Target tailoring and proton beam therapy to reduce small bowel dose in cervical cancer radiotherapy : A comparison of benefits.

PURPOSE: The aim of the study was to investigate the potential clinical benefit from both target tailoring by excluding the tumour-free proximal part of the uterus during image-guided adaptive radiotherapy (IGART) and improved dose conformity based on intensity-modulated proton therapy (IMPT). METHODS: The study included planning CTs from 11 previously treated patients with cervical cancer with a >4-cm tumour-free part of the proximal uterus on diagnostic magnetic resonance imaging (MRI). IGART and robustly optimised IMPT plans were generated for both conventional target volumes and for MRI-based target tailoring (where the non-invaded proximal part of the uterus was excluded), yielding four treatment plans per patient. For each plan, the V15Gy, V30Gy, V45Gy and Dmean for bladder, sigmoid, rectum and bowel bag were compared, and the normal tissue complication probability (NTCP) for ≥grade 2 acute small bowel toxicity was calculated. RESULTS: Both IMPT and MRI-based target tailoring resulted in significant reductions in V15Gy, V30Gy, V45Gy and Dmean for bladder and small bowel. IMPT reduced the NTCP for small bowel toxicity from 25% to 18%; this was further reduced to 9% when combined with MRI-based target tailoring. In four of the 11 patients (36%), NTCP reductions of >10% were estimated by IMPT, and in six of the 11 patients (55%) when combined with MRI-based target tailoring. This >10% NTCP reduction was expected if the V45Gy for bowel bag was >275 cm3 and >200 cm3, respectively, during standard IGART alone. CONCLUSIONS: In patients with cervical cancer, both proton therapy and MRI-based target tailoring lead to a significant reduction in the dose to surrounding organs at risk and small bowel toxicity.

The FIGO Stage IVA Versus IVB of Ovarian Cancer: Prognostic Value and Predictive Value for Neoadjuvant Chemotherapy.

OBJECTIVE: The revised version of the International Federation of Gynaecology and Obstetrics (FIGO) staging system (2014) for epithelial ovarian cancer includes a number of changes. One of these is the division of stage IV into 2 subgroups. Data on the prognostic and predictive significance of this classification are scarce. The effect of neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) in relation to the subclassification of FIGO stage IV is also unknown. METHODS: We used data of the EORTC 55971 trial, in which 670 patients with previous stage IIIC or IV epithelial ovarian cancer were randomly assigned to PDS or NACT; 160 patients had previous stage IV. Information on previous FIGO staging and presence of pleural effusion with positive cytology were used to classify tumors as either stage IVA or IVB. We tested the association between stage IVA/IVB and survival to evaluate the prognostic value and interactions between stage, treatment, and survival to evaluate the predictive performance. RESULTS: Among the 160 participants with previous stage IV disease, 103 (64%) were categorized as stage IVA and 57 (36%) as stage IVB tumors. Median overall survival was 24 months in FIGO stage IVA and 31 months in stage IVB patients (P = 0.044). Stage IVB patients treated with NACT had 9 months longer median overall survival compared with IVB patients undergoing PDS (P = 0.025), whereas in IVA patients, no significant difference was observed (24 vs 26 months, P = 0.48). CONCLUSIONS: The reclassification of FIGO stage IV into stage IVA or IVB was not prognostic as expected. Compared with stage IVA patients, stage IVB patients have a better overall survival and may benefit more from NACT.

Cost-effectiveness of laparoscopy as diagnostic tool before primary cytoreductive surgery in ovarian cancer.

OBJECTIVE: To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer. METHODS: An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices. RESULTS: We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were € 1400 per intervention, making the overall costs of both strategies comparable (difference € -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses. CONCLUSION: In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life.

Results of radical surgery in women with stage IB2/IIA2 cervical cancer.

