Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer.

BACKGROUND: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. MATERIALS AND METHODS: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. RESULTS: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. CONCLUSIONS: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.

Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option.

BACKGROUND: Ovarian cancer remains the most deadly gynecologic cancer with the majority of patients relapsing within 3 years of diagnosis. Traditional treatment paradigms linked to platinum sensitivity or resistance are currently being questioned in the setting of new diagnostic methods and treatment options. DESIGN: Authors carried out review of the literature on key topics in treatment of recurrent epithelial ovarian cancer (EOC) when platinum is still an option; including secondary surgical cytoreduction, chemotherapy, novel treatment options, and maintenance therapy. A treatment algorithm is proposed. RESULTS: Molecular characterization of EOC is critical to help guide treatment decisions. The role of secondary cytoreductive surgery is currently being evaluated with results from Gynecologic Oncology Group (GOG) 213 and anticipated results from DESKTOP III clinical trials. Chemotherapy backbone has remained relatively unchanged but utilizing non-platinum-based regimens is under investigation. In addition, maintenance therapy with anti-angiogenic therapy and Poly (ADP-ribose) Polymerase (PARP) inhibitors has emerged as the standard of care. Novel combinations, including immunotherapy and anti-angiogenesis agents, may further change the current landscape. CONCLUSIONS: The treatment of recurrent EOC is rapidly changing. Clinical trial design will need to continue to evolve as many novel therapies move to the upfront setting. Ultimately, the treatment of patients with recurrent EOC must incorporate individual patient and tumor factors.

Dual progestin therapy for fertility-sparing treatment of grade 2 endometrial adenocarcinoma.

•A case of grade 2 endometrial adenocarcinoma in a young woman desiring fertility-sparing treatment•Successful conservative management of refractory endometrial adenocarcinoma with dual progestin therapy•A brief review of conservative management in endometrial adenocarcinoma.

Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.

Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Quality of life after radical trachelectomy for early-stage cervical cancer: A 5-year prospective evaluation.

OBJECTIVES: To longitudinally assess quality of life (QOL) in women undergoing radical trachelectomy for early-stage cervical cancer. METHODS: We prospectively enrolled patients with stage IA1-IB1 cervical cancer prior to undergoing radical trachelectomy to complete validated QOL instruments. These instruments included the General Health-Related QOL (SF-12), Functional Assessment of Cancer Therapy-Cervix (FACT-Cx), MD Anderson Symptom Inventory (MDASI), Female Sexual Functioning Index (FSFI), and Satisfaction with Decision scale (SWD). Instruments were filled out at baseline, postoperatively at 6weeks, 6months, 1year, and annually thereafter for 4years. RESULTS: Thirty-nine patients enrolled in the study, and 32 patients were evaluable. The scores for FSFI-arousal (p=0.0002), lubrication (p<0.0001), orgasm (p=0.006), pain (p=0.01), satisfaction (p=0.03) and total score (p=0.004) showed a significant decline at 6weeks then returned to baseline levels by 6 months. The scores for FACT-Cx functional well-being (p=0.02) and physical well-being (p<0.0001), SF-12 bodily pain (p<0.0001), physical functioning (p<0.0001), role physical (p<0.0001), role emotional (p=0.03), social functioning (p=0.002), and MDASI total (p=0.04) showed significantly worsened symptoms at 6weeks then returned to baseline by 6months. The scores for FACT-Cx emotional well-being showed significant worsening of symptoms that persisted at 6-weeks (p=0.004), 6months (p=0.007), 1year (p=0.001), 2years (p=0.002), and 4 years (p=0.03). There was no difference in SWD. CONCLUSIONS: Several quality of life assessments decline immediately postoperatively after radical trachelectomy, however, return to baseline thereafter. The long-term emotional impact of this surgery highlights a need for perioperative counseling in these patients.

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Poor oral nutrition after allogeneic stem cell transplantation correlates significantly with severe graft-versus-host disease.

