Predictors of recurrence following laparoscopic radical hysterectomy for early-stage cervical cancer: A multi-institutional study.

OBJECTIVE: To assess predictors of recurrence following laparoscopic radical hysterectomy (LRH) for apparent early stage cervical cancer (CC). METHODS: This is a retrospective multi-institutional study reviewing data of consecutive patients who underwent LRH for FIGO 2009 stage IA1 (with lymphovascular space invasion (LVSI)), IA2 and IB1(≤4 cm) CC, between January 2006 and December 2017. The following histotypes were included: squamous, adenosquamous, and adenocarcinoma. Multivariable models were used to estimate adjusted odds ratio (OR) and corresponding 95% CI. Factors influencing disease-free survival (DFS) and disease-specific survival (DSS) were also explored. RESULTS: 428 patients were included in the analysis. With a median follow-up of 56 months (1-162) 54 patients recurred (12.6%). At multivariable analysis, tumor size (OR:1.04, 95%CI:1.01-1.09, p = .02), and presence of cervical residual tumor at final pathology (OR: 5.29, 95%CI:1.34-20.76, p = .02) were found as predictors of recurrence; conversely preoperative conization reduced the risk (OR:0.32, 95%CI:0.11-0.90, p = .03). These predictors remained significant also in the IB1 subgroup: tumor size: OR:1.05, 95%CI:1.01-1.09, p = .01; residual tumor at final pathology: OR: 6.26, 95%CI:1.58-24.83, p = .01; preoperative conization: OR:0.33, 95%CI:0.12-0.95, p = .04. Preoperative conization (HR: 0.29, 95%CI: 0.13-0.91; p = .03) and the presence of residual tumor on the cervix at the time of surgery (HR: 8.89; 95%CI: 1.39-17.23; p = .01) independently correlated with DFS. No independent factors were associated with DSS. CONCLUSIONS: In women with early stage CC the presence of high-volume disease at time of surgery represent an independent predictor of recurrence after LRH. Conversely, preoperative conization and the absence of residual disease at the time of surgery might play a protective role.

Moderate and severe fetal pyelectasis: Correlation between prenatal aspects and postnatal outcome.

BACKGROUND: Renal pelvic dilatation (RPD) is a frequent finding in fetal ultrasound. The aim of the study is to correlate the prenatally detected moderate and severe pyelectasis with the postnatal outcome. METHODS: A retrospective analysis involving 90 cases of prenatally detected moderate and severe RPD referred to our prenatal diagnosis centre with 18 months of urological follow-up. Prenatal ultrasound was correlated with postnatal renal function, assessed by plasmatic creatinine and/or renal scintigraphy performed before surgery. RESULTS: Cases were divided between two groups according to postnatal management: group A including 35 newborns (38.9%) that needed surgical treatment and group B with 55 patients (61.1%) who were managed conservatively. The group A presented higher median RPD (18 mm, IQR 12-25 mm) compared to the group B (11 mm, IQR 10-14 mm). The most common anomaly detected within group A was pelvi-ureteric junction (PUI) obstruction (43%). Within group B 32 cases (58%) showed spontaneous resolution of hydronephrosis during postnatal follow up. In case of moderate pyelectasis the risk of postnatal surgery was 25% and raised to 60% for severe RPD. In our study, 29 newborns showed pathologic scintigraphies: 25 required surgery while 4 did not find indication for surgery due to ipsilateral renal function irreversible damage. 6 patients had high creatinine level (>0.6 mg/dl). 35 cases out of 90 (39%) developed monolateral irreversible renal function impairment. CONCLUSION: Moderate and severe RPD are often correlated with postnatal renal damage, therefore a close multidisciplinary follow-up is required. Prenatal scanning is highly predictive of postnatal outcome and can address properly the prenatal counseling.

Valor clínico y pronóstico de la PET/TC con 18F-FDG en el cáncer de endometrio recurrente / Clinical and prognostic value of 18F-FDG PET/CT in recurrent endometrial carcinoma

