NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Time to first recurrence, pattern of recurrence, and survival after recurrence in endometrial cancer according to the molecular classification.

OBJECTIVE: Despite its generally favorable prognosis at primary diagnosis, recurrence of endometrial cancer remains an important clinical challenge. The aim of this study was to analyze the value of molecular classification in recurrent endometrial cancer. METHODS: This study included patients with recurrent endometrial cancer who underwent primary surgical treatment between 2004 and 2015 at the Karolinska University Hospital, Sweden and the Bern University Hospital, Switzerland (KImBer cohort) with molecular classification of the primary tumor. RESULTS: Out of 594 molecularly classified endometrial cancer patients, 101 patients experienced recurrence, consisting of 2 POLEmut, 33 MMRd, 30 p53abn, and 36 NSMP tumors. Mean age at recurrence was 71 years and mean follow-up was 54 months. Overall, median time to first recurrence was 16 months (95% CI 12-20); with the shortest median time in MMRd patients, with 13 months (95% CI 5-21). The pattern of recurrence was distinct among molecular subgroups: MMRd tumors experienced more locoregional, while p53abn cases showed more abdominal recurrences (P = .042). Median survival after recurrence was best for MMRd cases (43 months, 95% CI 11-76), compared to 39 months (95% CI 21-57) and 10 months (95% CI 7-13) for the NSMP and p53abn cases respectively (log-rank, P = .001). CONCLUSION: Molecular classification is a significant indicator of survival after recurrence in endometrial cancer patients, and patterns of recurrence differ by molecular subgroups. While MMRd endometrial cancer show more locoregional recurrence and the best survival rates after recurrence, p53abn patients experience abdominal recurrence more often and had the worst prognosis of all recurrent patients.

Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis.

OBJECTIVE: The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received ≥2 previous lines of platinum-based chemotherapy. METHODS: In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. RESULTS: Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 9.2 months (95% confidence interval [CI], 7.6-10.9) in the overall population. At 12 and 18 months, 38.5% and 24.3% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 7.3 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. CONCLUSION: Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.

Elderly gynaecological cancer patients at risk for poor end of life care: a population-based study from the Swedish Register of Palliative Care.

Introduction: Poorer end-of-life (EOL) care for elderly cancer patients has been reported. We assessed the impact of age on 13 indicators for the quality of EOL care as well as adherence to 6 national quality indicators in gynaecological cancer patients.Methods: Age-dependent differences in 13 palliative care quality indicators were studied in gynaecological cancer patients registered in the population-based Swedish Register of Palliative Care. Association between the patient's age and each quality indicator was analyzed by logistic regression, adjusted for place of death where appropriate. Adherence to six national quality indicators determined by the Swedish National Board of Health and Welfare was estimated in all patients.Results: We included 3940 patients with the following age distribution: 1.6% were 18-39 years of age, 12.3% 40-59 years, 37.2% 60-74 years, 28.9% 75-84 years and 20% were ≥85 years. Age-dependent differences in implementation rate were present for some of the 13 quality indicators. Compared to elderly cancer patients, younger patients were more likely to be cared for by a specialized palliative care service, more often informed about imminent death as well as assessed for pain. For most national quality indicators, the goal level was not met. Only for the 'on demand prescription for pain', the goal level was reached.Conclusions: EOL care did not meet national quality indicators in this population-based data from Sweden, in particular in the elderly population. Elderly gynaecological cancer patients are at high risk of poorer EOL care without the involvement of specialized palliative care services. Palliative care services need to be implemented across all institutions of EOL care to ensure good and equal care.

Poor concordance between CA-125 and RECIST at the time of disease progression in patients with platinum-resistant ovarian cancer: analysis of the AURELIA trial.