It has previously been shown that enteral nutrition has several advantages compared to parenteral nutrition (PN) in critically ill patients. The nutritional history was studied in 231 patients after allogeneic stem cell transplantation (SCT). Parenteral nutrition was given for a median of 10 (0-74) days. Patients with graft-versus-host disease (GVHD) grades III-IV received more PN (median 20, range 0-67) than patients with GVHD grades 0-II (10, 0-74, P=0.016). Eighty-five (37%) patients were not able to eat anything for a median of 4 days (1-37). We found a correlation between the number of days with no oral intake (before the diagnosis of acute GVHD) and the incidence of acute GVHD grades III-IV. In patients with 1-4 days of no oral intake, the incidence of grades III-IV acute GVHD was 6%, in those with 5-9 days it was 17%, and in those with >9 days it was 38%. On multivariate analysis, we found that more than 9 days with no oral intake was associated with acute GVHD grades III-IV (odds ratio 7.66, confidence interval 1.44-40.7, P=0.016). Poor oral intake early after SCT may be associated with an increased risk of developing severe acute GVHD.

Trends in health inequalities by educational level in a Norwegian total population study.

OBJECTIVE: To describe levels of inequality and trends in self reported morbidity by educational level in a total Norwegian county population in the mid-1980s and mid-1990s. DESIGN: Two cross sectional health surveys at an interval of 10 years in the Nord-Trøndelag Health Study, HUNT I (1984-86) and HUNT II (1995-97). SETTING: Primary health care, total county population study. PARTICIPANTS: Men and women, 25-69 years. MAIN RESULTS: There was a consistent pattern of increasing self reported health problems with decreasing educational level for three health variables: perceived health, any longstanding health problem, and having a chronic condition. A stable or slight decrease in inequalities over time was found. The prevalence odds ratio for perceived health less than good were 2.71 for men (95% confidence intervals (CI): 2.39 to 3.09) and 2.13 for women (95% CI: 1.85 to 2.46) in the first survey, 2.51 for men (95% CI: 2.27 to 2.78) and 2.06 for women (95% CI: 1.88 to 2.26) 10 years later. CONCLUSIONS: The magnitude of the socioeconomic gradients in health in this population seemed somewhat lower than in Norway as a whole and close to the average in studies from other European countries. There was a slight trend towards smaller differences despite rapid structural changes in working life, turbulence in economy, and more people experiencing unemployment.

Revision anterior cruciate surgery with use of bone-patellar tendon-bone autogenous grafts.

BACKGROUND: A prospective study was done to determine the functional results, patient satisfaction, and graft failure rate after fifty-seven consecutive revision replacements of the anterior cruciate ligament with use of a bone-patellar tendon-bone autogenous graft. METHODS: Fifty-four patients (fifty-five operations) were followed in this study. Concurrent operative procedures were performed during the revision procedure in thirty-seven knees (67%). These procedures included repair of a meniscal tear in twenty knees (36%) and reconstruction of deficient posterolateral or medial ligament structures in seventeen knees (31%). Nine knees (16%) had a high tibial osteotomy to correct varus malalignment before the revision operation. The results were evaluated with the Cincinnati Knee Rating System. RESULTS: There were significant improvements in the scores for pain (p < 0.0001), activities of daily living (p < 0.01), sports participation (p < 0.001), patient satisfaction (p < 0.0001), and overall rating of the knee (p < 0.0001). Thirty-three (60%) of the replaced ligaments were functional, nine (16%) were partially functional, and thirteen (24%) had failed. CONCLUSIONS: Many knees (93%) had compounding problems, including articular cartilage damage, prior meniscectomy, loss of secondary ligament restraints, varus malalignment, and concomitant ligament replacement or meniscal repair. Therefore, the results were generally less favorable than those following primary operations. The rate of graft failure was three times higher than our previously reported failure rate after primary replacements of the anterior cruciate ligament with a bone-patellar tendon-bone autogenous graft. Even so, symptoms and functional limitations with regard to daily and sports activities were found to have decreased and patient satisfaction improved. We advocate correction of varus malalignment prior to anterior cruciate procedures. Associated posterolateral ligament deficiencies should be surgically corrected during anterior cruciate procedures to prevent excessive loading on the graft from abnormal lateral tibiofemoral joint opening. Meniscal tears, including complex tears that extend into the avascular zone, can be concurrently repaired successfully during the revision.

