Investigating the Efficacy and Safety of Thalidomide for Treating Patients With ß-Thalassemia: A Meta-Analysis

At present, the main therapies for ß-thalassemia patients include regular blood transfusion and iron chelation, associating with a number of limitations. Thalidomide, a fetal hemoglobin (HbF) inducer that promotes γ-globin gene expression, has been reported to be effective for ß-thalassemia. Thus, this meta-analysis was conducted to assess the efficacy and safety of thalidomide for treating patients with ß-thalassemia. We searched the related studies from eight databases published from inception until December 1, 2021. The R 4.0.5 language programming was used to perform meta-analysis. After screening of retrieved articles, 12 articles were included that enrolled a total of 451 patients. The Cochrane Collaboration risk assessment tool was used to evaluate the quality and the bias risk of the randomized controlled trials (RCTs), and non randomized trials were assessed using Newcastle-Ottawa Scale (NOS). After treatment with thalidomide, the pooled overall response rate (ORR) was 85% (95% confidence interval (CI): 80–90%), and the pooled complete response rate (CRR) was 54% (95% confidence interval: 31–76%). Compared with the placebo group, the thalidomide group had higher odds of overall response rate (odds ratio = 20.4; 95% CI: 6.75–61.64) and complete response rate (odds ratio = 20.4; 95% CI: 6.75–61.64). A statistically significant increase in hemoglobin level and HbF level after treatment, while there was no statistically significant difference in adult hemoglobin (HbA) level, spleen size, and serum ferritin. According to the results of ORR and CRR, transfusion-dependent thalassemia (TDT) patients showed remarkable efficacy of thalidomide, 83 and 52% respectively. So we analyzed 30 transfusion-dependent thalassemia patients from three studies and found that the most frequent ß-globin gene mutations were CD41-42 (-TCTT), while response to thalidomide did not show any statistically significant relationship with XmnI polymorphism or CD41-42 (-TCTT) mutation. About 30% of patients experienced mild adverse effects of thalidomide. Collectively, thalidomide is a relatively safe and effective therapy to reduce the blood transfusion requirements and to increase Hb level in patients with ß-thalassemia.

Implications for Efficacy and Safety of Total Dose and Dose-Intensity of Neoadjuvant Gemcitabine-Cisplatin in Muscle-Invasive Bladder Cancer: Three-Week Versus Four-Week Regimen

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy is standard care prior to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: To assess efficacy and safety of two commonly used neoadjuvant schedules with different total doses and dose-intensities of gemcitabine and cisplatin (GC). METHODS: Data were collected retrospectively from all patients treated between 2010 and 2018 with neoadjuvant chemotherapy according to clinical routine at seven centres in Sweden and Denmark. Patients in Sweden received three cycles of a 4-week schedule (GC-4w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, 15, q 28 days) and in Denmark four cycles of a 3-week schedule (GC-3w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, q 21 days). Primary endpoint was pathological response at cystectomy (pT0N0 and < pT2N0). RESULTS: A total of 251 patients were treated with GC-4w and 455 with GC-3w. pT0N0 was significantly higher for patients treated with GC-3w compared to GC-4w, 46% versus 32% (adjusted odds ratio [aOR] 1.80; 95% confidence interval [CI] 1.16–2.80; P = 0.009); and for < pT2N0 60% versus 47% (aOR 1.08; 95% CI 0.70–1.66; P = 0.743). There were no significant differences between GC-4w and GC-3w regarding survival parameters. GC-3w patients discontinued treatment more frequently and showed a higher degree of neutropenia. CONCLUSIONS: A significantly higher complete response-rate was observed in the patient group treated with the more cisplatin-dose-intense 3-week schedule. The side-effect profile was in favor of the 4-week approach while relapse-free and overall survival were similar.

Safety and Efficacy Analysis of Selinexor-Based Treatment in Multiple Myeloma, a Meta-Analysis Based on Prospective Clinical Trials

