapy. Weekly cisplatin at a dose of 40 mg/m² was given concurrently. At a dose level of one, a total rectosigmoid D2cc dose between 67.2 Gy and 71.3 Gy at a biological equivalent dose of 2 Gy per fraction from carbon ion radiotherapy and 3D image-guided brachytherapy was prescribed. Six patients were enrolled into this dose level. No patients developed the pre-defined dose-limiting toxicities. For late toxicities, however, one patient developed Grade 3 rectal hemorrhage requiring transfusion at 10 months after treatment. The median survival time was 50.0 months for the five surviving patients. No further dose escalation was performed, and we determined the dose of level one as the recommended rectosigmoid dose. Although our results are preliminary, the study regimen encourages further investigation (registration: UMIN000013340).

Usefulness of CINtec® PLUS p16/Ki-67 double-staining in cytological screening of cervical cancer.

OBJECTIVE: This study evaluated the usefulness of p16(INK4a)/Ki-67 as a new biomarker in the diagnosis of human papillomavirus (HPV)-related cervical lesions. STUDY DESIGN: From 69 women with previous positive cytology, clinician-collected (CC) samples were obtained using a Cervex-Brush®. One month later, self-collected (SC) material was acquired using a Rovers® Viba-Brush. Liquid-based cytology specimens were prepared from both samples, and then the grades of squamous intraepithelial lesions (SIL) were determined; following immunostaining with CINtec® PLUS, HPV status was analyzed using a linear array. RESULTS: The mean double-positive cell scores (SCORE) in the CC samples were 3.2 in samples negative for intraepithelial lesions or malignancy, 1.3 in atypical squamous cells of undetermined significance, 87.1 in low-grade SIL, and 367 in high-grade SIL. According to HPV risk type, the mean SCORE was 16 in samples negative for HPV, 8.4 in low-risk HPV, 143 in high-risk HPV other than type 16, and 420 in HPV16 - with a statistical significance between high-risk HPV and type 16 (p < 0.05). The SCORE of the SC group was lower than that of the CC group because of the limited number of cells collected. CONCLUSIONS: The SCORE showed a significant correlation with HPV16 compared with lesser-degree lesions. CINtec PLUS is useful as a diagnostic marker of progression of lesions and a surrogate marker of an elevated risk of high-grade lesions with HPV16.

Comparison of self-collected and clinician-collected materials for cervical cytology and human papillomavirus genotyping: analysis by linear array assay.

OBJECTIVE: This study compared the usefulness of self-collected (SC) and clinician-collected (CC) materials for cervical cytology and human papillomavirus (HPV) genotyping. STUDY DESIGN: Fifty women with previous positive cytology and who were undergoing regular checkups were included in the study. CC samples were collected using a Cervex-Brush Combi with liquid-based cytology. One month later, SC material was acquired using the Rovers Viba-brush vaginal sampler, and fixed at home. Thin-layer specimens were prepared from both samples and HPV status was analyzed using a linear array. RESULTS: A total of 37/50 CC (74%) and 41/50 SC (82%) cases were positive for HPV. Pap tests identified high-grade squamous intraepithelial lesions in 11 (22%) and seven (14%) patients, low-grade squamous intraepithelial lesions in 19 (38%) and 16 (32%), atypical squamous cells of undetermined significance in 2 (4%) and 0 patients, and NILM (negative for intraepithelial lesion or malignancy) in 18 (36%) and 27 (54%) patients in the CC and SC groups, respectively. CONCLUSIONS: SC material had a lower positive cytology rate, but a higher HPV-positive rate than CC material. These results suggest that a combination of Pap and HPV tests on SC material may provide a diagnostic strategy with high sensitivity and specificity.

A new system for regulated functional gene expression for gene therapy applications: nuclear delivery of a p16INK4A-estrogen receptor carboxy terminal fusion protein only in the presence of estrogen.

