Incidence of and survival after surgical intervention for bowel obstruction in women with advanced ovarian cancer.

INTRODUCTION: Women with advanced ovarian cancer commonly present with peritoneal disease both at primary diagnosis and relapse, with risk of subsequent bowel obstruction. The aims of this study were to assess the cumulative incidence of and survival after intervention for bowel obstruction in women with advanced ovarian cancer, to identify factors predictive of survival and the extent to which the intended outcome of the intervention was achieved. MATERIAL AND METHODS: Women diagnosed with advanced ovarian cancer stages III and IV in 2009-2011 and 2014-2016 in the Stockholm-Gotland Region in Sweden were identified in the Swedish Quality Registry for Gynecologic Cancer. Through hospital records, types of intended and executed interventions for bowel obstruction were assessed, and as well as when in the course of oncologic treatment, the intervention was performed. Time from first intervention to death was analyzed with survival methodology and proportional hazard regression was used. RESULTS: Of 751 identified women, 108 had an intervention for bowel obstruction. Laparotomy was the most prevalent intervention and was used in 87% (94/108) of all women, with a success rate of 87% (82/94). An intervention for bowel obstruction was performed before or during first line treatment in 32% (35/108) with a cumulative incidence in the whole cohort of 14% (108/751, 95% confidence interval [CI] 11-16). Median survival after intervention for bowel obstruction was 4 months (95% CI 3-6). The hazard of death increased when the intervention was performed after completion of primary treatment (HR 4.46, 95% CI 1.61-12.29, P < 0.01), with a median survival of 3 months. In women subjected to radical surgery during primary treatment, the hazard of death after intervention for bowel obstruction decreased (hazard ratio [HR] 0.54, 95% CI 0.32-0.91, P = 0.02). CONCLUSIONS: Women with advanced ovarian cancer undergoing intervention for bowel obstruction have a dismal prognosis, regardless of which line of oncologic treatment the intervention was performed. In the majority of women an intervention for bowel obstruction was performed in a relapse situation with an even worse survival. Our findings emphasize the importance of a holistic approach in the decision-making before an intervention for bowel obstruction in women with advanced ovarian cancer.

The current status of cell-free human papillomavirus DNA as a biomarker in cervical cancer and other HPV-associated tumors: A review.

Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA), allowing for analysis of tumor DNA in a simple blood test, that is, liquid biopsy. Cervical cancer is one of the most common malignancies among women worldwide and high-risk human papillomavirus (HR-HPV) is the cause of the majority of cases. HR-HPV integrates into the host genome and is often present in multiple copies per cell and should thus also be released as ctDNA. Such ctHPV DNA is therefore a possible biomarker in cervical cancer. In this review, we first give a background on ctDNA in general and then a comprehensive review of studies on ctHPV DNA in cervical cancer and pre-malignant lesions that may develop in cervical cancer. Furthermore, studies on ctHPV DNA in other HPV related malignancies (eg, head-and-neck and anogenital cancers) are briefly reviewed. We conclude that detection of ctHPV DNA in plasma from patients with cervical cancer is feasible, although optimized protocols and ultra-sensitive techniques are required for sufficient sensitivity. Results from retrospective studies in both cervical cancer and other HPV-related malignancies suggests that ctHPV DNA is a promising prognostic biomarker, for example, for detecting relapses early. This paves the way for larger, preferably prospective studies investigating the clinical value of ctHPV DNA as a biomarker in cervical cancer. However, there are conflicting results whether ctHPV DNA can be found in blood from patients with pre-malignant lesions and further studies are needed to fully elucidate this question.

Circulating cell-free tumor human papillomavirus DNA is a promising biomarker in cervical cancer.

OBJECTIVES: Tumor cells release fragments of their DNA into the circulation, so called cell-free tumor DNA (ctDNA) or liquid biopsy. Here, we analyze if cell-free human papillomavirus DNA (ctHPV DNA) is detectable before, during and after treatment, in patients with cervical cancer or pre-malignant lesions that may develop into cervical cancer, and whether ctHPV DNA levels were correlated to patient or tumor characteristics and outcome. Furthermore, total cell-free DNA load is studied using cfAlbumin DNA as a surrogate marker. METHODS: 18 patients with locally advanced CC (LACC), 15 patients with early stage CC (ESCC) and 21 patients with pre-malignant lesions, all with verified HPV16, 18 or 45-positive lesions, were included. Pre- during- and post-treatment plasma were tested for HPV16, 18 & 45 and total cfDNA load using droplet digital PCR. RESULTS: ctHPV DNA was found in 94.4% and 26.7% of pre-treatment plasma of patients with LACC and ESCC respectively, while all samples from patients with pre-malignant lesions were negative. Higher levels of ctHPV DNA were correlated to higher FIGO2018 stage. Patients with LACC and persistent ctHPV DNA at end-of-treatment had significantly worse progression-free survival (PFS) than patients who had cleared the ctHPV DNA (p = 0.007). Patients with total ctDNA-levels above median in pre-treatment plasma had a worse PFS (p = 0.026), compared to patients with total ctDNA-levels below median. CONCLUSION: ctHPV DNA is a promising prognostic biomarker in locally advanced cervical cancer that should be studied further for clinical use.

