Cumulative Complete Response Research Articles

Suspected myometrial invasion on MRI is correlated with worse outcomes of fertility-preserving treatment in young women with endometrial cancer

PurposeMyometrial invasion of endometrial cancer (EC) impairs the effectiveness of progestin-based treatment and results in high risks of disease progression and relapse. However, it is difficult to decide whether myometrial invasion exists when suspected endometrial invasion is detected on magnetic resonance imaging (MRI). This study developed an MRI-guided hysteroscopic precise en bloc resection method to actually diagnose myometrial invasion in patients with EC and suspected myometrial invasion on MRI. The fertility-preserving outcomes of patients with EC and suspected myometrial invasion on MRI but negative pathological findings after en bloc resection was also evaluated.Materials and methodsEC patients with suspected myometrial invasion on MRI (n = 38) were prospectively enrolled and evaluated. Suspected myometrial invasion was identified on MR images and resected via an en bloc resection technique (resecting the endometrial lesion, basal layer, and underneath myometrium en bloc) under hysteroscopy for pathological examination. Patients with negative pathological findings received progestin-based conservative therapy. The clinical characteristics and fertility-preserving outcomes of these patients were compared with those of patients without any evidence of myometrial invasion on MRI (n = 98, reference group).ResultsAmong patients with suspected myometrial invasion on MRI, myometrial invasion was pathologically excluded in 29 patients (non-MI group). The cumulative complete response rate was lower in the non-MI group than in the reference group at the 8th month (43.4% vs. 64.9%, P = 0.040) and was not significant at the 18th month (87.5% vs. 96.8%, P = 0.11). The 24-month cumulative relapse rate was 31.2% in the non-MI group, versus 0% in the reference group (P < 0.0001).ConclusionMyometrial invasion was pathologically confirmed in approximately one-fourth of patients with suspected myometrial invasion on MRI. However, suspected myometrial invasion on MRI with negative pathological findings was correlated with worse fertility-preserving outcomes in young women with endometrial cancer.

Treatment of extramammary Paget disease with imiquimod in a real-life setting: a multicentre retrospective analysis in Spain.

Topical imiquimod has been shown to be an effective treatment for extramammary Paget disease (EMPD), although available evidence supporting its use is based on case reports and small series of patients. To investigate the therapeutic outcomes and analyse potential clinicopathological factors associated with the imiquimod response in a large cohort of patients with EMPD. Retrospective chart review of 125 patients with EMPD treated with imiquimod at 20 Spanish tertiary-care hospitals. During the study period, patients received 134 treatment regimens with imiquimod, with 70 (52.2%) treatments achieving a complete response (CR), 41 (30.6%) a partial response and 23 (17.2%) no response. The cumulative CR rates at 24 and 48 weeks of treatment were 46.3% and 71.8%, respectively, without significant differences between first-time and previously treated EMPD. Larger lesions (≥ 6 cm; P = 0.04) and EMPD affecting > 1 anatomical site (P = 0.002) were significantly associated with a worse treatment response. However, the CR rate did not differ significantly by the number of treatment applications (≤ 4 vs. > 4 times per week; P = 0.112). Among patients who achieved CR, 30 of 69 (43%) treatments resulted in local recurrences during a mean follow-up period of 36 months, with an estimated 3- and 5-year recurrence-free survival of 55.7% and 36.4%, respectively. Imiquimod appears as an effective therapeutic alternative for both first-line and previously treated EMPD lesions. However, a less favourable therapeutic response could be expected in larger lesions and those affecting > 1 anatomical site. Based on our results, a three to four times weekly regimen of imiquimod with a treatment duration of at least 6 months could be considered an appropriate therapeutic strategy for patients with EMPD.

Outcomes of fertility preservation treatments in patients with endometrial cancer with different molecular classifications based on an NGS panel.

The molecular classification of endometrial cancer has previously been shown to be associated with clinical outcomes. However, there are insufficient data to support the routine use of molecular classification for the treatment of patients seeking fertility preservation. Here, we retrospectively investigated 90 patients received fertility-sparing treatment. We used a next generation sequencing (NGS) panel to classify these patients into four subtypes. All patients received hormonal therapy combined with hysteroscopy. Therapeutic effects were evaluated by hysteroscopy every three months during the treatment. Patients with POLE mutations had the highest disease progression rate (50.0%, P=0.013), while the microsatellite instability-high (MSI-H) group had the highest recurrence rate (50.0%, P=0.042). PIK3CA mutation (hazard ratio (HR): 0.61; 95% confidence interval (CI): 0.37-0.99; P=0.046), overweight (HR: 0.56; 95% CI: 0.32-0.96; P=0.033) and obesity (HR: 0.44; 95% CI: 0.20-0.95; P=0.036) were associated with a significantly lower cumulative complete response (CR) rate. The combination of gonadotropin-releasing hormone analogues (GnRH-a) and letrozole (HR: 3.43; 95% CI: 1.81-6.52; P< 0.001) was associated with a significantly higher cumulative CR rate. KRAS mutation was significantly associated with disease progression (P=0.002). In wild-type TP53 patients, PTEN and PIK3CA mutations significantly prolonged the duration of treatment to achieve CR (log rank P=0.034; P=0.018). The implementation of molecular classification for EC patients undergoing fertility-sparing treatment is promising and can facilitate the selection of appropriate medical regimes to achieve better outcomes in patients with EC who require fertility preservation treatment.