BACKGROUND: Data on CA-125 as a predictor of disease progression (PD) in ovarian cancer come predominantly from patients with platinum-sensitive disease receiving chemotherapy alone. We assessed concordance between CA-125-defined and RECIST-defined PD using data from the Gynecologic Cancer InterGroup (GCIG) randomized phase III AURELIA trial in platinum-resistant ovarian cancer (PROC). PATIENTS AND METHODS: Patients with PROC were randomized to receive single-agent chemotherapy with or without bevacizumab. PD by CA-125 was defined according to GCIG criteria (except that confirmatory CA-125 measurement was not required). This exploratory analysis included patients with RECIST PD and a CA-125 reading ≤28 days before and ≤21 days after RECIST-defined PD. RESULTS: Of 218 eligible patients, only 94 (43%, 95% confidence interval 36% to 50%) had concordant RECIST and CA-125 PD status (42% in the chemotherapy-alone arm; 45% in the bevacizumab combination arm, P = 0.6). There was no evidence of CA-125-defined PD in the remaining 124 patients despite PD according to imaging. There were no significant differences in baseline characteristics between patients with PD defined by both RECIST and CA-125 and those with RECIST-only PD. CA-125 was even less sensitive in detecting PD in patients with early (<8 weeks after randomization) compared with later RECIST-defined PD (69% versus 53%, respectively, not meeting CA-125 criteria; P = 0.053). There was no significant difference in survival after PD in patients with concordant PD by RECIST and CA-125 versus those with PD only by RECIST. We validated our findings in an independent study population of PROC. CONCLUSIONS: In this platinum-resistant population, PD was typically detected earlier by imaging than by CA-125, irrespective of bevacizumab treatment. Disease status by CA-125 at the time of PD was not prognostic for overall survival. Regular radiologic assessment as well as symptom benefit assessment should be considered during PROC follow-up.

Body mass index and the risk of meningioma, glioma and schwannoma in a large prospective cohort study (The HUNT Study).

BACKGROUND: Obesity increases the risk for a number of solid malignant tumours. However, it is not clear whether body mass index (BMI) and height are associated with the risk of primary tumours of the central nervous system (CNS). METHODS: In a large population study (The Nord-Trøndelag Health Study (HUNT Study)) of 74 242 participants in Norway, weight and height were measured. During follow-up, incident CNS tumours were identified by individual linkage to the Norwegian Cancer Registry. Sex- and age-adjusted and multivariable Cox regression analyses were used to evaluate BMI and height in relation to the risk of meningioma, glioma and schwannoma. RESULTS: A total of 138 meningiomas, 148 gliomas and 39 schwannomas occurred during 23.5 years (median, range 0-25) of follow-up. In obese women (BMI ≥ 30 kg m(-2)), meningioma risk was 67% higher (hazard ratio (HR)=1.68, 95% confidence interval (CI): 0.97-2.92, P-trend=0.05) than in the reference group (BMI 20-24.9 kg m(-2)), whereas no association with obesity was observed in males. There was no association of BMI with glioma risk, but there was a negative association of overweight/obesity (BMI ≥ 25 kg m(-2)) with the risk of schwannoma (HR=0.48, 95% CI: 0.23-0.99). However, the schwannoma analysis was based on small numbers. Height was not associated with the risk for any tumour subgroup. CONCLUSION: These results suggest that BMI is positively associated with meningioma risk in women, and possibly, inversely associated with schwannoma risk.

Pelvic exenteration for vulvar cancer: Postoperative morbidity and oncologic outcome - A single center retrospective analysis.

BACKGROUND: Pelvic exenteration may be the only curative treatment for some patients with primary advanced or recurrent vulvar cancer but is associated with high morbidity. This study evaluated the clinical outcome of patients treated at a centralized service in Norway. METHODOLOGY: This retrospective study included patients treated with pelvic exenteration for primary locally advanced or recurrent vulvar cancer between 1996 and 2019 at Oslo University Hospital, Norway. Complications were coded according to the contracted Accordion classification. Relapse free survival (RFS), cancer specific survival (CSS) and overall survival (OS) were estimated with the Kaplan Meier method. RESULTS: The 30 patients were followed for a median of 4.94 years (95%CI: 3.37-NR). Exenteration due to primary vulvar cancer was carried out in 16 (53%) patients, 14 (47%) had recurrent vulvar cancer. Free histopathological margins were achieved in 28 (93%) patients. The 90 days morbidity for grade 3 complications was 63%, predominantly wound/surgical flap infections, 7% had no complications. 90 days mortality was 3%. Five-year RFS was 26% (95% CI 8-48%), OS was 50% (95%CI: 29-69%) and CSS was 64% (95% CI 43-79%). There was no significant difference in survival between patients with primary vs recurrent disease. The 3-year CSS for patients with negative lymph nodes and positive lymph nodes was 70% (95% CI 47-84%) and 30% (95% CI 1-72%), respectively. CONCLUSIONS: Acceptable oncologic outcomes after pelvic exenteration for primary and recurrent vulvar cancer can be achieved if surgery is centralized. Careful patient selection is imperative due to significant postoperative morbidity and considerable risk of relapse.