Background: Selinexor (SEL) is an orally bioavailable, highly-selective, and slowly-reversible small molecule that inhibits Exportin 1. Preclinical studies showed that SEL had synergistic antimyeloma activity with glucocorticoids, proteasome inhibitors (PIs) and immunomodulators. The combination of selinexor and dexamethasone (DEX) has been approved in the United States for patients with penta-refractory multiple myeloma in July 2019. This meta-analysis aimed to investigate the safety and efficacy of selinexor based treatment in Multiple myeloma.Methods: We systematically searched the Medline (PubMed), Embase, Web of Science, Cochrane Central Register of Controlled Trials Library databases and ClinicalTrials.gov. Outcome measures of efficacy included overall response rate (ORR), clinical benefit rate (CBR), stringent complete response rate (sCR), complete response rate (CR), very good partial response (VGPR), partial response rate (PR), minimal response (MR), rate of stable disease (SDR), rate of progressive disease (PDR) and median progression-free survival (mPFS). Safety was evaluated by the incidences of all grade adverse events and Grade≥3 adverse events. The subgroup analysis was conducted to analyze the difference in different combination treatment regimens (SEL + DEX + PIs vs SEL + DEX).Results: We included six studies with 477 patients. The pooled ORR, CBR, sCR, CR, VGPR, PR, MR, SDR, and PDR were 43% (18–67%), 55% (32–78%), 5% (−2–13%), 7% (4–11%), 14% (5–24%), 23% (15–31%), 11% (8–14%), 26% (14–38%) and 14% (4–23%), respectively. SEL + DEX + PIs treatment had higher ORR (54 vs 24%, p = 0.01), CBR (66 vs 37%, p = 0.01), sCR (10 vs 2%, p = 0.0008), and VGPR (23 vs 5%, p &lt; 0.00001) compared to SEL + DEX treatment, and lower PDR (4 vs 23%, p &lt; 0.00001) and SDR (17 vs 37%, p = 0.0006). The pooled incidences of any grade and grade≥3 were 45 and 30% in hematological AEs, and in non-hematological AEs were 40 and 30%, respectively. The most common all grade (68%) and grade≥3 (54%) hematological AE were both thrombocytopenia. Fatigue was the most common all grade (62%) and grade≥3 (16%) non-hematological AE. Compared to SEL + DEX treatment, SEL + DEX + PIs treatment had lower incidences of hyponatremia (39 vs 12%, p &lt; 0.00001), nausea (72 vs 52%, p &lt; 0.00001), vomiting (41 vs 23%, p &lt; 0.0001), and weight loss (42 vs 17%, p = 0.03) in all grade AEs. Meanwhile, SEL + DEX + PIs treatment had lower incidences of anemia (36 vs 16%, p = 0.02), fatigue (20 vs 13%, p = 0.04), hyponatremia (22 vs 5%, p &lt; 0.0001) than SEL + DEX treatment in grade≥3 AEs.Conclusion: Our meta-analysis revealed that selinexor-based regimens could offer reasonable efficacy and tolerable adverse events in patients with multiple myeloma. SEL + DEX + PIs treatments had higher efficacy and lower toxicities than SEL + DEX.

Pain as the evaluation criterion for bone metastasis radiosensitivity. Comparative efficacy of radiation therapy in patients with bone metastases of various primary tumors.

Purpose: Assessment of the comparative radiosensitivity of bone metastases of various nature and histogenesis. Material/methods: As part of a randomized study, 810 courses of 3D-conformal or IMRT / VIMAT radiotherapy were performed for bone metastases of various origins and localization with persistent pain syndrome. Radiotherapy protocol included hypofractionation regimes of 2, 3 or 4 fractions of 6,5 Gy with total dose of 13-26 Gy or standard fractionation regime with total dose of 46 Gy. Results: The overall effectiveness (сomplete and partial pain relief) of radiotherapy was 96.2%, complete response rate (CRR) – 56.2%, partial response rate – 40.0%. Pain relapse rate was 8.6%, on average after 9.5 months after irradiation. The independent predictors of the CRR were: the initial pain intensity [hazard ratio (RR): 0.48, confidence interval (CI): 0.40-0.58; p = 0.0001], dose/number of fractions (RR: 1.26, CI: 1.07-1.50; p = 0.0059) and primary tumor site (RR: 0.95, CI: 0.92-0,99; p = 0.0053). We constructed a scale of comparative radiosensitivity of bone metastases of various primary tumors, taking into account the complete response rate and the probability of surviving without pain relapse for 6, 12 and 24 months after radiotherapy. The radiosensitive group included metastases from breast and prostate cancer, melanoma, bladder and PNET (CRR 60% or more), and relatively radioresistant group - metastases from unknown origin, colon, stomach and kidney cancer (CRR 40% or less). Conclusion: More than 95% overall effectiveness of radiotherapy for bone metastases, with pain relapse rate of less than 10% of cases, allows us to consider widefield irradiation in doses of 19.5-26 Gy, in 3-4 fractions of 6.5 Gy, the preferred treatment for multifocal lesions. Dose escalation in patients with bone metastases of kidney, colon, lung cancer and metastases from unknown origin seems to be justified in the cases with a life expectancy of more than a year.