Objetivo: El carcinoma endometrial (CE) es un cáncer con un buen pronóstico general, excepto en los casos de CE recurrente o avanzado. El objetivo de este estudio fue evaluar el rendimiento diagnóstico y pronóstico y el impacto en el manejo terapéutico de la PET/TC con 18F-FDG en la sospecha de CE recurrente. Material y métodos: Se evaluaron retrospectivamente 157 pacientes con CE histológicamente probado y reestadificación de PET/TC con 18F-FDG por sospecha de recurrencia. Las imágenes PET se analizaron visualmente y semicuantitativamente midiendo SUVmax, VMT y GTL. Se tomó como referencia una combinación de seguimiento clínico/radiológico/histopatológico. La supervivencia libre de progresión (SLP) y la supervivencia global (SG) se calcularon usando las curvas de Kaplan-Meier. Resultados: Setenta y nueve pacientes tuvieron una PET/TC con 18F-FDG positiva que mostró la presencia de al menos una lesión hipermetabólica compatible con recurrencia, mientras que los 78 restantes fueron negativos. La sensibilidad, la especificidad, el valor predictivo positivo, el valor predictivo negativo y la precisión de la PET/TC con 18F-FDG fueron del 96, del 99, del 99, del 96 y del 97%, respectivamente, y fueron más altos en comparación con las imágenes convencionales: 97, 62, 72, 96 y 80%. Después de un seguimiento medio de 39meses, la recaída/progresión ocurrió en 58 pacientes y la muerte en 37, con un tiempo promedio de 22,1 y 27,6meses, respectivamente. Una PET/TC con 18F-FDG positiva y un estadio FIGO avanzado se asociaron significativamente con una SLP y SG más cortos. Los resultados de PET/TC tuvieron un impacto significativo en el abordaje terapéutico en 33 pacientes: evitaron terapias innecesarias en 28 y modificaron la terapia en 5. Conclusiones: La 18F-FDG-PET/TC tiene un muy buen rendimiento diagnóstico en pacientes con sospecha de CE recurrente, y tiene un importante valor pronóstico en la evaluación de SLP y SG. Además, la PET/TC permitió un cambio en la decisión de tratamiento en aproximadamente el 20% de los casos

Purpose: Endometrial carcinoma (EC) is a cancer with a good overall prognosis, except in cases of recurrent or advanced EC. The aim of this study was to assess the diagnostic performance, the prognostic value and the impact on therapeutic management of 18F-FDG PET/CT in suspected recurrent EC. Materials and methods: We retrospectively evaluated 157 patients with histologically proven EC and restaging 18F-FDG PET/CT for suspected recurrence. The PET images were analyzed visually and semi-quantitatively by measuring SUVmax, MTV and TLG. A combination of clinical/imaging follow-up and/or histopathology was taken as reference standard. Progression-free survival (PFS) and overall survival (OS) were computed using Kaplan-Meier curves. Results: Seventy-nine patients had positive 18F-FDG PET/CT showing the presence of at least one hypermetabolic lesion consistent with recurrence, while the remaining 78 were negative. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT were 96%, 99%, 99%, 96%, 97%, respectively, and were higher compared to conventional imaging: 97%, 62%, 72%, 96%, 80%. After a mean follow-up of 39months, relapse/progression occurred in 58 patients and death in 37 with an average time of 22.1 and 27.6months, respectively. A positive 18F-FDG PET/CT and advanced FIGO stage were significantly associated with shorter PFS and OS. PET/CT results had a significant impact on therapeutic approach in 33 patients: avoiding unnecessary therapies in 28 and modifying therapy in 5. Conclusions: 18F-FDG PET/CT has a very good diagnostic performance in patients with suspected recurrent EC and has an important prognostic value in assessing PFS and OS. Moreover, PET/CT allowed for a change in treatment decision in about 20% of cases

18F-FDG PET/TC en reestadificación y seguimiento de pacientes con sarcomas uterinos / Role of 18F-FDG PET/CT in restaging and follow-up of patients with uterine sarcomas

Objetivo: Los sarcomas uterinos son tumores raros con mal pronóstico debido a las altas tasas de recurrencia. El papel actual de la 18F-FDG PET/TC en la vigilancia posterior a la terapia aún no está establecido. Material y metodos: Cuarenta y una mujeres con sarcoma uterino se sometieron a 73 estudios 18F-FDG PET/TC para la reestadificación en la presunta recurrencia o durante el seguimiento en pacientes asintomáticos. Los resultados histopatológicos y/o el seguimiento clínico/de imágenes durante al menos 12 meses se consideraron el estándar de referencia. Se calculó la precisión diagnóstica y el impacto clínico de la 18F-FDG PET/TC. Resultados: treinta y tres estudios 18F-FDG PET/TC fueron positivos, mientras que los 40 estudios restantes fueron negativos. La sensibilidad general, la especificidad, el valor predictivo positivo (VP+), el valor predictivo negativo (VP-) y la precisión de la 18F-FDG PET/TC fueron del 88%, 98%, 97%, 91% y 93%. Considerando pacientes con sospecha clínica o radiológica de recidiva (n=47) y durante el seguimiento (n=26) la sensibilidad y especificidad, VP+, VP− y precisión de 18F-FDG PET/TC fueron del 89%, 100%, 100%, 86% y 94%, y 80%, 95%, 80%, 95% y 92% respectivamente. La 18F-FDG PET/TC tuvo un impacto clínico positivo en 9/73 (12%) estudios y cambió el manejo clínico en 8/41 (20%) pacientes. Conclusion: La 18F-FDG PET/TC es un método preciso para la detección y localización de recidivas a distancia en pacientes con sarcoma uterino con buena sensibilidad y especificidad e impacto significativo en la toma de decisiones clínicas