Open vs minimally invasive radical trachelectomy in early-stage cervical cancer: International Radical Trachelectomy Assessment Study.

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005-2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20-42) years for open surgery vs 31 (18-45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0-31) mm for open surgery and 12 (0.8-40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20-16.70) years for open surgery and 3.1 years (0.02-11.10) years for minimally invasive surgery (P<.001). At 4.5 years, 17 of 358 patients (4.7%) with open surgery and 18 of 288 patients (6.2%) with minimally invasive surgery had recurrence (P=.40). The 4.5-year disease-free survival rates were 94.3% (95% confidence interval, 91.6-97.0) for open surgery and 91.5% (95% confidence interval, 87.6-95.6) for minimally invasive surgery (log-rank P=.37). Post hoc propensity score analysis of recurrence risk showed no difference between surgical approaches (P=.42). At 4.5 years, there were 6 disease-related deaths (open surgery, 3; minimally invasive surgery, 3) (log-rank P=.49). The 4.5-year overall survival rates were 99.2% (95% confidence interval, 97.6-99.7) for open surgery and 99.0% (95% confidence interval, 79.0-99.8) for minimally invasive surgery. CONCLUSION: The 4.5-year disease-free survival rates did not differ between open radical trachelectomy and minimally invasive radical trachelectomy. However, recurrence rates in each group were low. Ongoing prospective studies of conservative management of early-stage cervical cancer may help guide future management.

Time-interval to adjuvant chemotherapy and postoperative management after upper abdominal surgical procedures in advanced ovarian cancer.

INTRODUCTION: In advanced epithelial ovarian cancer (EOC), longer time-interval from surgery to initiation of adjuvant chemotherapy (TITC) is associated with decreased survival. Adding upper abdominal surgical procedures (UAP) increases rates of both complete gross resection and postoperative complications in EOC. Our objective was to investigate the association of UAP and TITC. Moreover, if specific postoperative monitoring after the most prevalent UAP increases early detection and management of complications. MATERIAL AND METHODS: Women diagnosed with EOC 2014-2016 in the Stockholm/Gotland Region in Sweden were identified in the Swedish Quality Registry for Gynaecologic Cancer. The association between UAP and TITC was investigated by multivariable linear regression and adjusted for predefined confounders. The follow-up and detection of postoperative complications after diaphragm resection, splenectomy and cholecystectomy was examined. RESULTS: 240 women were selected for analysis. The TITC in women subjected to UAP was similar with a median of 30 days (p = 0.99). Moreover, despite a higher rate of postoperative and major complications (p < 0.001) and longer hospital stay (p < 0.001), in the adjusted analysis there was no association between UAP and prolonged TITC, with a mean difference of -2.27 days (95% Confidence Interval (CI), -5.99 to -1.45, p = 0.23). After the most prevalent UAP (diaphragm resection, splenectomy and cholecystectomy), eventual postoperative interventions were based on routine clinical management rather than procedure-specific postoperative surveillance. CONCLUSION: UAP does not prolong TITC despite an increased rate of postoperative complications and longer length of hospital stay. Clinical non-specific surveillance is sufficient to detect postoperative complications after the most prevalent UAP.

Ultra-radical upfront surgery does not improve survival in women with advanced epithelial ovarian cancer; a natural experiment in a complete population.