Efficacy of Photodynamic Therapy for the Treatment of Bowen’s Disease: A Meta-Analysis of Randomized Controlled Trials

<b><i>Background:</i></b> Photodynamic therapy is an established treatment option for Bowen’s disease. Our meta-analysis was aimed at evaluating the efficacy and recurrence of photodynamic therapy or other topical treatments (5-fluorouracil, cryotherapy) and of photodynamic therapy alone or in combination with other therapies (ablative fractional CO₂ laser or plum-blossom needle) for the treatment of Bowen’s disease. <b><i>Methods:</i></b> Trials that met our inclusion criteria were identified from PubMed, EMBASE, Web of Science, and Cochrane Library databases, and meta-analyses were conducted with RevMan V.5.4. The risk of bias was estimated with the Cochrane Collaboration’s risk of bias tools. Complete response rate, recurrence, pain/visual analogue scale score, cosmetic outcome, and adverse events were considered as outcomes. <b><i>Results:</i></b> Of the 2,439 records initially retrieved, 8 randomized controlled trials were included in this meta-analysis. According to our analyses, photodynamic therapy exhibited a significantly higher complete response rate (RR = 1.36, 95% CI [1.01, 1.84], <i>I</i>² = 86%, <i>p</i> = 0.04), less recurrence (RR = 0.53, 95% CI [0.30, 0.95], <i>I</i>² = 0%, <i>p</i> = 0.03), and better cosmetic outcome (RR = 1.34, 95% CI [1.15, 1.56], <i>I</i>² = 0%, <i>p</i> = 0.0002) compared with other treatments. Moreover, there was a significant difference between the complete response rate of photodynamic therapy combined with ablative fractional CO₂ laser and that of photodynamic therapy (RR = 1.85, 95% CI [1.38, 2.49], <i>I</i>² = 0%, <i>p</i> &#x3c; 0.0001). Photodynamic therapy combined with ablative fractional CO₂ laser or plum-blossom needle also showed significantly less recurrence (RR = 0.21, 95% CI [0.09, 0.51], <i>I</i>² = 0%, <i>p</i> = 0.0005) and a lower visual analogue scale score (RR = 0.51, 95% CI [0.06, 0.96], <i>I</i>² = 0%, <i>p</i> = 0.03) than photodynamic therapy alone. However, there was no significant difference in the complete response rate between photodynamic therapy combined with ablative continuous CO₂ laser and photodynamic therapy combined with ablative fractional CO₂ laser (RR = 1.00, 95% CI [0.54, 1.86], <i>I</i>² not applicable, <i>p</i> = 1.00). <b><i>Conclusions:</i></b> This meta-analysis shows that photodynamic therapy can be used in the treatment of Bowen’s disease with better efficacy, less recurrence, and better cosmetic outcomes than cryotherapy and 5-FU. Some methods, including ablative fractional CO₂ laser, can be applied in combination with photodynamic therapy to improve efficacy. However, which laser-assisted photodynamic therapy scheme has the most advantages in the treatment of Bowen’s disease warrants further exploration.

756 LONG-TERM OUTCOME AFTER ENDOSCOPIC SUBMUCOSAL DISSECTION FOR ENTIRE CIRCUMFERENTIAL CT1AN0M0 ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Endoscopic submucosal dissection (ESD) is the standard treatment for cT1a esophageal squamous cell carcinoma (ESCC), however its indication for the entire circumferential lesions is still controversial because of the risk of severe stricture after ESD. Therefore, several treatment options are performed based on physicians’ choice, however, each clinical course is unclear. This study aimed to clarify the long-term outcome after ESD for patients with entire circumferential cT1aN0M0 ESCC, comparing with esophagectomy or chemoradiotherapy. Methods Patients with entire circumferential cT1aN0M0 SESCC treated with ESD, chemoradiotherapy, or esophagectomy as the initial treatment between January 2010 and December 2016 in our institution were included. Patients who had a history of any malignancy at cStage II-IV within 5 years were excluded. The 5-year overall survival (OS), 5-year disease-free survival (DFS), stricture rate, refractory stricture rate (defined as requiring &gt;6 dilations), curative resection (defined as pT1a without lymphovascular invasion and negative for vertical margin in the pathological evaluation) rate of ESD, and complete response rate of chemoradiotherapy were evaluated for each treatment. Results Of the 48 eligible patients, 25/13/10 patients were performed ESD/chemoradiotherapy/esophagectomy as an initial treatment. Curative resections rate of ESD was 72%, and additional esophagectomy and chemoradiotherapy were performed in three and one patients with non-curative resection. Complete response rate of chemoradiotherapy was 100%, however, 4 patients had recurrence thereafter. No recurrences occurred after esophagectomy in all patients treated with esophagectomy. During median follow-up of 83 months, stricture and refractory stricture rate was 80/44% after ESD, 0/0% after chemoradiotherapy, and 20/10% after esophagectomy. The 5-year OS/DFS was 91/87% after ESD, 92/59% after chemoradiotherapy, and 90/90% after esophagectomy. Conclusion While some patients required additional treatments due to non-curative resection, the long-term survival after ESD for circumferential cT1aN0M0 ESCC was similar as those after chemoradiotherapy or esophagectomy. In contrast, the stricture and refractory stricture rate after ESD was higher than others. Further investigation in a large cohort is necessary to clarify the indication criteria of ESD for patients with the lesion.