Purpose: Uterine sarcomas are rare tumors with poor prognosis due to the high recurrence rates. The current role of 18F-FDG PET/CT in the post-therapy surveillance is not established yet. Materials and Methods: Forty-one women with uterine sarcoma underwent 73 18F-FDG PET/CT for restaging in suspected recurrence or during follow-up in asymptomatic patients. Histopathology results and/or clinical/imaging follow-up for at least 12 months were considered the reference standard. The diagnostic accuracy and clinical impact of 18F-FDG PET/CT was calculated. Results: Thirty-three 18F-FDG PET/CT were positive, while the remaining 40 studies were negative. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F-FDG PET/CT were 88%, 98%, 97%, 91% and 93%, respectively. Considering patients with clinical or radiological suspicion of recurrence (n=47) and those during follow-up (n=26), sensitivity, specificity, PPV, NPV and accuracy of 18F-FDG PET/CT were 89%, 100%, 100%, 86% and 94%, and 80%, 95%, 80%, 95% and 92%, respectively. 18F-FDG PET/CT had a positive clinical impact in 9/73 (12%) studies and changed the clinical management in 8/41 (20%) patients. Conclusions: 18F-FDG PET/CT seems to be an accurate method for detection and localization of local and distant recurrence in patients with uterine sarcoma with good sensitivity and specificity and significant impact on clinical decision making

Role of 18F-FDG PET/CT in restaging and follow-up of patients with uterine sarcomas. / 18F-FDG PET/TC en reestadificación y seguimiento de pacientes con sarcomas uterinos.

PURPOSE: Uterine sarcomas are rare tumors with poor prognosis due to the high recurrence rates. The current role of 18F-FDG PET/CT in the post-therapy surveillance is not established yet. MATERIALS AND METHODS: Forty-one women with uterine sarcoma underwent 73 18F-FDG PET/CT for restaging in suspected recurrence or during follow-up in asymptomatic patients. Histopathology results and/or clinical/imaging follow-up for at least 12 months were considered the reference standard. The diagnostic accuracy and clinical impact of 18F-FDG PET/CT was calculated. RESULTS: Thirty-three 18F-FDG PET/CT were positive, while the remaining 40 studies were negative. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F-FDG PET/CT were 88%, 98%, 97%, 91% and 93%, respectively. Considering patients with clinical or radiological suspicion of recurrence (n=47) and those during follow-up (n=26), sensitivity, specificity, PPV, NPV and accuracy of 18F-FDG PET/CT were 89%, 100%, 100%, 86% and 94%, and 80%, 95%, 80%, 95% and 92%, respectively. 18F-FDG PET/CT had a positive clinical impact in 9/73 (12%) studies and changed the clinical management in 8/41 (20%) patients. CONCLUSIONS: 18F-FDG PET/CT seems to be an accurate method for detection and localization of local and distant recurrence in patients with uterine sarcoma with good sensitivity and specificity and significant impact on clinical decision making.

Clinical and prognostic value of 18F-FDG PET/CT in recurrent endometrial carcinoma. / Valor clínico y pronóstico de la PET/TC con 18F-FDG en el cáncer de endometrio recurrente.