Fertility-preserving treatment outcomes in endometrial cancer and atypical hyperplasia patients with different molecular profiles

Objective: To investigate the impact of molecular classification and key oncogenes on the oncologic outcomes in patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) receiving fertility-preserving treatment. Methods: Patients with EC and AEH undergoing progestin-based fertility-preserving treatment and receiving molecular classification as well as key oncogenes test at Obstetrics and Gynecology Hospital, Fudan University from January 2021 to March 2023 were reviewed. Hysteroscopic lesion resection and endometrial biopsy were performed before initiating hormone therapy and every 3 months during the treatment to evaluate the efficacy. The risk factors which had impact on the treatment outcomes in EC and AEH patients were further analyzed. Results: Of the 171 patients analyzed, the median age was 32 years, including 86 patients with EC and 85 patients with AEH. The distribution of molecular classification was as follows: 157 cases (91.8%) were classified as having no specific molecular profile (NSMP); 9 cases (5.3%), mismatch repair deficient (MMR-d); 3 cases (1.8%), POLE-mutated; 2 cases (1.2%), p53 abnormal. No difference was found in the cumulative 40-week complete response (CR) rate between the patients having NSMP or MMR-d (61.6% vs 60.0%; P=0.593), while the patients having MMR-d had increased risk than those having NSMP to have recurrence after CR (50.0% vs 14.4%; P=0.005). Multi-variant analysis showed PTEN gene multi-loci mutation (HR=0.413, 95%CI: 0.259-0.658; P<0.001) and PIK3CA gene mutation (HR=0.499, 95%CI: 0.310-0.804; P=0.004) were associated with a lower cumulative 40-week CR rate, and progestin-insensitivity (HR=3.825, 95%CI: 1.570-9.317; P=0.003) and MMR-d (HR=9.014, 95%CI: 1.734-46.873; P=0.009) were independent risk factors of recurrence in EC and AEH patients. Conclusions: No difference in cumulative 40-week CR rate is found in the patients having NSMP or MMR-d who received progestin-based fertility-preserving treatment, where the use of hysteroscopy during the treatment might be the reason, while those having MMR-d have a higher risk of recurrence after CR. Oncogene mutation of PTEN or PIK3CA gene might be associated with a lower response to progestin treatment. The molecular profiles help predict the fertility-preserving treatment outcomes in EC and AEH patients.

Multimodal assessment after total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy in locally advanced rectal cancer accurately predicts complete responders.

This study aimed to compare local regrowth rates after total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy (SNCRT) in locally advanced rectal cancer (LARC) patients that were strictly selected and assessed with a multimodal approach. Secondary outcomes were 4-year disease-free (DFS) and overall survival (OS) rates. Locally advanced rectal cancer patients without distant metastases treated at Koç Healthcare Group between January 2014 and January 2021 were included. Patients were assessed for complete response with a combination of digital rectal exam, endoscopy, and magnetic resonance imaging with a dedicated rectum protocol. The systemic evaluation was performed with an upper abdomen MRI using intravenous hepatobiliary contrast agent and a thorax CT. Of the 270 patients with LARC, 182 fulfilled the inclusion criteria. Ninety-seven (53.3%) underwent TNT, while 85 (46.7%) underwent SNCRT. A cumulative combination of pathological and sustained clinical complete response was significantly higher in the TNT group than in the SNCRT (45.4% vs. 20.0%, p < 0.0001). After a median follow-up of 48months, seven patients in the W&W group had regrowth [TNT: 4 (10.8%) vs. SNCRT: 3 (23.1%), p = 0.357]. Based on pathological examination, complete/near complete mesorectum rates (p = 1.000) and circumferential resection margin positivity rates (p = 1.000) were similar between the groups. The 4-year DFS and OS rates were comparable. The patients with clinical or pathological complete response had significantly longer overall survival (p = 0.017) regardless of the type of neoadjuvant treatment. Multimodal assessment after TNT effectively detects complete responders, resulting in low local recurrence and increased cumulative complete response rates. However, these outcomes did not translate into a survival advantage.

Effects of Weight Status and Related Metabolic Disorders on Fertility-Sparing Treatment Outcomes in Endometrial Atypical Hyperplasia and Endometrial Cancer: A Retrospective Study.