INTRODUCTION: There is ongoing discussion about the primary treatment of women with bulky early-stage cervical cancer. Because of the high number of patients who need adjuvant (chemo)radiotherapy after initial surgical treatment, some state that primary (chemo)radiotherapy should be the treatment of choice to prevent morbidity. The aim of our study is to assess the results of radical surgery for women with bulky early-stage cervical cancer in terms of recurrence patterns and survival. MATERIALS AND METHODS: We conducted a retrospective cohort study. We included 129 women who underwent a radical hysterectomy with pelvic lymphadenectomy for stage IB2/IIA2 cervical cancer between 1984 and June 2010. Disease-specific survival was measured using a Kaplan-Meier method and univariate and multivariate regression analyses were performed to determine prognostic factors associated with survival. A literature search was performed to analyze our data in the context of findings from the literature. RESULTS: Five-year disease-specific survival was 84%. Fifty percent of the women received adjuvant treatment. The pelvic recurrence rate was 8%. With our multivariate analysis we found that histology, tumor diameter, and parametrial involvement were independently associated with disease-specific survival. Our literature search showed wide diversity in rates of adjuvant treatment after initial surgery as well as for survival and recurrence rates. CONCLUSIONS: In the context of current knowledge about survival and side effects of various treatments for bulky early-stage cervical cancer, radical surgery is a good treatment option in these patients. Depending on the type of surgery used, adjuvant radiotherapy can be minimized.

Quantification of delineation errors of the gross tumor volume on magnetic resonance imaging in uterine cervical cancer using pathology data and deformation correction.

BACKGROUND: To safely optimize target volumes using magnetic resonance imaging (MRI) for uterine cervical cancer radiation therapy, MRI findings need to be validated. The aim of this study was to correlate pre-operatively acquired MRI and surgical specimen imaging for uterine cervical cancer patients using deformable image registration and quantify gross tumor volume (GTV) delineation discrepancies. MATERIAL AND METHODS: For 16 retrospectively selected early-stage uterine cervical cancer patients, the cervix-uterus structure, uterine cavity and the GTV were delineated on 2D pathology photos after macroscopic intersection and corresponding pre-operatively acquired T2-weighted 2D sagittal MR images. Segmentations of pathology photos and MR images were simultaneously registered using a three-step multi-image registration strategy. The registration outcome was evaluated by the Dice similarity coefficient (DSC) and the surface distance error (SDE). In addition, GTV expansions within the cervix-uterus structure needed to obtain 95% GTV coverage were determined. RESULTS: After three-step multi-image registration, the median DSC and median SDE were 0.98 and 0.4 mm (cervix-uterus) and 0.90 and 0.4 mm (uterine cavity), respectively. The average SDE around the GTV was 0.7 mm (range, 0.1 mm - 2.6 mm). An underestimation of MRI-based GTV delineations was found when no margin was applied, indicated by a mean GTV coverage of 61%. To obtain 95% GTV coverage for 90% of the patients, a minimum 12.0 mm margin around MRI-based GTVs was needed. CONCLUSION: The presented three-step multi-image registration strategy was suitable and accurate to correlate MRI and pathology data for uterine cervical cancer patients. To cover the pathology-based GTV, a margin of at least 12.0 mm around GTV delineations on T2-weighted MRI is needed.

Evaluation of response to hormone therapy in patients with measurable adult granulosa cell tumors of the ovary.

INTRODUCTION: The aim of this study was to retrospectively determine the objective response rate to hormone therapy (HT) for patients with a measurable adult granulosa cell tumor (GCT) of the ovary in a consecutive series of patients. MATERIAL AND METHODS: All patients with an adult GCT who were treated with HT [steroidal progestins, selective estrogen receptor modulators, aromatase inhibitors and gonadotropin-releasing hormone agonists] within three referral hospitals were identified and their records were screened for HT administration. The main outcome measure was the objective response rate to HT. RESULTS: We identified 127 patients with an adult GCT, of whom 81 (64%) had a recurrence. Twenty-five of these patients (20%) were treated with hormones, of whom 22 had measurable disease at the start of their treatment, i.e. a tumor of more than 1 cm in diameter as seen on imaging, either as a recurrence or as residual disease. The pooled objective response rate, defined as the proportion of patients whose best overall response to hormone therapy was either complete response or partial response to HT, was 18% (4/22) (95% confidence interval 6-41%). In one patient (4.5%) a complete response and in three (14%) a partial response was described. Fourteen patients (64%) had stable disease and in four patients (18%) disease was progressive. CONCLUSIONS: Although several case reports described good responses to HT in patients with a GCT, we found a response in only four of 22 patients in this relatively large consecutive series of patients.

Cytoreductive surgery followed by chemotherapy versus chemotherapy alone for recurrent platinum-sensitive epithelial ovarian cancer (SOCceR trial): a multicenter randomised controlled study.