Effect of Concurrent Chemoradiation for Advanced Head and Neck Malignancy in a Tertiary Care Centre, Kerala

BACKGROUND Concurrent chemotherapy is a well-established treatment modality for locally advanced head and neck cancer. The concept of concurrent chemotherapy and radiation was introduced in an attempt to improve the local control and possibly influence the survival because of the high rate of local and distant failures observed with the combination of surgery and postoperative radiation. The relevance of this study was to assess the efficacy of our treatment and patience compliance and also study the effect in patients treated with cisplatin based concurrent chemo radiotherapy in advanced head and neck cancer. METHODS The prospective study was conducted in the Department of Radiotherapy, Government Medical college, Thrissur, Kerala comprising the newly diagnosed patients with locally advanced head & neck cancers over one year. Conventional radiotherapy with a dose of 66 Gy in 33 fractions over 6.5 weeks was given concurrently with Inj cisplatin 100 mg / 2 IV every 3 weeks and periodically followed up for one year. RESULTS This study revealed that complete response rate was higher in 61 – 70 year age group compared to lower age groups. Complete response cases were slightly higher in T1 disease compared to higher stages. Regarding nodal status, complete response and DFS were more in N0 tumours and worst in N3 tumours. It was found that complete response rates were slightly higher in stage III than stage IV. Comparing the grade of the tumour, complete response cases were slightly higher in WD and MD compared to PD. Complete response rate and disease free survival (DFS) were slightly higher in cases who had more than two chemotherapy cycles compared to one cycle. CONCLUSIONS Concurrent chemo radiation was not well tolerated in our study group. Only 23.5 % patients were able to complete the planned treatment. The positive side was that complete response was found in about 79.4 % of study patients & DFS at one year was 80 %. KEY WORDS Concurrent Chemo Radiation, Head and Neck Cancer, Cisplatin

Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure

ObjectiveThe prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R-DLBCL) after second-line treatment failure is extremely poor. This study prospectively observed the efficacy and safety of decitabine with a modified cisplatin, cytarabine, and dexamethasone (DHAP) regimen in R/R-DLBCL patients who failed second-line treatment.MethodsTwenty-one R/R-DLBCL patients were enrolled and treated with decitabine and a modified DHAP regimen. The primary endpoints were overall response rate (ORR) and safety. The secondary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsORR reached 50% (complete response rate, 35%), five patients (25%) had stable disease (SD) with disease control rate (DCR) of 75%. Subgroup analysis revealed patients over fifty years old had a higher complete response rate compared to younger patients (P = 0.005), and relapsed patients had a better complete response rate than refractory patients (P = 0.031). Median PFS was 7 months (95% confidence interval, 5.1-8.9 months). Median OS was not achieved. One-year OS was 59.0% (95% CI, 35.5%-82.5%), and two-year OS was 51.6% (95% confidence interval, 26.9%-76.3%). The main adverse events (AEs) were grade 3/4 hematologic toxicities such as neutropenia (90%), anemia (50%), and thrombocytopenia (70%). Other main non-hematologic AEs were grade 1/2 nausea/vomiting (40%) and infection (50%). No renal toxicity or treatment-related death occurred.ConclusionDecitabine with a modified DHAP regimen can improve the treatment response and prognosis of R/R-DLBCL patients with good tolerance to AEs, suggesting this regimen has potential as a possible new treatment option for R/R-DLBCL patients after second-line treatment failure.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03579082.