Simple SummaryFertility-sparing treatment for young women with endometrial atypical hyperplasia or endometrioid endometrial cancer has become an important priority. The aim of our retrospective study was to evaluate the effects of different weight statuses and related metabolic disorders on the oncological and reproductive outcomes of fertility-sparing treatment. We found that there was a parabola-shaped relationship between the cumulative complete response rate of treatment and BMI. The apex of the curve was observed at a BMI of 21–22 kg/m2. Furthermore, we demonstrated that hyperuricemia was an independent risk factor for the failure of conservative treatment, correlating with a lower cumulative 32-week CR rate and longer treatment duration. Our results indicate that a target BMI interval for weight management should be appropriately established for patients with EAH/EEC. Early active interventions for related metabolic disorders, preferably before 32 weeks of treatment, should be provided to improve treatment efficacy.Background: Although obesity was an independent risk factor for fertility-sparing treatment in endometrial atypical hyperplasia (EAH) and endometrioid endometrial cancer (EEC), the roles of other weight statuses and related metabolism were unclear. This study aimed to investigate the body mass index (BMI) interval that produced optimal treatment efficacy and the effects of related metabolic disorders in EAH/EEC patients. Methods: A total of 286 patients (including 209 EAH and 77 well-differentiated EEC) under progestin therapy were retrospectively analyzed. The cumulative complete response (CR) rate, relapse rate, and fertility outcomes were compared among different weight or metabolic statuses. Results: Underweight and overweight/obese status significantly decreased the cumulative 16-week and 32-week CR rate (p = 0.004, p = 0.022, respectively). The highest 16-week CR rate was observed at a BMI of 21–22 kg/m2 in the overall population (p = 0.033). Obesity (HR 0.37, 95%CI 0.15–0.90, p = 0.029) and PCOS (HR 0.55, 95%CI 0.31–0.99, p = 0.047) were associated with lower 16-week CR rate. Hyperuricemia (HR 0.66, 95%CI 0.45–0.99, p = 0.043) was associated with lower 32-week CR rate. The 16-week and 32-week CR rate (p = 0.036, p = 0.008, respectively) were significantly lower in patients exhibiting both obesity and hyperuricemia. Conclusions: The optimal fertility-sparing treatment efficacy was observed at a BMI of 21–22 kg/m2 in EAH/EEC. Hyperuricemia was an independent risk factor for long-term treatment outcomes.

Adoptive therapy with cytomegalovirus‐specific T cells for cytomegalovirus infection after haploidentical stem cell transplantation and factors affecting efficacy

Adoptive therapy with cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as an effective method for CMV infection. However, the efficacy reportedly ranges from 50-90%, and factors affecting anti-CMV efficacy have not been established. We investigated the safety and efficacy of adoptive therapy with CMV-CTLs for CMV infection in 190 patients after haploidentical stem cell transplantation (haplo-SCT), and importantly, we analyzed the main factors affecting antiviral efficacy. The CMV peak titer decreased from 19 (range, 1.0-503.0) × 103 copies/ml to 3.9 (range, 0-112) × 103 copies/ml after CMV-CTL infusion. The cumulative complete response (CR) rates in the 1st , 4th , and 6th weeks after the first CMV-CTL infusion were 37.9% (95% CI 35.0%-40.8%), 76.8% (95% CI 70.7%-82.9%), and 89.5% (95% CI 85.2%-93.8%), respectively. In multivariate analysis, persistent CMV infection prior to CMV-CTL infusion (HR 2.29, 95% CI 1.29-4.06, P=0.005) and basiliximab treatment within 2 weeks of CMV-CTL infusion (HR 1.87, 95% CI 1.06-3.81, P=0.031) were independent predictors of poor antiviral efficacy of CMV-CTL therapy. Our data showed that adoptive therapy with CMV-CTLs is a safe and effective treatment for CMV infection after haplo-SCT. Persistent CMV infection and basiliximab treatment are correlated with poor anti-CMV efficacy of CMV-CTL therapy. This article is protected by copyright. All rights reserved.