BACKGROUND: Improvement in treatment for patients with recurrent ovarian cancer is needed. Standard therapy in patients with platinum-sensitive recurrent ovarian cancer consists of platinum-based chemotherapy. Median overall survival is reported between 18 and 35 months. Currently, the role of surgery in recurrent ovarian cancer is not clear. In selective patients a survival benefit up to 62 months is reported for patients undergoing complete secondary cytoreductive surgery. Whether cytoreductive surgery in recurrent platinum-sensitive ovarian cancer is beneficial remains questionable due to the lack of level I-II evidence. METHODS/DESIGN: Multicentre randomized controlled trial, including all nine gynecologic oncologic centres in the Netherlands and their affiliated hospitals. Eligible patients are women, with first recurrence of FIGO stage Ic-IV platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, who meet the inclusion criteria. Participants are randomized between the standard treatment consisting of at least six cycles of intravenous platinum based chemotherapy and the experimental treatment which consists of secondary cytoreductive surgery followed by at least six cycles of intravenous platinum based chemotherapy. Primary outcome measure is progression free survival. In total 230 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Where the role of cytoreductive surgery is widely accepted in the initial treatment of ovarian cancer, its value in recurrent platinum-sensitive epithelial ovarian cancer has not been established so far. A better understanding of the benefits and patients selection criteria for secondary cytoreductive surgery has to be obtained. Therefore the 4th ovarian cancer consensus conference in 2010 stated that randomized controlled phase 3 trials evaluating the role of surgery in platinum-sensitive recurrent epithelial ovarian cancer are urgently needed. We present a recently started multicentre randomized controlled trial that will investigate the role of secondary cytoreductive surgery followed by chemotherapy will improve progression free survival in selected patients with first recurrence of platinum-sensitive epithelial ovarian cancer.

Hormone therapy in ovarian granulosa cell tumors: a systematic review.

OBJECTIVE: This systematic review assessed the effectiveness of hormone therapy (HT) in patients with a granulosa cell tumor (GCT) of the ovary. METHODS: Medline (OVID), EMBASE (OVID), the Cochrane Central Register of Controlled Trials (CENTRAL), prospective trial registers and PubMed (as supplied by publisher-subset) were searched up to January 13, 2014. No restrictions were applied. Two reviewers independently screened studies for eligibility and extracted data using a standardized, piloted extraction form. Studies evaluating the response to hormone therapy in patients with a GCT were included. The primary outcome was the objective response rate (ORR) to hormone therapy. RESULTS: In total, nineteen studies including 31 patients were eligible. Pooled ORR to hormone therapy was 71.0% (95% Confidence Interval 52-85). In 25.8% a complete response and in 45.2% a partial response was described. Four patients had stable disease. In five patients disease was progressive. Various hormone treatments showed different results, for instance aromatase inhibitors (AI) demonstrated response in nine out of nine therapies (100%) and tamoxifen in none out of three (0%). Median progression free survival (PFS) after the start of hormone therapy was 18 months (range 0-60). CONCLUSIONS: Despite the limited available data, hormone therapy appears to be a good treatment alternative for patients with advanced-stage or recurrent GCT. However, study quality is poor and prospective studies are needed to confirm clinical benefit of hormone therapy in GCTs.

Post-operative radiotherapy in patients with early stage cervical cancer.

OBJECTIVE: The aim of this study is to investigate the impact of treatment policy changes in cervical cancer patients treated with adjuvant (chemo) radiotherapy. METHODS: Between 1970 and 2007, 292 patients received adjuvant radiotherapy after a radical hysterectomy with pelvic lymphadenectomy for early stage cervical carcinoma. All patients received pelvic radiotherapy (40 Gy-46 Gy in 1.8 Gy-2 Gy/fraction). Vaginal vault brachytherapy boost (10-14 Gy) was increasingly used for patients with high-risk factors, and since 1993 systematically applied in patients with at least 2 of the 3 risk factors: adenocarcinoma, nodal involvement and parametrial invasion. Cisplatin-based chemotherapy was introduced in this group of patients from 2000. RESULTS: The 5-year cumulative risk of local recurrence (CRLR) was 13% (95%CI 9%-17%), resulting in an overall 5-year survival (OS) of 78% (95%CI 83%-73%). Since 1970, the OR for the 5-year locoregional recurrence risk (LRR) decreased from 2.5 to 1.15 (linear-OR=-0.02/year). The OR for the 5-year mortality risk reduced from 2.2 in 1970 to 1.0 in 2007 (linear-OR=-0.03/year). The largest risk reductions were observed before 1990 with a minor rise after 2002. The risk of severe late toxicity reduced from 1.8% to 1.5% (linear-OR=-0.03/year). The addition of concomitant adjuvant chemotherapy since 2000 may have benefited a subgroup of patients with squamous cell carcinoma, but not the patients with adenocarcinoma, and after introduction of chemotherapy the risk of severe late toxicity tripled from 2% to 7%. CONCLUSION: Since 1970, tumour recurrence risk and mortality have decreased, as radiation dose increased. The potential benefit of concomitant adjuvant chemotherapy could not be demonstrated in this nonrandomized study.