OBJECTIVE: Ultra-radical surgery to achieve complete resection in advanced epithelial ovarian cancer (EOC) has been widely accepted without strong supporting data. Our objective was to assess overall survival after a structured shift to an ultra-radical upfront surgical treatment algorithm and to investigate changes in the distribution of primary treatments after this shift. PATIENTS AND METHODS: In this population-based cohort study, all women with suspected EOC in the Stockholm-Gotland region of Sweden reported to the Swedish Quality Registry for Gynecologic Cancer (SQRGC) and National Cancer Registry (NCR) were selected in two 3-year cohorts, based on year of diagnosis (before (cohort1) or after (cohort 2) change in surgical treatment algorithm) and followed for at least three years. 5-year overall survival (OS) in non-surgically and surgically treated women was analyzed. Moreover, proportional distribution of primary treatment was evaluated. RESULTS: 752 women were included in the final analysis (n = 364 and 388 in cohort 1 and 2 respectively) with a median follow-up of 29 and 27 months. The complete resection rate increased from 37 to 67% (p ≤ 0.001) as well as proportion non-surgically treated women, 24 to 33%. No improvement in OS was observed in non-surgically (HR 0.76 (95% CI, 0.58-1.01); p = 0.06) or surgically treated (HR 0.94 (95% CI, 0.75-1.18); p = 0.59) women, even when complete resection was achieved (HR 1.31 (95% CI, 0.89-1.92); p = 0.17). CONCLUSION: A shift to ultra-radical upfront surgery in EOC did not improve survival despite a significant increase in complete resection rate. Identifying the limitations of surgical treatment remains a challenge.

Surgery performed later in the week is associated with failure to achieve complete radical surgical resection in advanced ovarian cancer.

Background: The surgical treatment of advanced ovarian cancer aims to resect all visible tumor to no gross residual, these procedures are often extensive with need of prolonged attention to detail. Our objective was to investigate the association between week-day of surgery, time of year (season) when surgery was performed and non-radical surgery (surgical failure) in advanced ovarian cancer.Material and methods: Women diagnosed with primary invasive epithelial ovarian cancer in the Stockholm/Gotland Region, Sweden were identified in the regional Swedish Quality Registry of Gynecologic Cancer (SQRGC). Data of all women with International Federation of Gynecology and Obstetrics (FIGO) stages III and IV were validated against the National Cancer Registry. Women subjected to surgery with curative intent were selected and included in the analysis. Uni- and multivariable regression analyses were performed.Results: Out of 538 women identified in the SQRGC-string ovary between 2014 and 2016, 240 were eligible for analysis. In 29% of women, complete radical resection was not achieved. There was a significant trend of increased non-radical resection when surgery was performed from Monday through Thursday (p = .03). The adjusted odds of non-radical surgery increased if surgery was performed on Thursday rather than Monday (Odds Ratio (OR) 3.04, 95% Confidence Interval (CI) 1.05-8.79, p = .04). Surgery performed during summer compared to the rest of the year, did not significantly increase the adjusted odds of non-radical surgery (OR 1.92, 95% CI 0.91-4.07, p = .09).Conclusion: Complete surgical resection of tumor is one of the strongest prognostic factors for survival in advanced epithelial ovarian cancer. For this reason, advanced ovarian cancer surgery should be scheduled early in the week.

Robot-assisted approach to cervical cancer (RACC): an international multi-center, open-label randomized controlled trial.

BACKGROUND: Radical hysterectomy with pelvic lymphadenectomy represents the standard treatment for early-stage cervical cancer. Results from a recent randomized controlled trial demonstrate that minimally invasive surgery is inferior to laparotomy with regards to disease-free and overall survival. PRIMARY OBJECTIVE: To investigate the oncologic safety of robot-assisted surgery for early-stage cervical cancer as compared with standard laparotomy. STUDY HYPOTHESIS: Robot-assisted laparoscopic radical hysterectomy is non-inferior to laparotomy in regards to recurrence-free survival with the advantage of fewer post-operative complications and superior patient-reported outcomes. TRIAL DESIGN: Prospective, multi-institutional, international, open-label randomized clinical trial. Consecutive women with early-stage cervical cancer will be assessed for eligibility and subsequently randomized 1:1 to either robot-assisted laparoscopic surgery or laparotomy. Institutional review board approval will be required from all participating institutions. The trial is coordinated from Karolinska University Hospital, Sweden. MAJOR INCLUSION/EXCLUSION CRITERIA: Women over 18 with cervical cancer FIGO (2018) stages IB1, IB2, and IIA1 squamous, adenocarcinoma, or adenosquamous will be included. Women are not eligible if they have evidence of metastatic disease, serious co-morbidity, or a secondary invasive neoplasm in the past 5 years. PRIMARY ENDPOINT: Recurrence-free survival at 5 years between women who underwent robot-assisted laparoscopic surgery versus laparotomy for early-stage cervical cancer. SAMPLE SIZE: The clinical non-inferiority margin in this study is defined as a 5-year recurrence-free survival not worsened by >7.5%. With an expected recurrence-free survival of 85%, the study needs to observe 127 events with a one-sided level of significance (α) of 5% and a power (1-ß) of 80%. With 5 years of recruitment and 3 years of follow-up, the necessary number of events will be reached if the study can recruit a total of 768 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Trial launch is estimated to be May 2019 and the trial is estimated to close in May 2027 with presentation of data shortly thereafter. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT03719547).