Magnetismm-3: An Open-Label, Multicenter, Non-Randomized Phase 2 Study of Elranatamab (PF-06863135) in Patients with Relapsed or Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is a hematological B-cell malignancy that remains incurable for most patients. Almost all patients, including those who initially respond to treatment, are expected to relapse and subsequently cycle through multiple lines of treatment. The addition of proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies has improved patient outcomes; however, survival of patients after these agents is very poor and highlights an unmet medical need in the relapsed/refractory MM population. Elranatamab (PF-06863135) is a humanized bi-specific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells, with binding resulting in T-cell mediated cytotoxicity. Elranatamab preclinical studies have demonstrated anti-tumor activity and delayed tumor progression. A Phase 1 study, MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136), with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for patients with relapsed/refractory MM is ongoing.Study Design and Methods: MagnetisMM-3 is an open-label, multicenter, non-randomized, Phase 2 study to evaluate the efficacy and safety of elranatamab monotherapy in patients with relapsed/refractory MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ClinicalTrials.gov ID: NCT04649359). Approximately 150 patients will be enrolled to one of two independent parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed therapy (Cohort B). The primary endpoint is objective response rate, according to International Myeloma Working Group [IMWG] response criteria. Secondary endpoints include duration of response, cumulative complete response (CR) rate, duration of cumulative CR, progression-free survival, time to response, minimal residual disease negativity rate, overall survival, safety, plasma concentrations, and immunogenicity of elranatamab.Key inclusion criteria are age ≥18 years, MM diagnosis according to IMWG criteria and with measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL by SPEP, Urinary M-protein excretion ≥200 mg/24 hours by UPEP; Serum immunoglobulin free light chain ≥10 mg/dL (≥100 mg/L) and abnormal serum immunoglobulin kappa to lambda free light chain ratio (<0.26 or >1.65). Eligible patients should also have ECOG performance status ≤2, be refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and be relapsed/refractory to their last treatment regimen. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, active, uncontrolled bacterial, fungal or viral infections, stem cell transplant within 12 weeks of enrollment, any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or having received previous administration of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the first dose of elranatamab. This study is, or is planned to be, open at centers in the USA, Australia, Canada, Belgium, France, Germany, Japan, Poland, Spain, and the UK. DisclosuresLesokhin: Genetech: Research Funding; Serametrix, Inc: Patents & Royalties; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Iida: Ono: Honoraria, Research Funding; Glaxo SmithKlein: Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding. Ma: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Sullivan: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

The role of prolonged progestin treatment and factors predicting successful fertility-sparing treatment for early endometrial endometrioid adenocarcinoma

ObjectiveFertility-sparing progestin therapy is highly effective in selected young women with endometrial cancer. In present study, we attempted to evaluate the role of prolonged medication and identify factors predicting successful treatment, and also assess fertility outcomes among young women with early stage endometrial endometrioid carcinoma (EC). Study designWe retrospectively reviewed clinical data from patients aged <45 years with well-differentiated EC at presumed stage IA (without myometrial invasion) who wished to preserve fertility. They were managed with oral progestin at Kaohsiung Chang Gung Memorial Hospital between June 2005 and June 2019. ResultsForty-five patients were included with a median follow-up of 53.5 months (range 12–170 months). Forty-one patients (91.1%) had complete remission, the cumulative complete response (CR) rates at 3, 6, 9, 12, and >12 months were 17.7%, 48.9%, 60.0%, 68.9% and 91.1%, respectively. Among the 41 responders, 23 attempted to conceive and nine (39.1%) achieved pregnancy with 12 live newborn infants. Eleven (27.5%) responders experienced recurrence at a median of 22 months from CR (range 3–54 months). Multivariate Cox regression analysis revealed that non-diabetes (HR: 4.59; 95% CI: 1.62–12.98) and endometrial thickness <2 cm (HR: 0.39; 95% CI: 1.41–17.67) were significantly factors associated with treatment response. ConclusionsWe concluded that prolonged oral progestin treatment was possible with a certain proportion of responders (24.4%) being responded after one year. Diabetes controlled on metformin and endometrial thickness <2 cm could be used as surrogate markers to predict better treatment response.

Optimal duration of fertility-sparing hormonal treatment for early-stage endometrioid endometrial cancer

ObjectivesTo analyze the oncologic outcomes of long-term fertility-sparing treatment (FST) in patients with early-stage endometrial cancer (EC) and to determine the optimal duration of FST that would not hamper survival outcomes. MethodsPatients undergoing FST for presumed stage IA, grade 1 EC between 2005 and 2018 were retrospectively analyzed. Oncologic outcomes were compared between the group with ≤6 months of FST and the group with >6 months of FST. Segmented regression analysis was used to estimate the dynamic changes in cumulative complete response (CR) rates according to FST duration. ResultsA total of 122 patients received oral progestin, with concurrent levonorgestrel-releasing intrauterine device use in 108 (88.5%) and 105 (86.1%) achieved CR with a median time to achieve CR of 10 (3–42) months. Of the patients not achieving CR at 6 months of FST, 95.1% (78/82) continued further FST. The overall CR rate (88.9% [32/36] vs. 84.9% [73/86], P = 0.436] was not significantly different between the groups with ≤6 and > 6 months of FST. The changes in cumulative CR rates were significantly different between the two segments divided by 15 months from the initial FST (P = 0.0015, segmented regression analysis). The overall progressive disease (PD) rate was 3.3% (4/122), and PD was first detected during 9–12 months of FST. ConclusionPatients not achieving CR and not showing PD at 6 months of FST could continue further FST. If disease progression is excluded, 15 months of FST can be considered as the cutoff for the optimal FST duration.