Arthroscopic repair of meniscus tears extending into the avascular zone with or without anterior cruciate ligament reconstruction in patients 40 years of age and older.

PURPOSE: The purpose of this study was to prospectively determine the outcome of meniscal repairs for tears that extended into the central one-third zone of the meniscus, or had a rim width of 4 mm or greater, in a case series of patients 40 years of age and older. TYPE OF STUDY: Prospective case series. MATERIALS AND METHODS: Thirty meniscal repairs in 29 patients were evaluated by a comprehensive examination (28 repairs) a mean of 34 months postoperatively, by follow-up arthroscopy (6 repairs) a mean of 24 months postoperatively, or both. The mean age of the patients at the time of the meniscal repair was 45 years (range, 40 to 58 years). Twenty-one patients (72%) also had ruptures of the anterior cruciate ligament, which were reconstructed at the time of the meniscal repair with bone-patellar tendon-bone autografts (16 patients) or allografts (5 patients). The Cincinnati Knee Rating System was used to rate symptoms, functional limitations with sports and daily activities, patient perception of the knee condition, and sports and occupational rating levels. RESULTS: At a mean of 33 months postoperatively, 26 meniscal repairs (87%) were asymptomatic for tibiofemoral joint symptoms and had not required subsequent surgery. Three repairs failed to heal, requiring partial meniscectomy, and 1 knee with tibiofemoral symptoms related to the repair was treated conservatively. There was no significant effect of the side of the meniscal repair, chronicity of injury, or condition of the articular cartilage on the presence of tibiofemoral symptoms or meniscal resection. Concomitant anterior cruciate ligament reconstruction appeared to increase the rate of asymptomatic meniscal repairs. The patient rating of overall knee condition was normal/very good in 76%, good in 12%, and fair/poor in 12%. CONCLUSIONS: In athletically active patients, we recommend the preservation of meniscal tissue wherever possible regardless of age, basing indications for the procedure on current and future activity levels.

[The problem-based medical curriculum in Trondheim--did it turn out as planned?]. / Det problembaserte legestudiet i Trondheim--ble det slik det var planlagt?

BACKGROUND: A problem-based (PBL) medical curriculum was implemented in 1993 at the Medical School of the Norwegian University of Science and Technology. The objective of this study was to examine how the planned reduction in scheduled activities, the emphasis on student-centred learning, and the integration of disciplines have been implemented. MATERIAL AND METHODS: The schedules in the old and new programmes were the main sources of data. Each scheduled activity was coded according to discipline taught and chosen learning method. RESULTS: The number of hours spent on scheduled activities was much higher in the new programme (n = 4,009) than in the intended (n = 2,974), and it was even slightly higher than in the old programme (n = 3,785). In contrast to plans there was less student-centered learning, and basic science was mainly taught during the two first years. INTERPRETATION: Contrary to plans, the new curriculum in Trondheim has not become a pure PBL curriculum. It is a hybrid model involving a number of learning methods. A high degree of autonomy of the individual faculty members in the planning, and resistance to change among faculty members may have caused less radical changes. This is not necessarily negative; the new model may be a pragmatic synthesis between new and traditional medical education.

Prevention of permanent arthrofibrosis after anterior cruciate ligament reconstruction alone or combined with associated procedures: a prospective study in 443 knees.