Development and internal validation of a prognostic model to predict recurrence free survival in patients with adult granulosa cell tumors of the ovary.

OBJECTIVE: Models to predict the probability of recurrence free survival exist for various types of malignancies, but a model for recurrence free survival in individuals with an adult granulosa cell tumor (GCT) of the ovary is lacking. We aimed to develop and internally validate such a prognostic model. METHODS: We performed a multicenter retrospective cohort study of patients with a GCT. Demographic, clinical and pathological information were considered as potential predictors. Univariable and multivariable analyses were performed using a Cox proportional hazards model. Using backward stepwise selection we identified the combination of predictors that best predicted recurrence free survival. Discrimination (c-statistic) and calibration were used to assess model performance. The model was internally validated using bootstrapping techniques to correct for overfitting. To increase clinical applicability of the model we developed a nomogram to allow individual prediction of recurrence free survival. RESULTS: We identified 127 patients with a GCT (median follow-up time was 131 months (IQR 70-215)). Recurrence of GCT occurred in 81 out of 127 patients (64%). The following four variables jointly best predicted recurrence free survival; clinical stage, Body Mass Index (BMI), tumor diameter and mitotic index. The model had a c-statistic of 0.73 (95% CI 0.66-0.80) and showed accurate calibration. CONCLUSIONS: Recurrence free survival in patients with an adult GCT of the ovary can be accurately predicted by a combination of BMI, clinical stage, tumor diameter and mitotic index. The introduced nomogram could facilitate in counseling patients and may help to guide patients and caregivers in joint decisions on post-treatment surveillance.

Effectiveness of chemotherapy in measurable granulosa cell tumors: a retrospective study and review of literature.

OBJECTIVE: Patients with irresectable granulosa cell tumors (GCTs) often receive chemotherapy. The effectiveness of this approach, however, is uncertain. The aim of our study was to assess the response rate to chemotherapy for residual and recurrent inoperable GCT. METHODS: All consecutive chemotherapy-naive patients in 3 referral hospitals who were treated with chemotherapy for residual or recurrent GCT between 1968 and 2011 were included. Main outcome was the response according to Response Evaluation Criteria in Solid Tumor criteria. A literature search in MEDLINE through PubMed was performed, from inception to August 19, 2013. RESULTS: Twenty-seven patients with a GCT who received chemotherapy were identified. Eighteen patients were not evaluable because they had either no measurable disease, or no imaging was performed before and after chemotherapy. One of the 9 evaluable patients (11%) had a complete response, and 1 patient (11%) had a partial response, resulting in a response rate of 22% (95% confidence interval, 0%-49%). Seven patients (78%) had stable disease (range, 2-50 months), and none had progressive disease. Fifteen studies that assessed response rates to chemotherapy on measurable disease in a total of 224 patients showed a response rate of 50% (95% confidence interval, 44%-57%). Strict criteria of response, however, were not uniformly applied in the majority of these published series. CONCLUSIONS: In the present study, we present only a moderate beneficial effect of chemotherapy in patients with irresectable GCT with measurable disease. Comparison with previous studies is hampered by a lack of standardized response evaluation in the majority of studies. Given the toxicity of platinum-based chemotherapy, administering this treatment should be a well-considered decision.

Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition.

Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5 °C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized on-demand induction of HR deficiency, an approach that we term induced synthetic lethality.

The incidence of endometrial hyperplasia and cancer in 1031 patients with a granulosa cell tumor of the ovary: long-term follow-up in a population-based cohort study.