First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)--a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG.

BACKGROUND: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel. PATIENTS AND METHODS: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients). RESULTS: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC. CONCLUSION: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.

[Long term results of transseptal suture of the middle turbinate during sinus surgery]. / Langzeitergebnisse der transseptalen Naht der mittleren Nasenmuscheln bei Siebbeinoperationen.

BACKGROUND: Synechia formation between the middle turbinate (MT) and the lateral nasal wall is a common postoperative complication in endoscopic sinus surgery (ESS) often resulting in revision surgery. To keep the middle meatus open several procedures were described in order to medialise the MT. Long term results of these techniques are missing. The purpose of the study was to evaluate the long term results of fixing the heads of the MT to the septum by a resorbable septal-turbinate-suture (STS). MATERIAL AND METHODS: 17 patients were included in the retrospective study. All patients underwent ESS with STS because of chronic rhinosinusitis with (8) and without polyps (9). The median follow-up was 81 months (range, 36-105 months). In a total 34 nasal cavities were postoperatively examined by endoscopy. Additionally, rhinomanometry and olfaction test were performed. RESULTS: The MT was found in a central position in between septum and lateral wall in 10 nasal cavities (30 % ), in a more medial position in 24 (70 % ) and none in a lateral position. Only 2 patients presented unilateral synechia to the lateral wall and one unilateral to the septum. CONCLUSIONS: Synechia of the MT to the lateral nasal wall in ESS can be effectively avoided by a STS. The long term results showed that STS maintains the MT in a medial position with a free middle meatus without impairing the olfactory function.

The impact of BMI on subgroups of uterine cancer.

BACKGROUND: Obesity increases the risk of uterine cancer, but results by histological type have differed. METHODS: We followed 36,755 women for 17.8 years for uterine cancers. RESULTS AND CONCLUSION: Body mass index (BMI) was positively associated with uterine cancers as a whole, particularly for endometrioid adenocarcinomas, for which the relative risk for very obese women (BMI: > or = 40 kg m(-2)) compared with lean (BMI: 20-24 kg m(-2)) women, was 11.1 (95% confidence interval: 5.2-23.8).

Body mass, diabetes and smoking, and endometrial cancer risk: a follow-up study.

We examined the relationship of body mass index (BMI), diabetes and smoking to endometrial cancer risk in a cohort of 36 761 Norwegian women during 15.7 years of follow-up. In multivariable analyses of 222 incident cases of endometrial cancer, identified by linkage to the Norwegian Cancer Registry, there was a strong increase in risk with increasing BMI (P-trend <0.001). Compared to the reference (BMI 20-24 kg m(-2)), the adjusted relative risk (RR) was 0.53 (95% confidence interval (CI): 0.19-1.47) for BMI<20 kg m(-2), 4.28 (95% CI: 2.58-7.09) for BMI of 35-39 kg m(-2) and 6.36 (95% CI: 3.08-13.16) for BMI>or=40 kg m(-2). Women with known diabetes at baseline were at three-fold higher risk (RR 3.13, 95% CI: 1.92-5.11) than those without diabetes; women who reported current smoking at baseline were at reduced risk compared to never smokers (RR 0.55, 95% CI: 0.35-0.86). The strong linear positive association of BMI with endometrial cancer risk and a strongly increased risk among women with diabetes suggest that any increase in body mass in the female population will increase endometrial cancer incidence.

Administration of the cytoprotectant amifostine.

This article provides guidelines for the use of amifostine (Ethyol, Alza Pharmaceuticals, Palo Alto, CA, and U.S. Bioscience, Inc., West Conshohocken, PA), a pancytoprotective agent approved for reducing renal toxicity associated with cisplatin administration in patients with advanced ovarian or non-small cell lung cancer. Pretreatment with amifostine reduces the incidence of serious and cumulative chemotherapy-induced toxicities, thus improving quality of life, and allows administration of optimal doses and scheduling of chemotherapy and radiation therapy, translating into improved survival. Practical guidelines for administration of amifostine are provided in an effort to ameliorate emesis, amifostine's principle side effect.

[Cystoid macular edema and visual acuity with intracapsular cataract extraction and Choyce anterior chamber lens vs. extracapsular cataract extraction and posterior chamber lens in the partner eye]. / Zystoides Makulaödem und Sehschärfe bei ICCE und Choyce-VKL vs. ECCE und HKL am Partnerauge.