International radical trachelectomy assessment: IRTA study.

BACKGROUND: Radical trachelectomy is considered a viable option for fertility preservation in patients with low-risk, early-stage cervical cancer. Standard approaches include laparotomy or minimally invasive surgery when performing radical trachelectomy. PRIMARY OBJECTIVE: To compare disease-free survival between patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive (laparoscopic or robotic) radical trachelectomy. STUDY HYPOTHESIS: We hypothesize that minimally invasive radical trachelectomy has similar oncologic outcomes to those of the open approach. STUDY DESIGN: This is a collaborative, multi-institutional, international, retrospective study. Patients who underwent a radical trachelectomy and lymphadenectomy between January 1, 2005 and December 31, 2017 will be included. Institutional review board approval will be required. Each institution will be provided access to a study-specific REDCap (Research Electronic Data Capture) database maintained by MD Anderson Cancer Center and will be responsible for entering patient data. INCLUSION CRITERIA: Patients with squamous, adenocarcinoma, or adenosquamous cervical cancer FIGO (2009) stages IA2 and IB1 (≤2 cm) will be included. Surgery performed by the open approach or minimally invasive approach (laparoscopy or robotics). Tumor size ≤2 cm, by physical examination, ultrasound, MRI, CT, or positron emission tomography (at least one should confirm a tumor size ≤2 cm). Centers must contribute at least 15 cases of radical trachelectomy (open, minimally invasive, or both). EXCLUSION CRITERIA: Prior neoadjuvant chemotherapy or radiotherapy to the pelvis for cervical cancer at any time, prior lymphadenectomy, or pelvic retroperitoneal surgery, pregnant patients, aborted trachelectomy (intra-operative conversion to radical hysterectomy), or vaginal approach. PRIMARY ENDPOINT: The primary endpoint is disease-free survival measured as the time from surgery until recurrence or death due to disease. To evaluate the primary objective, we will compare disease-free survival among patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive radical trachelectomy. SAMPLE SIZE: An estimated 535 patients will be included; 256 open and 279 minimally invasive radical trachelectomy. Previous studies have shown that recurrence rates in the open group range from 3.8% to 7.6%. Assuming that the 4.5-year disease-free survival rate for patients who underwent open surgery is 95.0%, we have 80% power to detect a 0.44 HR using α level 0.10. This corresponds to an 89.0% disease-free survival rate at 4.5 years in the minimally invasive group.

A Pilot Study on Diagnostic Performance of Contrast-Enhanced Ultrasonography for Detection of Early Cervical Cancer.

In this cohort study of 49 women with all stages of cervical cancer and 21 healthy controls, we compared contrast-enhanced ultrasonography (CEUS) filling pattern and semi-quantitative parameters in the two groups. Participants were examined with conventional grayscale and power Doppler ultrasound (US) followed by CEUS, using a 2.5 mL bolus of intravenous contrast agent. CEUS video clips were analyzed with regard to contrast distribution (focal or global) and semi-quantitative parameters. Focal contrast distribution was found in 3% (1/32) of the women with no tumor versus 89% (34/38) of women with histologically detectable tumor. A semi-quantitative analysis showed that the amount of contrast over a period of the whole tumor (area under the curve [AUC[ 0.92, 95% confidence interval [CI] 0.87-1.0), and the maximal intensity area (AUC 0.94, 95% CI 0.84-1.0) could accurately distinguish tumors from healthy tissue. In conclusion, the CEUS parameters differ significantly between tumors and healthy cervical tissue.

[Birth asphyxia, neonatal risk factors for hypoxic ischemic encephalopathy]. / Fósturköfnun og heilakvilli--áhaettuthaettir og afleidingar fyrir nýbura.

OBJECTIVE: Neonates suffering from severe birth asphyxia may develop hypoxic ischemic encephalopathy (HIE), some of which develop permanent neurological damage. As the incidence of asphyxia and HIE in Iceland is unknown, this study was conducted. Furthermore, we evaluated the association between some neonatal risk factors and the development of HIE. MATERIAL AND METHODS: All term infants born at LSH from 1997-2001 with birth asphyxia, defined as 5 minute Apgar score or=<6, were included in the study. Clinical information, length and weight, Apgar scores at 1, 5 and 10 minutes normoblasts count, initial pH and hemoglobin levels were retrospectively collected. RESULTS: The incidence of HIE after birth asphyxia was 1.4/1000. The infants who developed HIE had significantly lower birth weight and Apgar scores at one, five and ten minutes. They also had lower umbilical artery pH, had more base deficit and lower serum bicarbonate concentrations than the infants who did not develop HIE. CONCLUSION: The incidence of HIE was low compared to other studies. Birth asphyxia resulting in HIE is associated with lower birth weight, Apgar scores, pH and neonatal hemoglobin levels at birth. We conclude that neonates with low hemoglobin level are at increased risk for developing HIE and that low pH and Apgar scores may predict worse outcomes after birth asphyxia.