OBJECTIVE: Concurrent presence of endometrial hyperplasia or cancer in patients with granulosa cell tumors (GCTs) is common, with reported incidences of 25.6% to 65.5%. Consequently, bilateral salpingo-oophorectomy and hysterectomy is usually recommended in patients with a GCT, but this remains debatable. Our aim was to evaluate the need for hysterectomy in patients with GCTs by studying the incidence of pathologically confirmed endometrial abnormalities at the time of diagnosis of GCT and during follow-up. MATERIALS/METHODS: All cases of GCT between 1991 and 2012 were evaluated for endometrial pathology using the Dutch nationwide network and registry of histopathology and cytopathology (PALGA). RESULTS: A total of 1031 cases of GCT were identified at a mean ± SD age of 55 ± 17 years. The incidence of GCTs in the period 1991-2012 was 0.61 per 100,000 women per year. Concurrent endometrial cancer at the time of diagnosis of GCT was found in 58 patients (5.9%) and endometrial hyperplasia in 251 patients (25.5%), including complex hyperplasia in 89 patients (9.1%) and simple hyperplasia in 162 patients (16.5%). Long-term follow-up of 490 patients (47.5%) without a hysterectomy showed that endometrial abnormalities were found in 10 patients (2.0%) of which 2 had endometrial cancer. Interestingly, 8 (80%) of the 10 patients with endometrial abnormalities had recurrent GCT at the time of diagnosis of endometrial hyperplasia or cancer. CONCLUSIONS: Our data suggest that after surgical removal of GCT, development of an endometrial abnormality, especially cancer, is very rare. Therefore, hysterectomy is not recommended in patients with a GCT without endometrial abnormalities at the time of diagnosis.

Laparoscopy to predict the result of primary cytoreductive surgery in advanced ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled study.

BACKGROUND: Standard treatment of advanced ovarian cancer is surgery and chemotherapy. The goal of surgery is to remove all macroscopic tumour, as the amount of residual tumour is the most important prognostic factor for survival. When removal off all tumour is considered not feasible, neoadjuvant chemotherapy (NACT) in combination with interval debulking surgery (IDS) is performed. Current methods of staging are not always accurate in predicting surgical outcome, since approximately 40% of patients will have more than 1 cm residual tumour after primary debulking surgery (PDS). In this study we aim to assess whether adding laparoscopy to the diagnostic work-up of patients suspected of advanced ovarian carcinoma may prevent unsuccessful primary debulking surgery for ovarian cancer. METHODS: Multicentre randomized controlled trial, including all gynaecologic oncologic centres in the Netherlands and their affiliated hospitals. Patients are eligible when they are planned for PDS after conventional staging. Participants are randomized between direct PDS or additional diagnostic laparoscopy. Depending on the result of laparoscopy patients are treated by PDS within three weeks, followed by six courses of platinum based chemotherapy or with NACT and IDS 3-4 weeks after three courses of chemotherapy, followed by another three courses of chemotherapy. Primary outcome measure is the proportion of PDS's leaving more than one centimetre tumour residual in each arm. In total 200 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Patients who have disease considered to be resectable to less than one centimetre should undergo PDS to improve prognosis. However, there is a need for better diagnostic procedures because the current number of debulking surgeries leaving more than one centimetre residual tumour is still high. Laparoscopy before starting treatment for ovarian cancer can be an additional diagnostic tool to predict the outcome of PDS. Despite the absence of strong evidence and despite the possible complications, laparoscopy is already implemented in many countries. We propose a randomized multicentre trial to provide evidence on the effectiveness of laparoscopy before primary surgery for advanced stage ovarian cancer patients. TRIAL REGISTRATION: Netherlands Trial Register number NTR2644.

A critical assessment of SELDI-TOF-MS for biomarker discovery in serum and tissue of patients with an ovarian mass.