Fertility-preserving treatment outcome in endometrial cancer or atypical hyperplasia patients with polycystic ovary syndrome.

ObjectiveThis study aimed to investigate the impact of polycystic ovary syndrome (PCOS) on fertility-sparing treatment in young patients with atypical endometrial hyperplasia (AEH) or endometrioid endometrial cancer (EEC).MethodsA total of 285 patients with EEC (n=76, FIGO stage IA, without myometrium invasion) or AEH (n=209) who received progestin-based fertility-sparing treatment were evaluated retrospectively. Among the 285 patients, 103 (36.1%), including 70 AEH cases and 33 EEC cases, were diagnosed with PCOS. General characteristics, cumulative 16- and 32-week complete response (CR) rate, pregnancy outcome and recurrence were compared between patients with or without PCOS.ResultsThe cumulative 16-week CR rate was lower in the PCOS group than in the non-PCOS group (18.4% vs. 33.8%, p=0.006). Patients with PCOS took longer treatment duration to achieve CR (7.0 months vs. 5.4 months, p=0.006) and shorter time to relapse after CR (9.6 months vs. 17.6 months, p=0.040) compared with non-PCOS group. After adjusting for patient age, body mass index, PCOS, homeostasis model assessment-insulin resistance index, and serum testosterone levels, we found that body mass index ≥25 kg/m2 (HR=0.583; 95% CI=0.365–0.932; p=0.024) and PCOS (HR=0.545; 95% CI=0.324–0.917; p=0.022) were significantly correlated with lower 16-week CR rate.ConclusionPCOS was associated with lower 16-week CR rate, longer treatment duration and shorter recurrence interval in patients with AEH or EEC receiving fertility-preserving treatment.

Characteristics of progestin-insensitive early stage endometrial cancer and atypical hyperplasia patients receiving second-line fertility-sparing treatment.

ObjectiveThis study investigated the characteristics of progestin-insensitive endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) patients receiving fertility-sparing treatments and assessed the therapeutic effects of second-line fertility-preserving treatments.MethodsThree hundred and thirty-eight patients with EEC (n=75) or AEH (n=263) receiving fertility-preserving treatment were retrospectively analyzed. ‘Progestin-insensitive’ was defined as meeting one of the following criteria: 1) presented with progressed disease at any time during conservative treatment, 2) remained with stable disease after 7 months of treatment, and/or 3) did not achieve complete response (CR) after 10 months of treatment. Clinical characteristics and treatment results of progestin-insensitive patients receiving second-line treatment and those of progestin-sensitive patients were compared.ResultsEight-two patients (59 AEH and 23 EEC) were defined as progestin-insensitive and 256 as progestin-sensitive. In multivariate analysis, body mass index ≥28.0 kg/m2 (odds ratio [OR]=1.898) and lesion size >2 cm (OR=2.077) were independent predictors of progestin-insensitive status. Compared to AEH patients, progestin-insensitive EEC patients had poorer second-line treatment responses (28-week cumulative CR rate after changing second-line treatment, 56.3% vs. 85.4%, p=0.011). No statistical difference was found in CR rate among different second-line treatments.ConclusionObesity and larger lesion size were independent risk factors associated with progestin-insensitive status. In progestin-insensitive patients receiving second-line treatment, EEC patients had lower CR rate comparing with AEH patients. Further study with larger sample size is needed to evaluate efficacy of different second-line treatments for progestin insensitive patients.

Prognosis of medication-related osteonecrosis of the jaws in metastatic prostate cancer patients.

The aim of this study was to find out the prognosis of medication-related osteonecrosis of the jaws (MRONJ) in prostate cancer patients who received two different types of antiresorptive agents for bone metastasis. We retrospectively surveyed a cohort of 95 metastatic prostate cancer patients with 122 MRONJ lesions treated in a single medical center. Treatment outcomes and prognostic factors were investigated. The cumulative complete response rate was calculated with the Kaplan-Meier method, and significance was examined with the log-rank and Breslow tests. Cox regression was used for the univariate and multivariate analyses of prognostic factors. The cumulative complete response rate of all patients at 12months was 37.8%, and that of patients treated with zoledronic acid and denosumab was 22.9% and 70.5%, respectively. Denosumab, pretreatment C-terminal telopeptide of collagen I (CTX) level >150pg/ml, and anemia were identified as independent prognostic factors in a multivariate analysis with adjusted hazard ratios of 3.18 (95% confidence interval [CI], 1.24-8.11), 3.24 (95% CI, 1.39-7.53), and 0.42 (95% CI, 0.19-0.93), respectively. A higher pretreatment level of CTX, using denosumab as the antiresorptive agent and without anemia, indicates a better treatment outcome of MRONJ in prostate cancer patients.