The clinical use of gene therapy requires tight regulation of the gene of interest and functional expression only when it is needed. Thus, it is necessary to develop ways of regulating functional gene expression with exogenous stimuli. Many regulatable systems are currently under development. For example, the tetracycline-dependent transcriptional switch has been successfully employed for in vivo preclinical applications. However, there are no examples of regulatable systems that have been employed in human clinical trials. In the present study, we established an adenovirus-delivered functional gene expression system that is regulated by estrogen. This system uses p16INK4A fused at its C-terminus to the ligand-binding domain of the estrogen receptor (DeltaERalpha). We were able to establish cell lines expressing this gene wherein the functional expression of p16INK4A is estrogen-dependent and causes the arrest of several ovarian cancer cell lines. This inducible and adenovirus-mediated gene transfer system may allow gene therapy using nuclear functioning genes in postmenopausal or ovariectomized women.

Clusterin expression inversely correlates with chemosensitivity and predicts poor survival in patients with locally advanced cervical cancer treated with cisplatin-based neoadjuvant chemotherapy and radical hysterectomy.

Overexpression of clusterin, an antiapoptotic molecule, has been reported to induce resistance to chemotherapy in a variety of cancer cell types. The aim of this study was to evaluate the significance of clusterin expression to predict response to platinum-based neoadjuvant chemotherapy and survival of patients with invasive cervical cancer who subsequently underwent radical hysterectomy. Biopsy specimens of invasive cervical cancer before neoadjuvant chemotherapy were obtained from 46 patients who subsequently underwent radical hysterectomy at Hokkaido University Hospital and Gunma University Hospital from 1994 to 2007. The expression of clusterin protein was analyzed by immunohistochemistry. Findings were evaluated in relation to several clinicopathological factors. Survival analyses were performed by the Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. Clusterin protein was mainly present in the cytoplasm of cervical cancer cells. The expression of clusterin protein in cervical cancer tissues before neoadjuvant chemotherapy was significantly related to poor response to chemotherapy among factors analyzed. Univariate analysis on prognostic factors showed that response to chemotherapy (p = 0.01), lymph node metastasis (p = 0.02), and clusterin expression (p = 0.02) were related to survival. Multivariate analysis revealed that lymph node metastasis (p = 0.03), and clusterin expression (p = 0.03) were independent prognostic factors for survival of cervical cancer patients. We conclude that clusterin expression could be a new molecular marker to predict response to platinum-based chemotherapy and survival of patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy.

Prevalence, viral load, and physical status of HPV 16 and 18 in cervical adenosquamous carcinoma.

Adenosquamous carcinoma of the uterine cervix is a rare mixture of malignant squamous and glandular epithelial elements and accounts for approximately 10% of cervical carcinomas. The aims of the present study were to evaluate the prevalence, physical status, and viral load of HPV 16 and 18 in adenosquamous carcinoma. Formalin-fixed paraffin-embedded tissue samples from 20 cases of histologically diagnosed adenosquamous carcinoma were examined. The squamous and glandular components were separately microdissected and analyzed for their HPV DNA subtype, viral load, and physical status using real-time polymerase chain reaction (PCR). The percentages of HPV 16- and 18-positive cases among all the HPV-positive cases were 36.8% (7/19) and 57.9% (11/19) in the squamous epithelial elements and 33.3% (6/18) and 61.1% (11/18) in the glandular elements, respectively. PCR analysis with E2 primers revealed that seven of eleven (63.6%) HPV 18-positive cases had the pure integrated form in both elements. The mean HPV 16 DNA copy numbers/cell was 7.22 in the squamous elements and 1.33 in the glandular elements (p=0.04) while the corresponding mean HPV 18 DNA copy numbers/cell was 1.50 and 0.89, respectively. The prevalence of HPV 18 in adenosquamous carcinoma was high and many HPV 18-positive cases were the pure integrated form resulting in very low copy numbers/cell. It is possible that more aggressive transformation with early integration of HPV 18 results in cases with greater chromosomal instabilities, higher growth rates, and rapid progression.

Immunochemical analysis of HPV L1 capsid protein and p16 protein in liquid-based cytology samples from uterine cervical lesions.