BACKGROUND: Less than 25% of patients with a pelvic mass who are presented to a gynecologist will eventually be diagnosed with epithelial ovarian cancer. Since there is no reliable test to differentiate between different ovarian tumors, accurate classification could facilitate adequate referral to a gynecological oncologist, improving survival. The goal of our study was to assess the potential value of a SELDI-TOF-MS based classifier for discriminating between patients with a pelvic mass. METHODS: Our study design included a well-defined patient population, stringent protocols and an independent validation cohort. We compared serum samples of 53 ovarian cancer patients, 18 patients with tumors of low malignant potential, and 57 patients with a benign ovarian tumor on different ProteinChip arrays. In addition, from a subset of 84 patients, tumor tissues were collected and microdissection was used to isolate a pure and homogenous cell population. RESULTS: Diagonal Linear Discriminant Analysis (DLDA) and Support Vector Machine (SVM) classification on serum samples comparing cancer versus benign tumors, yielded models with a classification accuracy of 71-81% (cross-validation), and 73-81% on the independent validation set. Cancer and benign tissues could be classified with 95-99% accuracy using cross-validation. Tumors of low malignant potential showed protein expression patterns different from both benign and cancer tissues. Remarkably, none of the peaks differentially expressed in serum samples were found to be differentially expressed in the tissue lysates of those same groups. CONCLUSION: Although SELDI-TOF-MS can produce reliable classification results in serum samples of ovarian cancer patients, it will not be applicable in routine patient care. On the other hand, protein profiling of microdissected tumor tissue may lead to a better understanding of oncogenesis and could still be a source of new serum biomarkers leading to novel methods for differentiating between different histological subtypes.

Can we predict vesicovaginal or rectovaginal fistula formation in patients with stage IVA cervical cancer?

INTRODUCTION: Patients with cervical carcinoma that invade the bladder or rectum (International Federation of Obstetrics and Gynecology stage IVA) have a high risk to develop vesicovaginal and/or rectovaginal fistulae. If we could identify pretreatment factors that predict fistula formation, these patients could be offered less debilitating treatment. MATERIALS AND METHODS: Data were retrieved from the database of consecutive patients diagnosed with stage IVA cervical cancer from 1992 to 2008. Overall survival and fistula-free survival were calculated using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were used to study the association between pretreatment prognostic variables and fistula formation. RESULTS: Thirty patients with stage IVA cervical cancer were diagnosed. Extension to the bladder was present in 27 patients; three patients had only rectal involvement. Twenty-three patients (77%) had curative radiotherapy with or without chemotherapy and/or hyperthermia. Seven patients (23%) received only palliative therapy or no treatment at all. The 5-year overall survival in the curatively treated group was 42%. Five (22%) of these 23 patients developed one or more fistulae: 3 vesicovaginal, 1 rectovaginal, and 1 vesicovaginal and rectovaginal fistulae. The 5-year fistula-free survival of this group was 64%. No significant association was found between the prognostic variables and fistula formation. CONCLUSIONS: The risk to develop vesicovaginal and/or rectovaginal fistulae is high after curative radiotherapy with or without chemotherapy and/or hyperthermia in patients with stage IVA cervical cancer. We could not identify further pretreatment factors that might have predicted fistula formation.

The role of mast cell stabilization in treatment of postoperative ileus: a pilot study.

OBJECTIVES: Although postoperative ileus (POI) is considered multifactorial, intestinal inflammation resulting from manipulation-induced mast cell activation is recognized as an important pathophysiological mechanism. Therefore, mast cell stabilization may represent a new therapeutic approach to shortening POI. The aim of this paper was to study the effect of ketotifen, a mast cell stabilizer, on postoperative gastrointestinal transit in patients who underwent abdominal surgery. METHODS: In this pilot study, 60 patients undergoing major abdominal surgery for gynecological malignancy with standardized anesthesia were randomized to treatment with ketotifen (4 or 12 mg) or placebo. Patients were treated for 6 days, starting 3 days before surgery. Gastric emptying of liquids, selected as a primary outcome parameter, was measured 24 h after surgery using scintigraphy. Secondary end points were (scintigraphically assessed) colonic transit, represented as geometrical center of activity (segment 1(cecum) to 7(stool)) and clinical parameters. RESULTS: Gastric retention 1 h after liquid intake was significantly reduced by 12 mg (median 3% (1-7), P=0.01), but not by 4 mg ketotifen (18% (3-45), P=0.6) compared with placebo (16% (5-75)). Twenty-four hour colonic transit in placebo was 0.8 (0.0-1.1) vs. 1.2 (0.2-1.4) colon segments in the 12 mg ketotifen group (P=0.07). Abdominal cramps were significantly relieved in patients treated with 12 mg ketotifen, whereas other clinical parameters were not affected. CONCLUSIONS: Ketotifen significantly improves gastric emptying after abdominal surgery and warrants further exploration of mast cell stabilizers as putative therapy for POI.

Classification-based comparison of pre-processing methods for interpretation of mass spectrometry generated clinical datasets.