We prospectively determined the effectiveness of an immediate knee motion and early intervention program to prevent permanent motion limitations in a consecutive series of patients who had anterior cruciate ligament autogenous patellar tendon reconstruction for isolated rupture (219 knees) or combined with other procedures (224 knees). The subjects were placed into either a progressive or delayed rehabilitation program and were followed for at least 12 months postoperatively. At follow-up a normal range of motion (0 degrees to at least 135 degrees) was found in 436 knees (98%), and mild losses of extension (-5 degrees) were found in 7 knees. Twenty-three knees (5%) required interventions; 9 had extension casts, 9 had gentle manipulations under anesthesia, 3 had arthroscopic debridements, and 2 had continuous epidural anesthetic and inpatient therapy. All of these 23 knees regained full motion. The 7 patients with mild losses of extension had refused treatment intervention. The 0% incidence rate of permanent arthrofibrosis, and 0.7% reoperation rate for knee motion limitations, demonstrated the effectiveness of our program.

High tibial osteotomy and ligament reconstruction for varus angulated anterior cruciate ligament-deficient knees.

In a consecutive series, we treated 41 young patients who had anterior cruciate ligament deficiency, lower limb varus angulation, and varying amounts of posterolateral ligament deficiency. Seventy-three percent of the patients (N = 30) had lost the medial meniscus and 63% (N = 26) had marked articular cartilage damage in the medial compartment. All patients were treated with high tibial osteotomy and, in the majority (N = 34), anterior cruciate ligament reconstruction a mean of 8 months later. Posterolateral reconstructions were also required in 18 knees. A 100% follow-up was obtained at a mean of 4.5 years after osteotomy. Gait analysis testing was done in 17 knees before and after osteotomy. At follow-up, a reduction in pain was found in 71% (29 knees); elimination of giving way, in 85% (35 knees); and resumption of light recreational activities without symptoms, in 66% (27 knees). The patient rating of the knee condition was normal or very good in 37% (15 knees) and good in 34% (14 knees). The mean Cincinnati Knee Rating Score significantly improved from 63 to 82 points. The mean adduction moment, 35% higher than controls preoperatively, significantly decreased to below normal values postoperatively. Correction of varus alignment was maintained in 33 knees (80%). We recommend osteotomy in addition to ligament reconstructive procedures in these knees with complex injury patterns.

Ligand-dependent interactions of coactivators steroid receptor coactivator-1 and peroxisome proliferator-activated receptor binding protein with nuclear hormone receptors can be imaged in live cells and are required for transcription.

Members of the nuclear receptor superfamily are thought to activate transcription by recruitment of one or more recently identified coactivator complexes. Here we demonstrate that both peroxisome proliferator-activated receptor binding protein (PBP) and steroid receptor coactivator-1 (SRC-1) are required for ligand-dependent transcription of transiently transfected and chromosomally integrated reporter genes by the estrogen receptor (ER) and retinoic acid receptor (RAR). To examine ligand-dependent interactions between nuclear receptors and specific coactivators in living cells, these proteins were tagged with cyan (CFP) and yellow (YFP) mutants of the green fluorescent protein. Fluorescence resonance energy transfer (FRET) from the CFP to the YFP indicated interaction between the receptor and coactivator. CFP fusions to RAR or its ligand-binding domain exhibited rapid ligand-dependent FRET to YFP-tagged nuclear receptor interaction domains of the coactivators SRC-1 and PBP. The ER-ligand-binding domain, unlike RAR, also exhibited some basal interaction with coactivators in unstimulated cells that was abolished by the receptor antagonists tamoxifen or ICI182,780. Inhibition of FRET by tamoxifen but not ICI182,780 could be reversed by estradiol, whereas estradiol-enhanced FRET could not be inhibited by either antagonist, indicating that ligand effects can show varying degrees of hysteresis. These findings suggest that ligand-dependent transcriptional activities of the RAR and ER require concurrent or sequential recruitment of SRC-1 and PBP-containing coactivator complexes.