Prognosis of medication-related osteonecrosis of the jaws in cancer patients using antiresorptive agent zoledronic acid

Anti-resorptive agents are commonly used in cancer patients with bone metastasis or multiple myeloma (MM). An adverse event termed medication-related osteonecrosis of the jaws (MRONJ) was discovered in patients using these agents but relatively little attention has been paid to its prognosis. Our aims were to find out the treatment outcomes and prognostic indicators of MRONJ in cancer patients who received zoledronic acid as antiresorptive therapy. We retrospectively surveyed a cohort of 133 cancer patients who received zoledronic acid. A total of 150 MRONJ lesions were included for investigation. Cumulative complete response rate after treatment was calculated with the Kaplan-Meier method, and significance was examined with the log-rank tests. Cox regression was used for univariate and multivariate analyses of prognostic factors. The cumulative complete response rate of all patients at 24 months was 53.2%, and those of patients with MM, breast cancer and prostate cancer were 27.8%, 60.7% and 68.0%, respectively. Having MM was identified as an independent prognostic factor in a multivariate analysis with adjusted hazard ratios of 0.28 (95% confidence interval, 0.09-0.83). For cancer patients with ONJ related to zoledronic acid, patients with MM endure a worse treatment outcome.

Efficacy and Safety of Lenalidomide Based Regimens in Diffuse Large B Cell Lymphoma: A Systematic Review and Meta-Analysis of Clinical Trials

Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in the US. Lenalidomide (Len), an immunomodulator, is used in the treatment of multiple hematological malignancies. This systematic review and meta-analysis aimed to assess the efficacy and safety of Lenalidomide based regimens in Newly Diagnosed (ND) and Relapsed/Refractory (R/R) DLBCL. Methods : A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following mesh terms and Emtree terms, "Lenalidomide" OR "Revlimid" AND "diffuse large B cell lymphoma" from the inception of literature till 06/20/2020. We screened 1640 articles and included 2 randomized clinical trials (N=72) and 21 single-arm clinical trials (N=860) in this meta-analysis. We excluded case reports, case series, preclinical trials, review articles, meta-analysis, observational studies, and clinical trials not providing any information about the lenalidomide efficacy or safety in DLBCL. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results : In 23 studies (N=932), Len based regimens were used in patients with age 19-92 years (range) Table 1. In 5 trials on R/R patients (N=252), Len was used as a maintenance therapy. Cumulative overall response rate (ORR) and cumulative complete response (CR) were 0.27 (95% CI 0.21; 0.33, I2=0%) (Fig1) and 0.10 (95% CI 0.07; 0.16, 8%) (Fig2), respectively. In one phase III trial, the ORR and CR were significantly improved in the Len arm vs investigator's choice drug. In 4 trials on R/R patients (N=207), Len with monoclonal antibodies (MoAb) was used. Cumulative ORR and CR were 0.40 (95% CI 0.28; 0.54, I2=71%) and 0.28 (95% CI 0.17; 0.42, I2=72%), respectively. In a trial on R/R patients (N=33), Len with Gemcitabine, Rituximab, and Oxaliplatin was used. Cumulative ORR and CR were 0.61 (95% CI 0.43; 0.76, I2=0%) and 0.39 (95% CI 0.24; 0.57, I2=0%), respectively. In a trial on R/R patients (N=15), Len with RICE was used with ORR and CR of 0.73 (95% CI 0.47; 0.90, I2=0%) and 0.60 (95% CI 0.35; 0.81, I2=0%), respectively. In a trial on R/R patients(N=55), Len with Everolimus was used. ORR and CR were 0.27 (95% CI 0.17; 0.40, I2=0%) and 0.07 (95% CI 0.03; 0.18, I2=0%), respectively. In a trial on R/R patients (N=19), Len with R-ESHAP was used. ORR and CR were 0.79 (95% CI 0.55; 0.92, I2=0%) and 0.47 (95% CI 0.27; 0.69, I2=0%), respectively. In a phase III trial on R/R patients (N=21), Len with Gemcitabine and Rituximab was used vs. placebo The ORR and CR were significantly improved in the Len arm vs placebo. In 4 trials on ND patients (N=158), Len with R-CHOP was used and the cumulative ORR and CR were 0.94 (95% CI 0.88; 0.97, I2=12%) and 0.81 (0.75; 0.87, I2=0%), respectively. In a trial on ND patients (N=15), Len with R-EPOCH was used with ORR and CR of 0.93 (95% CI 0.65; 0.99, I2=0%) and 0.87 (95% CI 0.59; 0.97, I2=0%), respectively. In 2 trials (N=103), Len with Ibrutinib and Rituximab was used. In R/R patients (N=45), cumulative ORR and CR were 0.38 (95% CI 0.25; 0.53, I2=0%) and 0.24 (95% CI 0.14; 0.39, I2=0%), respectively. In ND patients (N=58) has ORR and CR 0.86 (95% CI 0.75; 0.93, I2=0%), respectively. In 2 trials with a combination of ND and R/R patients (N=54), Len with Rituximab and Bendamustine was used. Cumulative ORR and CR were 0.63 (95% CI 0.49; 0.75, I2=0%) and 0.39 (95% CI 0.27; 0.52, I2=0%), respectively. The most common serious treatment-related adverse events (TRAE) were infection, thromboembolism, fatigue, sepsis, respiratory, neurological, cardiac (arrhythmias), gastrointestinal, rash, seizures, and hematological side effects (Table 1). Conclusion : Based on early phase trials, Len based regimens are well tolerated and effective in the treatment of both ND and R/R DLBCL patients. Combinations of lenalidomide with Tafasitamab and R-ESHAP have shown the highest response in R/R patients and combination with R-CHOP has shown the best response in ND patients. In randomized trials, lenalidomide has shown significant improvement in the survival of DLBCL patients as compared to placebo or physician's choice drug. Additional double-blind multicenter randomized clinical trials are needed to compare the efficacy and safety of lenalidomide based regimens in DLBCL patients. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Response and relapse rates after treatment with long-acting somatostatin analogs in multifocal or recurrent type-1 gastric carcinoids: A systematic review and meta-analysis.