BACKGROUND: HPV L1 capsid protein is expressed together with the production of infectious viral particles, but its expression and relation to p16 expression, which has been a surrogate marker for human papilloma virus (HPV) infection in cervix, are little studied in cytology samples. The authors aimed to elucidate the relation between L1 capsid protein and p16 protein expressions in liquid-based samples from uterine cervical lesions. METHODS: Immunochemical analyses using antibodies against L1 capsid protein and p16 protein were carried out on cytological materials obtained from uterine cervical lesions of low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and squamous cell carcinomas (SCCs). RESULTS: L1 capsid protein was positive in 30% of LSILs and 12% of HSILs, but in 0% of SCCs. In contrast, p16 protein was positive in 55% of LSILs, 100% of HSILs, and 100% of SCCs. L1-positive cells were only observed in the superficial layer, whereas p16-positive cells were seen throughout the full thickness of the epithelium. The relation between L1 capsid protein and p16 protein, p16(-)/L1(+) cases represented 44% of LSILs, but 0% of HSILs, and 0% of SCCs, whereas p16(+)/L1(-) cases represented 82% of LSILs, 88% of HSILs, and 100% of SCCs. CONCLUSIONS: Expression of L1 capsid protein decreased with lesion progression from LSILs to HSILs and SCCs, whereas p16 protein was positive in all HSILs and SCCs. The correlation between L1 and p16 expressions suggests that L1(-)/p16(+) cases have the potential for progression, whereas L1(+)/p16(-) and L1(-)/p16(-) cases may be nonprogressive lesions or potentially in remission.

Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: A potential biomarker and molecular target therapy.

Alterations of the Akt/mTOR pathway have been observed in numerous types of cancer, thus this pathway represents an exciting new target for molecular therapeutics. We investigated the expression of activated Akt (p-Akt) and mTOR (p-mTOR) in patients with adenocarcinoma of the cervix and the involvement of the p-Akt/p-mTOR pathway in response to combination of inhibitor agents, rapamycin and LY294002, with conventional therapy, cisplatin, in vitro. Immunohistochemistry analysis of p-Akt and p-mTOR was conducted in 26 patients with adenocarcinoma of the cervix. Western blot analysis was performed to determine the protein expression involved in response to chemotherapy in cervical cancer cell lines. The results showed that p-Akt and p-mTOR were identified in 50% and 53.8% of adenocarcinoma of the cervix. The expression of p-mTOR was a significant independent marker for prognosis. A significant correlation between p-Akt and p-mTOR was observed. There was no correlation between their expressions with any of clinicopathological factors. In the in vitro study, cisplatin at CPI(50) targets both the apoptosis and survival pathway by activating the caspase-cascade; inhibiting Akt, mTOR, p70S6K, and 4EBP1. Combination of rapamycin with cisplatin induced synergistic interaction. On the other hand, combination with LY294002 resulted in either synergistic or antagonistic effect depending on the doses given. Rapamycin pretreatment potentiated cisplatin-induced apoptosis cell death and enhanced blocking of the survival pathway. Overall, the expression of p-mTOR is a significant prognostic marker of adenocarcinoma of the cervix and a potential molecular target for the treatment of cervical cancer. Inhibition of the mTOR pathway contributes to cisplatin-induced apoptosis in cervical cancer cell lines.

Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy.

The present study was designed to clarify the expression and prognostic significance of activated Akt and mTOR in cervical cancer and their correlation with response to neoadjuvant chemotherapy (NAC). Immunohistochemical analysis for p-Akt and p-mTOR expression was performed on paraffin-embedded biopsy specimens from 25 patients with advanced cervical cancer (stage Ib2-IIb). We correlated this finding with various clinicopathological variables and prognosis by uni- and multivariate analyses. All patients received cisplatin-based NAC, and primary tumor response was evaluated by RECIST criteria and then classified as a positive or negative response. Activation of Akt was detected in the cytoplasm and nucleus of the cancer cells in 12 patients (48%), whereas p-mTOR was detected in the cytoplasm and membrane of the cancer cells in 13 patients (52%). Post NAC evaluation of the primary tumor revealed 68% (17/25) responsive tumors. The expression of p-mTOR and distant metastasis significantly correlated with the response to NAC (p = 0.0101 and p = 0.0107); however, there was no significant correlation between p-Akt and p-mTOR expression and any of the clinicopathological characteristics of the patients. In the univariate analysis, activated Akt and mTOR were found to be significant prognostic indicators (p < 0.05). In multivariate analysis, p-mTOR expression retained its significance as an independent poor prognostic marker (p = 0.0178). In summary, our present study showed that cervical cancer expressed Akt and mTOR activation. Moreover, the expression of phosphorylated mTOR may have a role as a marker to predict response to chemotherapy and survival of cervical cancer patients who are treated with cisplatin-based neoadjuvant chemotherapy. Our results suggest that the mTOR cascade may be a promising target for therapeutic intervention in cervical cancer.