A prospective study was conducted on 65 patients who had a cataract operation. One eye had intracapsular cataract extraction (ICCE) with a Choyce-IX anterior chamber lens (ACL) and the fellow eye extracapsular cataract extraction (ECCE) with a posterior chamber lens (PCL). To evaluate the cystoid macular edema (CME), a fluorescence angiogram was recorded on the day of discharge and after 6 months. The severity of the CME was classified in three stages (degrees I-III). At discharge, no eye had CME grade III. CME grade I or grade II was seen in the ICCE group in 23% and in the ECCE group in 7.6%. After 6 months one eye of each group showed CME grade III (1.5%). CME grades I and II were seen after ICCE in 13.8% and 7.8% while the eyes with ECCE presented CME in 6.1% of grade I and of grade II, respectively. Visual acuity (VA) in the eyes with grades I and II CME was the same as in eyes without CME. The VA (median) of the ICCE group was 0.8 and of the ECCE 0.7. Because of infection of the capsular bag (toxic lens syndrome), in one case the PCL together with the capsular bag had to be explanted after 7 months. As for visual acuity and clinically significant CME (grade III), there was no statistical difference between ICCE plus Choyce-IX ACL eyes versus ECCE plus PCL eyes in the same patient.

Differential expression of c-Met, its ligand HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue.

AIMS: Tyrosine kinase receptors Her2/neu and c-Met play an important role in breast cancer development and progression. Our aim was to determine the expression of c-Met, its ligand hepatocyte growth factor/scatter factor (HGF/SF) and Her2/neu in ductal carcinoma in situ (DCIS) lesions of the breast (n = 39) by two different immunocytochemical techniques, classical immunohistochemistry and immunofluorescence, and to correlate their expression levels with histopathological and clinical characteristics. METHODS AND RESULTS: Both methods revealed similar c-Met staining patterns in both the in situ component and the adjacent normal tissue (P < 0.001). However, an imbalance in c-Met expression between tumour and surrounding normal tissue was correlated with high-grade DCIS (Van Nuys Grade 3). No correlation existed between Her2/neu and c-Met expression. High HGF/SF immunoreactivity was observed in 43.6% of the cases, yet the adjacent cellular stroma revealed only low levels of HGF/SF. No correlation existed between c-Met, Her2/neu or HGF/SF expression and clinicopathological factors. CONCLUSION: An imbalance in c-Met expression between tumour and surrounding normal tissue is associated with an aggressive DCIS phenotype. Moreover, c-Met and HGF/SF may contribute to tumour development by different means than those controlled by Her2/neu.

[Total calcium or ionized calcium? A comparative study]. / Gesamtcalcium oder ionisiertes Calcium? Eine vergleichende Studie.

Determining ionized calcium after CO2 equilibration of serum with subsequent electronic conversion to pH 7.40 (Ca2+corr) gives a practicable value for the diagnosis of calcium metabolism. "Anaerobic" sampling, necessary for the measurement of the actual calcium ion concentration, is obviated. Protein or albumin concentration in serum and complex-bound calcium do not interfere. Comparison of sera from 54 patients with bone metastases or myeloma, as well as from 300 patients with other diseases, indicate that the sensitivity of Ca2+corr in the diagnosis of hypercalcaemia is about twice or three times that of total calcium and that the latter's specificity - at least when ignoring protein concentration - is unsatisfactory with 18-45% "falsely" reduced values.

Two-dimensional granular flow in a vibrated small-angle funnel

We have studied the flow of a single layer of uniform balls in a small-angle funnel when it is vibrated parallel to the flow. Generally, we measured the flow rate as a function of a dimensionless acceleration Gamma. However, for sufficiently small outlet widths, the flow can jam so we also measured the elapsed times between balls and their correlations to study jam dynamics. In particular, we found that when the funnel angle beta was larger than approximately 4 degrees, a stable jam always formed for Gamma<1 and the flow stopped. For Gamma approximately 1-4, jams still occurred, but now they broke and reformed, although they could last approximately 100 s, resulting in long-time correlations in the flow. The elapsed time distributions in this case show distinct, possibly algebraic, tails. Beyond Gamma approximately 4, the flow no longer jammed and the flow rate became constant. The general behavior has been mapped out in a rough phase diagram.