BACKGROUND: Mass spectrometry is increasingly being used to discover proteins or protein profiles associated with disease. Experimental design of mass-spectrometry studies has come under close scrutiny and the importance of strict protocols for sample collection is now understood. However, the question of how best to process the large quantities of data generated is still unanswered. Main challenges for the analysis are the choice of proper pre-processing and classification methods. While these two issues have been investigated in isolation, we propose to use the classification of patient samples as a clinically relevant benchmark for the evaluation of pre-processing methods. RESULTS: Two in-house generated clinical SELDI-TOF MS datasets are used in this study as an example of high throughput mass-spectrometry data. We perform a systematic comparison of two commonly used pre-processing methods as implemented in Ciphergen ProteinChip Software and in the Cromwell package. With respect to reproducibility, Ciphergen and Cromwell pre-processing are largely comparable. We find that the overlap between peaks detected by either Ciphergen ProteinChip Software or Cromwell is large. This is especially the case for the more stringent peak detection settings. Moreover, similarity of the estimated intensities between matched peaks is high.We evaluate the pre-processing methods using five different classification methods. Classification is done in a double cross-validation protocol using repeated random sampling to obtain an unbiased estimate of classification accuracy. No pre-processing method significantly outperforms the other for all peak detection settings evaluated. CONCLUSION: We use classification of patient samples as a clinically relevant benchmark for the evaluation of pre-processing methods. Both pre-processing methods lead to similar classification results on an ovarian cancer and a Gaucher disease dataset. However, the settings for pre-processing parameters lead to large differences in classification accuracy and are therefore of crucial importance. We advocate the evaluation over a range of parameter settings when comparing pre-processing methods. Our analysis also demonstrates that reliable classification results can be obtained with a combination of strict sample handling and a well-defined classification protocol on clinical samples.

Validation of existing prognostic models in patients with early-stage cervical cancer.

OBJECTIVE: Models that predict survival and recurrence in patients with early-stage cervical cancer are important tools in patient management. We validated 12 existing prognostic models in an independent population of patients with early-stage cervical cancer. MATERIALS AND METHODS: We searched the literature for prognostic models in patients with surgically treated early-stage cervical cancer. The prognostic performance of these models was assessed in a consecutive group of surgically treated patients with early-stage cervical cancer treated in our hospital between 1982 and 2004. The performance of the models was visually assessed with calibration plots, which display the relation between the predicted and observed survival. RESULTS: Twelve published prognostic models met the inclusion criteria. The models categorized the patients into two to four risk groups. Prognostic factors most frequently used in these models were depth of invasion, lymph node metastasis, vascu/vascular space involvement, and tumor size. The models were validated in 563 consecutive patients with early-stage cervical cancer. All of the models underestimated the recurrence-free survival or disease-specific survival in our patients. Only two models performed reasonably well in our population. The use of more than three prognostic categories in the models was not meaningful. CONCLUSION: In general, the models underestimated the survival. Only 2 of the 12 prognostic models for patients with early-stage cervical cancer were valid for the prediction of the recurrence-free or disease-specific survival in our patient population.

Frequency of pelvic lymph node metastases and parametrial involvement in stage IA2 cervical cancer: a population-based study and literature review.

UNLABELLED: The frequency of lymph node metastases in stage IA2 cervical cancer is reported to range from 0% to 9.7%. Treatment recommendations vary likewise from a cone biopsy to a Wertheim radical hysterectomy and pelvic lymph node dissection. The objective of this study was to get insight into the true frequency of lymph node metastases and/or parametrial involvement in stage IA2 cervical cancer. METHODS: : The hospital records of 48 patients with stage IA2 cervical carcinoma who registered from 1994 to 2006 were reviewed, and a literature search was performed. RESULTS: : Of 48 registered patients, 14 were confirmed to have stage IA2. No lymph node metastases or parametrial invasion and recurrences were found. The collated literature data showed a risk of lymph node metastases of 4.8% (range, 0%-9.7%). The presence of adenocarcinoma and the absence of lymph vascular space invasion resulted in a low risk on lymph node metastases (0.3% and 1.3%, respectively). Parametrial involvement has not been reported. CONCLUSIONS: : The risk of the selected patients with stage IA2 cervical cancer on lymph node metastases is low. In patients with stage IA2 squamous cell cancer with lymph vascular space invasion, a standard pelvic lymph node dissection should be recommended. Parametrectomy should be included if the nodes are positive. In the other patients, the treatment can be individualized and does not have to include lymph node dissection or parametrectomy.