Differential sensitivity of paclitaxel-induced apoptosis in human esophageal squamous cell carcinoma cell lines.

PURPOSE: Paclitaxel is a highly effective chemotherapy agent against adenocarcinomas and squamous cell carcinomas of the esophagus. However, its precise effects in human esophageal cancer cells are not well understood. This study was designed to examine the relationship between cell-cycle phases of paclitaxel-activated checkpoints and to elucidate the molecular pathway of the effect of paclitaxel in human esophageal squamous cell carcinoma (ESCC) cell lines. METHODS: The three human ESCC cell lines--TE-2, TE-13 and TE-14--were examined for their response to paclitaxel. ESCC cells were treated with various concentrations of paclitaxel for 1-3 days using MTT assay. The cell-cycle progression and apoptosis were examined by flow cytometry. DNA fragmentation assay was carried out to confirm the fragmented cells as hallmark for apoptotic cells. In additional, the expression of apoptosis-related proteins in ESCC-treated cells was then examined by Western blot analysis. RESULTS: TE-14 cells demonstrated the highest sensitivity among all cells. G2/M cell-cycle arrest occurs prior to paclitaxel-induced apoptosis in ESCC cells. The fragmentation of chromatin was observed in drug treated TE-13 and TE-14 cells by flow cytometry and DNA ladder formation. In contrast, the measurement for TE-2 cells was more suggestive of phenotype a resistant in response to paclitaxel treatment. Western blot analysis results showed that the mitochondrial pathway might be involved in paclitaxel-induced apoptosis in ESCC cell lines. CONCLUSION: Differential sensitivity was observed in human ESCC cell lines in response to paclitaxel treatment. G2/M arrest occurs with a prior to paclitaxel-induced apoptosis and might be mediated by the mitochondrial (intrinsic) apoptosis pathway in human ESCC cells.

A new, accurate and conventional five-point method for quantitative evaluation of ascites using plain computed tomography in cancer patients.

BACKGROUND: To assess the exact response of the malignant ascites to the treatment, the objective measurement of the volume of ascites is essential. We have developed a simple method to measure the volume of ascites by using standard abdomino-pelvic computed tomography (CT). The aim of the study is to validate the accuracy of the measurements by comparing them with the standard volume calculation by using 3D-CT. METHODS: Twelve consecutive patients with cancer who had measurable ascites underwent 15 helical CT examinations. On conventional CT images, the thickness of ascites in centimeters was measured in three planes such as the bilateral subphrenic space (A and B), the bilateral paracolic space (C and D) and the pre-bladder space (E), and the average thickness: (A + B + C + D + E)/5 was then multiplied by the area of standard abdominal cavity in the anterior projection, that was assumed to be 1000 cm(2), to yield the volume of ascites: (A + B + C + D + E) x 200 (ml). The volume of ascites was compared with the exact volume, that was obtained from 3D-CT with the volume rendering method. RESULTS: The volume of ascites measured by the present method and the volume rendering method ranged from 140 to 4040 ml and from 86 to 4279 ml, respectively. The correlation was statistically significant with a correlation coefficient of 0.956 (P < 0.01) using the Spearman's rank correlation. In 13 examinations with the exact volume > or =300 ml, the average ratio of the absolute difference in the volume was 12.9 +/- 13.9% as compared with 62.8 and 162.0% in two examinations with the exact volume < 300 ml. CONCLUSION: The preliminary study indicated that the present five-point method using a conventional CT was accurate in patients with the volume of ascites > or =300 ml. Because this procedure is simple and easy to perform, it should be feasible in many hospitals for the follow-up of ascites after treatment.

Diagnostic accuracy of FDG PET imaging for the detection of recurrent or metastatic gynecologic cancer.