Survey: acceptability of opportunistic bilateral salpingectomy in Flanders

Background: The VVOG (Flemish Society of Obstetrics and Gynaecology) published a consensus statement promoting opportunistic bilateral salpingectomy (OBS). Objectives: The aim of the study was to obtain insight into the current opinion and general practice of Flemish gynaecologists to counsel and perform OBS. Materials and Methods: A questionnaire was distributed to Flemish gynaecologists three months following publication. Main outcome measures: The drawbacks and incentives to counsel and perform OBS were questioned. Results: Complete response rate was obtained from 99 gynaecologists (17%) and 37 trainees (19%). The majority of respondents (77%) always counselled for OBS in patients scheduled for hysterectomy without oophorectomy. Eighteen per cent counselled only above a certain age cut off and/or if patient was already menopausal. The most important incentive to counsel in cases of hysterectomy by the abdominal approach and vaginal hysterectomy (VH) was the opportunity to prevent ovarian cancer. The yet-undetermined risk of premature ovarian failure was mentioned as the most important barrier in counselling women for OBS in those undergoing hysterectomy by the abdominal approach. For VH, the respondents saw the risk of complications and increased surgical time as the most important barriers. Sixty-one percent of gynaecologists preferred to perform bilateral salpingectomy as sterilisation method. Conclusions: Our study suggests that the concept of OBS is already well known in Flanders. There is a positive attitude towards the routine implementation of OBS, although some barriers and doubts about an age cut-off still exist in practice.

Discrepancies in response and immune-related adverse events (irAE) of anti-PD-1 monotherapy between races and primary sites in patients (pts) with advanced nonacral cutaneous melanoma (NACM).

9530 Background: Ultraviolet (UV)-induced high tumor mutation burden (TMB) of NACM is associated with response to anti-PD-1 monotherapy (aPD-1). Anatomic location of the primary lesion (reflecting UV exposure) and race (reflecting eumelanin level) may serve as surrogates for TMB and be associated with varying response and irAE patterns. Methods: Pts with advanced NACM receiving aPD-1 between 2009-2019 were retrospectively analyzed from 5 institutions in the US, Australia and China. Best response, survival (PFS and OS), and organ/system-specific irAEs were compared by race (Caucasian [C] vs non-Caucasian [NC]) and primary anatomic site. Results: Among 697 patients, 616 were C, 81 were NC. Complete response rate (CRR) was 24.8% (95%CI, 21.4-28.4) and 2.6% (95%CI, 0.3-9.1) and ORR was 54.9% (95%CI, 50.9-58.9) and 15.6% (95%CI, 8.3-25.6) in C and NC, respectively (both P<.001). Median PFS was 16.5 (95%CI, 12.0-23.1) and 5.2 (95%CI, 3.6-7.6) months, median OS was 60.5 (95%CI, 49.9-not reached [NR]) and 29.2 (95%CI, 17.9-NR) months, in C and NC, respectively (P<.001 and =.04). In multivariate analyses, C had significantly higher CRR (OR 13.4, 95%CI 3.1-57.4), ORR (OR 10.6, 95%CI 4.6-24.5), and longer PFS (HR 0.5, 95%CI 0.4-0.7) than NC. Compared to a head primary site, NACM from less UV-exposed regions had significantly lower CRR (upper trunk, OR 0.6, 95%CI 0.4-0.96; lower limb, OR 0.5, 95%CI 0.2-0.9), ORR (lower limb, OR 0.6, 95%CI 0.3-0.9) and poorer PFS (perineum/buttock, HR 2.1, 95%CI 1.2-3.5; lower limb, HR 1.6, 95%CI 1.2-2.2) and OS (perineum/buttock, HR 3.8, 95%CI 2.2-6.8; lower limb, HR 1.7, 95%CI 1.2-2.4). Overall irAE incidence was similar between C and NC but irAE subtypes varied. C had significantly higher incidence of GI (12.2%, 95%CI 9.5-15.3% vs 1.2%, 95%CI, 0.03-6.7%, P=.001), respiratory (10.3%, 95%CI 7.8-13.2% vs 0, P<.001) and grade 3/4 (15.4%, 95%CI 12.4-18.8% vs 6.2%, 95%CI 2.0-13.8%, P=.03) irAEs; and lower incidence of endocrine (13.8%, 95%CI 10.9-17.0% vs 32.1%, 95%CI 22.2-43.4%, P<.001) and liver (4.8%, 95%CI 3.2-7.1% vs 13.6%, 95%CI, 7.0-23.0%, P=.005) irAEs. IrAEs did not vary by primary NACM site. Conclusions: Race and primary site are independently correlated with distinct response and survival outcomes in pts with advanced NACM receiving aPD-1. IrAE subtypes vary by race although overall irAE incidence does not.