PURPOSE: Endometrial carcinoma (EC) is a cancer with a good overall prognosis, except in cases of recurrent or advanced EC. The aim of this study was to assess the diagnostic performance, the prognostic value and the impact on therapeutic management of 18F-FDG PET/CT in suspected recurrent EC. MATERIALS AND METHODS: We retrospectively evaluated 157 patients with histologically proven EC and restaging 18F-FDG PET/CT for suspected recurrence. The PET images were analyzed visually and semi-quantitatively by measuring SUVmax, MTV and TLG. A combination of clinical/imaging follow-up and/or histopathology was taken as reference standard. Progression-free survival (PFS) and overall survival (OS) were computed using Kaplan-Meier curves. RESULTS: Seventy-nine patients had positive 18F-FDG PET/CT showing the presence of at least one hypermetabolic lesion consistent with recurrence, while the remaining 78 were negative. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG PET/CT were 96%, 99%, 99%, 96%, 97%, respectively, and were higher compared to conventional imaging: 97%, 62%, 72%, 96%, 80%. After a mean follow-up of 39months, relapse/progression occurred in 58 patients and death in 37 with an average time of 22.1 and 27.6months, respectively. A positive 18F-FDG PET/CT and advanced FIGO stage were significantly associated with shorter PFS and OS. PET/CT results had a significant impact on therapeutic approach in 33 patients: avoiding unnecessary therapies in 28 and modifying therapy in 5. CONCLUSIONS: 18F-FDG PET/CT has a very good diagnostic performance in patients with suspected recurrent EC and has an important prognostic value in assessing PFS and OS. Moreover, PET/CT allowed for a change in treatment decision in about 20% of cases.

Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients.

BACKGROUND: To date, no good marker for screening or disease monitoring of endometrial cancer (EC) is available. The aims of this study were to investigate HE4 gene, protein expression and serum HE4 (sHE4) levels in a panel of ECs and normal endometria (NEs) and to correlate sHE4 with patient clinicopathological characteristics and prognosis. METHODS: Using quantitative real-time PCR we tested 46 ECs and 20 NEs for HE4 gene expression. Protein expression was analysed by immunohistochemistry on tissue microarrays in 153 ECs and 33 NEs. Pre-operative serum samples from 138 EC and 76 NE patients were analysed with HE4-EIA assay. Association between sHE4 and patient clinicopathological characteristics or outcome was evaluated. RESULTS: Protein and HE4 gene were significantly upregulated in EC tissues and sera, compared with controls. High sHE4 levels were significantly associated with worse EC clinical characteristics. By univariate survival analysis, high sHE4 levels significantly correlated with decreased overall survival, progression-free survival and disease-free survival, retaining their independent prognostic value on the poorly differentiated EC cohort. CONCLUSION: We demonstrate, for the first time, that high sHE4 levels correlates with an aggressive EC phenotype and may constitute an independent prognostic factor for poorly differentiated-ECs. Determination of sHE4 could be clinically useful in identifying high-risk EC patients for a more aggressive adjuvant therapy.

Trefoil factor 3: a novel serum marker identified by gene expression profiling in high-grade endometrial carcinomas.

This study identifies the genetic fingerprint of poorly differentiated endometrioid endometrial carcinomas (G3-EEC) and analyses the potential utility of trefoil factor 3 (TFF3) as novel serum marker in G3-EEC. Affymetrix microarrays were used to identify the gene expression patterns of 19 snap-frozen G3-EEC and 15 normal endometrium (NE) biopsies. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry were used to validate TFF3 expression. Finally, TFF3 serum levels were determined by ELISA in 25 G3-EEC patients, 42 healthy controls, and in 13 endometrial hyperplasia patients. Hierarchical cluster analysis showed TFF3 as the top differentially expressed gene between 363 upregulated genes in G3-EEC, when compared with NE. Trefoil factor 3 gene expression levels analysed by qRT-PCR significantly correlated with Affymetrix results (P<0.001; rs=0.85). By immunohistochemistry, TFF3 protein was significatively more expressed in EEC compared with NE (P<0.01), with cytoplasmatic positivity in 79% G3-EEC and 18% NE. Patients harbouring G3-EECs had significantly higher TFF3 serum concentration by ELISA when compared with healthy patients (P<0.001) or patients harbouring endometrial hyperplasia (P=0.012). In conclusion, TFF3 is highly expressed at gene and protein level in G3-EEC. Further investigations on a wider set of samples are warranted to validate TFF3 as a novel serum marker for early detection and/or monitoring of G3-EEC patients.

HER-2/neu overexpression and amplification in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry, real-time reverse transcription-polymerase chain reaction, and fluorescence in situ hybridization.