PURPOSE: This study evaluated the diagnostic role and accuracy of positron emission tomography (PET) using 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) for the detection of tumor foci in patients with suspected recurrent or metastatic lesions of gynecologic cancers. MATERIALS AND METHODS: FDG PET imaging was performed on 51 patients with a previous history of gynecologic cancer who were referred for a clinical suspicion of recurrent disease. PET acquisition was started 50-60 min after the intravenous injection of 5-6 MBq/kg FDG in all patients. The PET images were interpreted visually, and tracer uptake was quantitated as the standardized uptake value adjusted to body weight (SUV) in the lesions showing FDG uptake. The accuracy of the PET results was assessed by a consensual verdict based on histology, cytology, other imaging and clinical follow-up. RESULTS: FDG PET correctly diagnosed 33 of 36 patients with recurrent disease and 12 of 15 patients without recurrence. On patient-based analysis, the sensitivity, specificity and accuracy of FDG PET were 91.7%, 80.0% and 88.2%, respectively, depending on the selected scheme for visual scoring of the lesions. The area index in receiver-operating characteristic analysis was 0.95 for patient detection. Malignant lesions accumulated significantly more FDG than the benign ones (the mean SUVs were 3.7 +/- 1.9 and 1.6 +/- 1.1, respectively, p = 0.004). The sensitivity and specificity in correct identification of tumor recurrence or metastases using a threshold SUV 1.9 were 88.8% and 66.7% in contrast to the visual analysis (sensitivity 96.4%, specificity 50%) on a lesion-based analysis. The partial volume effect of SUV in a few small lesions and the presence of bone lesions in which FDG uptake was relatively low might be the reason for the lower sensitivity in SUV analysis. FDG PET was valuable when CT/MRI was negative or inconclusive, and in patients with elevated tumor marker levels as well as with normal tumor marker levels when recurrence was suspected clinically. However, PET failed to visualize some small metastatic lesions in lung and bone, and showed falsely high FDG uptake in some benign lesions. CONCLUSION: The results indicated that FDG PET is a reliable and accurate diagnostic method for detecting recurrent or metastatic gynecologic cancer particularly lymph node metastases. Although the sensitivity of PET for detecting small metastases was relatively limited, the overall sensitivity of FDG PET was significantly higher than morphologic imaging.

Usefulness of liquid-based cytology specimens for the immunocytochemical study of p16 expression and human papillomavirus testing: a comparative study using simultaneously sampled histology materials.

BACKGROUND: In cervical lesions, the overexpression of p16 is reported to be closely associated with high-risk human papillomavirus (HPV) infection. The objective of the current study was to confirm the usefulness of liquid-based cervical specimens for p16 staining as well as tissue sections. METHODS: A total of 98 patients with cervical lesions were entered into the current study. After the cytologic examination using liquid-based cervical smears, the same slides were immunostained for p16 and were compared with slides of simultaneously obtained, immunohistologically stained tissue sections. Moreover, the status of the HPV infection was examined by polymerase chain reaction using residual cytologic samples. RESULTS: Using liquid-based Pap smears, 98 cases were diagnosed as atypical squamous cells of undetermined significance (38 cases), low-grade squamous intraepithelial lesion (12 cases), high-grade squamous intraepithelial lesion (HSIL) (33 cases), and invasive carcinoma (15 cases). The concordance rate between the cytologic and histologic diagnoses was found to be higher in high-grade lesions compared with low-grade lesions. Immunohistochemistry revealed that all HSIL and invasive carcinoma cases contained p16-positive cells in the liquid-based Pap smears and diffuse p16 staining was observed in all high-grade lesions with greater than CIN Grade 3 cervical intraepithelial neoplasia except for two adenocarcinoma cases. Of the 98 cases, 60 were found to be positive for high-risk HPV and 55 of these 60 HPV-positive cases were found to be p16 positive on cytologic examination. There were 16 cases that demonstrated marked discrepancies between the cytologic and histologic diagnoses. CONCLUSIONS: The results of the current study confirmed that the immunohistochemical detection of p16 was more sensitive and specific than HPV status in cervical lesions using a liquid-based method as well as tissue samples, suggesting that p16 should be used as a satisfactory biomarker for the primary screening of cervical cytology.