[Birth asphyxia and hypoxic ischemic encephalopathy, incidence and obstetric risk factors]. / Fósturköfnun og heilakvilli af völdum súrefnisthurrdar--tídni og áhaettuthaettir á medgöngu og í faedingu.

OBJECTIVE: Modern medical practice has changed dramatically during the past decades because of improved technology. Still, fetal surveillance during labor is relatively unchanged since 1960 s when fetal heart rate monitoring (FHR) became standard practice. Newborn infants are still suffering from birth asphyxia and in severe cases leading to hypoxic ischemic encephalopathy (HIE) which sometimes results in permanent neurological damage. The incidence of birth asphyxia and HIE in Iceland is unknown and so are the risk factors for severe asphyxia. The objective of this study was to assess the incidence, obstetric risk factors and the sequela of severe asphyxia at Landspitali university hospital (LSH). MATERIAL AND METHODS: All term infants born at LSH from 1.1.1997- 31.12.2001 with birth asphyxia, defined as five minute Apgar score %lt;6, were included in the study (n=127). Clinical information were collected retrospectively from maternal records on maternal diseases during pregnancy, cardiotocogram (CTG), type of birth, the presence of meconium and operative delivery rates. Information was also collected regarding birth asphyxia and HIE in the neonatal period. RESULTS: The incidence of birth asphyxia was 9.4/1000 live term births during the study period, with increasing incidence during the three last years. The incidence of HIE was 1.4/ 1,000 live term births. Severe maternal diseases during pregnancy were not a significant risk factor for asphyxia. The amniotic fluid was meconium stained in fifty percent of cases and the umbilical cord was wrapped around the fetal neck in 41% of cases. Abnormal CTG tracing was observed in 66% of cases in the study group and in 79% of the HIE cases. Operative deliveries were significantly more common in the study cohort compared with other deliveries at LSH at the same time: ventouse delivery 22% vs 6.8% (p<0,001), forceps delivery 6.3% vs 1,03% (p<0,001), emergency cesarean section 19.7% vs 11.4% ( p=0,008). CONCLUSION: The incidence of birth asphyxia is higher in LSH compared with the incidence found in other studies. Signs of fetal distress on CTG and delivery with operative interventions are common. With current available methods to detect intrapartum asphyxia there is a poor correlation with CTG and the development of HIE after severe asphyxia. The presence of severe maternal diseases does not correlate with increased incidence of asphyxia, presumably due to increased surveillance of these pregnancies and a lower treshold for intervention during delivery. In low risk pregnancies there is a lack of appropriate methods with high sensitivity and specificity to detect intrapartum asphyxia.

[Postgraduate medical education in Iceland; medical students' and residents' attitude]. / Afstada unglaekna og laeknanema til sérfraedináms á Islandi.

BACKGROUND: Various parties have expressed interest in establishing formal postgraduate medical education programs. The interest of residents and medical students to such programs in Iceland has not been evaluated before. METHODS: A questionnaire was sent to 146 interns and residents and 84 senior medical students. The following variables were analyzed: Gender, attitude towards postgraduate training in Iceland, interest to participate in such training, preferred specialty and which factors might influence their decision. RESULTS: 100 subjects completed the questionnaire (response rate 45%), 61 interns and residents and 39 medical students. Of those completing the questionnaire, most interns and residents (97%) and medical students (87%) agreed or agreed strongly with the concept of postgraduate training in Iceland. The majority of responders wanted to undergo part of their postgraduate training in Iceland if this option would be available. Those who preferred postgraduate training in Iceland did so for the following reasons: The importance of "hands-on" training, availability of consultants, favorable social setting and organized teaching. Those who wanted to do all their postgraduate training abroad rated case variability, "hands-on" training, organized teaching and research opportunities as the main factors influencing their decision. CONCLUSIONS: Interns, residents and medical students are in favor of undergoing part of their postgraduate training in Iceland. Those who chose to train abroad rated case variability and research opportunities higher than those in favor of training in Iceland.