Uterine serous papillary carcinoma (USPC) is a rare and highly malignant form of endometrial cancer (EC) characterized by early metastasis, chemoresistance, and high mortality rate. Little is known about USPC tumorigenesis even if recently a HER-2/neu role has been suggested in its development and progression. The aim of the present study was to evaluate HER-2 expression by immunohistochemistry (IHC) in 12 USPC formalin-fixed, paraffin-embedded (FFPE) samples. Moreover, we looked at the correlation between HER-2 protein expression and HER-2/neu gene amplification by fluorescence in situ hybridization (FISH), other than HER-2/neu messenger RNA expression by quantitative real-time reverse transcription (RT)-polymerase chain reaction (PCR). Finally, these results have been compared with commonly evaluated clinical features in EC patients, in order to define the potential prognostic value of HER-2/neu overexpression in USPCs. A high expression of HER-2 protein by IHC was noted in 2 of 12 patients (16.6%), and the same cases showed specific HER-2/neu gene amplification by FISH. All the samples investigated displayed a perfect concordance between IHC and FISH data. Five (41.6%) of 12 tumors demonstrated polysomy of chromosome 17 and, focusing on the 2 USPCs that showed HER-2/neu overexpression, one of them (50%) was polysomic for chromosome 17. All the other USPC cases (58.4%) showed to be disomic for chromosome 17. Quantitative RT real-time PCR performed on complementary DNA obtained from all FFPE USPC samples showed a complete correlation with FISH and IHC data. Moreover, HER-2/neu overexpression was associated with a poorer overall survival and a very low relapse-free survival time, thus being considered a candidate marker of worse overall prognosis in USPC. The use of trastuzumab (Herceptin), a monoclonal antibody directed against HER-2/neu, for the therapy of patients with HER-2/neu-positive USPCs should be further investigated in clinical trials.

Pattern of failure and value of follow-up procedures in endometrial and cervical cancer patients.

OBJECTIVE: The aim of this study was to evaluate the outcome benefit of follow-up protocols for patients with recurrent endometrial and cervical cancer. METHODS: A retrospective review on patients primarily treated at the Division of Gynecologic Oncology, University of Brescia, was performed. We focused our attention on recurrent patients and we evaluated the pattern of relapse and the presence of symptoms or signs of disease at recurrence and evidence of disease on routine follow-up test or visits. RESULTS: The vast majority of recurrences occurred within the first 3 years after primary treatment (78% and 87% in endometrial and cervical cancers, respectively). A better overall survival from relapse was observed when vaginal relapse was compared to other sites in endometrial cancer patients and when pelvic recurrence was compared to distant sites in cervical cancer cases. Recurrent endometrial and cervical cancer patients were symptomatic in 52% and 65% of cases, respectively. Among asymptomatic recurrent endometrial cancer cases, pelvic examination, abdominal or pelvic ultrasound and CT could detect 92% of relapses, while the vast majority of cervical cancer relapses could be diagnosed by pelvic examination and/or CT (85%). CONCLUSION: Endometrial cancer patients showed a significantly better prognosis when the recurrence was detected during follow-up visits, thus supporting the real advantage of our surveillance programs, while no statistically significant differences were found in survival of cervical cancer patients between the symptomatic and the asymptomatic group.

Correlation between serological immune response analyzed by a new ELISA for HPV-16/18 E7 oncoprotein and clinical characteristics of cervical cancer patients.

Human papillomaviruses (HPVs), particularly HPV-16/18, are linked to cervical cancer development. Full-length, recombinant HPV-16/18 E7 oncoproteins were used in a new streptavidin-biotin capture ELISA method to investigate anti-HPV E7 antibody prevalence in serum. Sera from 99 healthy women, 70 cervical cancer patients, and 30 patients with cervical pre-invasive neoplasia were analyzed. Anti-HPV-16/18 E7 positivity was found in 53% of cervical cancer patients, in 40% with cervical pre-invasive neoplasia, and in 8% of healthy women. Serum samples from 12 cervical cancer patients were obtained at different time intervals during the treatment. Eleven out of 12 showed a correspondence between HPV-E7 antibody levels (decreasing versus increasing) and the type of response (clinically complete or partial response versus progression or stable disease) at each serological evaluation. Five patients with recurrent HPV-16/18-positive cervical carcinoma were analyzed before and after vaccination with HPV-16/18 E7-pulsed autologous dendritic cells; anti-HPV-16/18 E7 positivity was found in 3 out of 5 women. In conclusion, this assay could potentially be used as an adjunctive tool to monitor the type of response to treatment and possibly to detect antibody induction in cervical cancer patients after vaccination, as a potential marker to evaluate its efficacy.