Type-1 gastric neuroendocrine tumors represent a recurring disease and long-acting somatostatin analogs can inhibit both gastrin release and endocrine cell proliferation. The efficacy and timing of this treatment are still unclear. We performed a systematic review of the literature to clarify the role of somatostatin analog treatment in type-1 gastric neuroendocrine tumors. A computerized literature search was performed using relevant keywords to identify all the pertinent articles published in the last 15 years. Eight studies were included in this systematic review on somatostatin analogs in type-1 gastric neuroendocrine tumors. A complete response rate ranged from 25-100%. When only the six prospective studies were considered, no significant heterogeneity was observed, and the pooled cumulative complete response rate was 84.5% (confidence interval 73.8-92.8). Three studies evaluated the type-1 gastric neuroendocrine tumor recurrence, with a cumulative relapse rate of 30.2% (confidence interval 13.1-50.6) after 34 months. Somatostatin analogs, namely lanreotide and octreotide, have an excellent response rate, with a good safety profile in selected type-1 gastric neuroendocrine tumors, which cannot be safely managed by endoscopic follow-up or resection due to multiple or frequently recurring disease. After therapy discontinuation, the cumulative relapse rate observed after a median 34-month follow-up was relatively high (30.2%).

Clinical efficacy and safety of anticoagulation therapy for Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: a retrospective multicenter cohort study.

Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome(PA-HSOS) has been reported to have high mortality. We evaluated the efficacy and safety of anticoagulation therapy for the patients with PA-HSOS. We collected clinical data on 249 PA-HSOS patients from January 2012 to December 2017 at four tertiary care hospitals. Among them, 151 patients received anticoagulation therapy, and 98 patients received supportive treatment. The outcomes were analyzed using the Fine and Gray competing risk analysis method and Cox regression model. The cumulative complete response rate was higher in the anticoagulation group than in the supportive group (60.9 vs 36.7%; P < 0.0001). The cumulative mortality was 12.6% in the anticoagulation group compared with 43.9% in the supportive group (P < 0.0001). In subgroup analysis, for mild, moderate, severe, and very severe groups, the adjusted hazard ratios [95% confidence interval (CI)] for complete response rates were 7.05 (3.00-16.59), 5.26 (2.31-12.42), 2.59 (0.85-7.87), and 2.05 (0.61-6.92), respectively; and the adjusted hazard ratios (95% CI) for mortalities were 0.02 (0.01-0.09), 0.04 (0.01-0.14), 0.19 (0.01-3.98), and 0.07 (0.02-1.27), respectively (P < 0.0001). There was no significant difference between both groups in the incidence of bleeding events (P = 0.674). Anticoagulation therapy improves clinical remission and the survival in selected patients with mild or moderate PA-HSOS. Anticoagulation therapy has a similar safety profile to supportive therapy.

Clinical Efficacy and Safety of Anticoagulation Therapy for Pyrrolizidine Alkaloids-Induced Hepatic Sinusoidal Obstruction Syndrome: A Retrospective Multicenter Cohort Study

Objectives: Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome (PA-HSOS) has been reported to have high mortality. Limited data were available about the outcomes of anticoagulation therapy in PA-HSOS. We aimed to evaluate the efficacy and safety of anticoagulation therapy for the patients with PA-HSOS and also to explore the possible predictors for anticoagulation efficacy. Methods: We collected clinical data on a total of 249 PA-HSOS patients from January 2012 to December 2017 at 4 tertiary care hospitals in China. 151 patients received anticoagulation therapy plus symptomatic treatment, and 98 patients received symptomatic treatment. The efficacy and safety outcomes were analyzed using Fine and Gray competing risk analysis method and Cox regression model. The predictors for complete response to anticoagulation therapy in PA-HSOS patients were investigated using clinical data. Results: The cumulative complete response rate was higher in the anticoagulation group than in the supportive group (60.9% vs36.7%, adjusted HR, 4.51; p<0.0001). The cumulative mortality was 12.6% in the anticoagulation group compared with 43.9% in the supportive group (adjusted HR, 0.07; p<0.0001). In subgroup analysis, for mild, moderate, severe, and very severe groups, the adjusted HRs (95% CI) for complete response rates were 7.05 (3.00-16.59), 5.26 (2.31-12.42), 2.59 (0.85- 7.87), and 2.05 (0.61-6.92), respectively; and the adjusted HRs (95% CI) for mortalities were 0.02 (0.01-0.09), 0.04 (0.01-0.14), 0.19 (0.01- 3.98), and 0.07 (0.02-1.27), respectively (p<0.0001 for the interaction test). Lower total bilirubin level (HR 0.98) and longer treatment duration (HR 1.27) predicted higher complete response rates of anticoagulation therapy. Conclusions: Anticoagulation therapy improves clinical remission and the survival in selected patients with mild or moderate PA-HSOS. Anticoagulation therapy has a similar safety profile to supportive therapy. Trial Registration: The study was registered in the chictr.Org database (ChiCTR1800017775). Funding Statement: National Natural Science Foundation of China (No. 8157040652) and Nanjing Medical Science and technique Development Foundation (No. QRX17037). Declaration of Interests: All authors report no relevant financial or personal conflicts of interest. Ethics Approval Statement: This is a retrospective, multicenter cohort study conducted at four Chinese tertiary care hospitals. This study was approved by local ethic committees.

Insulin resistance and overweight prolonged fertility-sparing treatment duration in endometrial atypical hyperplasia patients.

ObjectiveOur previous study showed that insulin resistance (IR) was related to endometrial hyperplasia as well as endometrial cancer. But the exact impact of IR on fertility-sparing treatment in endometrial hyperplasic disease is unclear. This study investigated how IR affects fertility-sparing treatment in endometrial atypical hyperplasia (EAH) patients.MethodsThe 151 EAH patients received fertility-sparing treatment were retrospectively investigated. All patients received high-dose progestin combined with hysteroscopy. Therapeutic effects were evaluated by hysteroscopy every 3 months during the treatment.ResultsThe median age was 33.0 years old (range, 21–54 years old). Sixty-one patients (40.4%) were insulin resistant. Three patients were excluded from the analysis because they chose hysterectomy within 3 months after initiation of progestin treatment. The 141 out of 148 (95.3%) patients achieved complete response (CR). No difference was found in cumulative CR rate between those with or without IR (90.2% vs. 95.6%, p=0.320). IR significantly affected therapeutic duration to achieve CR (8.1±0.5 months with IR vs. 6.1±0.4 months without IR, p=0.004). Overweight (body mass index [BMI]≥25 kg/m2) was associated with higher risk of treatment failure (odds ratio=5.61; 95% confidence interval=1.11–28.35; p=0.040) and longer therapeutic duration to achieve CR (7.6±0.5 months vs. 6.3±0.4 months, p=0.019). EAH patients with both IR and overweight (IR+BMI+) had the longest therapeutic time compared with other patients (8.8±0.6 months vs. 5.6±0.7, 6.3±0.4, and 6.4±0.8 months for IR−BMI+, IR−BMI−, and IR+BMI−, respectively, p=0.006).ConclusionIR and overweight were associated with longer therapeutic duration in EAH patients receiving progestin-based fertility-sparing treatment.

Frontline treatment with chemoimmunotherapy for limited-stage ocular adnexal MALT lymphoma with adverse factors: a phase II study

BackgroundRadiotherapy is a commonly used treatment for limited-stage ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) but showed a substantial relapse risk if the disease involves beyond-conjunctiva or bilateral conjunctivae. Systemic chemoimmunotherapy may be an alternative frontline therapy for the limited disease with those adverse prognostic factors.Patients and methodsWe designed a multicenter, phase II study of the chemoimmunotherapy, rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) for the treatment of patients with limited-stage OAML with bilateral or beyond-conjunctival involvement. Thirty-three patients with Ann Arbor stage I OAML with the adverse factors were enrolled. Patients received six cycles of R-CVP followed by two cycles of rituximab therapy.ResultsAt the end of treatment, all the enrolled patients had responded. The cumulative complete response achievement was 93.9% at 2 years. At a median follow-up of 50.6 months, three patients had progressed. Progression-free survival and overall survival at 4 years was 90.3±5.3% and 100%, respectively.ConclusionsThis phase II study demonstrated durable efficacy of R-CVP chemoimmunotherapy, which has promise as an alternative frontline therapy for the limited-stage OAML patients with adverse prognostic factors.Clinical trial registrationNCT01427114.