Including Induction Chemotherapy Research Articles

Sarcopenia with decreased total psoas muscle area in children with high-risk neuroblastoma

BackgroundWe calculated psoas muscle area (PMA) z-scores in high-risk neuroblastoma patients undergoing treatment to examine the clinical significance of sarcopenia in this cohort. MethodsWe analyzed retrospective data from patients aged 0–18 who were diagnosed with abdominal neuroblastoma between 2005 and 2019 at Samsung Medical Center. Patients categorized as high-risk undergone induction chemotherapy, neuroblastoma excision, and tandem high-dose chemotherapy with autologous stem cell transplantation (HDCT/auto-SCT) were selected. L3-4 lumbar levels on axial CT images were identified and we measured the areas of the left and right psoas muscles to determine tPMA. Total PMA z-scores were calculated using an open online tool. ResultsThere were 45 boys and 25 girls with a mean age of 3.86 years. CT images taken at initial diagnosis and after tandem HDCT/auto-SCT were selected to calculate tPMA z-scores. Mean elapsed time between the two measurements was 12.91 ± 1.73 months. Mean tPMA z-score significantly decreased from −0.21 ± 1.29 to −0.66 ± 0.97 (p = 0.022). Length of hospital stay was significantly longer in the group of patients whose tPMA z-scores decreased by more than .45 (177.62 ± 28.82 days vs. 165.75 ± 21.34 days, p = 0.049). Presence of sarcopenia at initial diagnosis was a significant risk factor for bacterial infection during neuroblastoma treatment.Conclusion: tPMA z-scores in high-risk neuroblastoma patients decreased significantly following a treatment regimen that included induction chemotherapy, tumor resection surgery, and HDCT/auto-SCT. A greater decrease in tPMA z-score was associated with longer hospital stay during treatment.

Prevalence and Outcome of Vexas Syndrome in Unrelated Hematopoietic Stem Cell Transplantation

Introduction Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a newly identified monogenic disorder defined by somatic UBA1 mutations in hematopoietic progenitor cells, resulting in bone marrow failure (BMF) and systemic inflammation. This syndrome is frequently associated with myelodysplastic syndrome (MDS) or plasma cell dyscrasia. Although high-dose corticosteroids alleviate symptoms and cytopenia, allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested as a potentially curative treatment. This study evaluated the safety and efficacy of unrelated HSCT for treating VEXAS syndrome and its prevalence in patients with hematologic diseases. Methods We conducted retrospective screening for UBA1 mutations in patients with BMF or plasma cell neoplasms who underwent their first HSCT from unrelated donors in Japan between 1995 and 2020. Pre-HSCT blood DNA samples and clinical data were collected from the Japanese Data Center for Hematopoietic Cell Transplantation. Multiplex real-time PCR was used to detect the most common pathogenic UBA1 mutations, including p.M41L (c.121A>C), p.M41V (c.121A>G), and p.M41T (c.122T>C), with detection limits of 0.13%, 0.5%, and 1%, respectively. The presence of these mutations was confirmed using Sanger sequencing and droplet digital PCR. In addition, we examined UBA1 mutations in 2 patients previously diagnosed with MDS but suspected of having VEXAS syndrome based on specific clinical features. Results Among 4340 patients with either BMF or plasma cell neoplasms who underwent unrelated HSCT, 1771 had available pre-HSCT blood DNA samples. The diagnoses of the 1771 patients included MDS (n = 1264), acquired aplastic anemia (n = 375), inherited BMF syndromes (n = 89), plasma cell neoplasms (n = 23), and other acquired BMF syndromes (n = 20). The median patient age at HSCT was 46 (range, 0-75; interquartile range, 20-59) years old, and the male-to-female ratio was 1.6:1. Pathogenic UBA1 mutations were detected in 2 of the 1771 patients (0.11%), both of whom were male MDS patients older than the median age (cases 1 and 2); thus, the prevalence of VEXAS syndrome within this patient subgroup was 0.36%. Both patients received chemotherapy before unrelated donor bone marrow transplantation (BMT), including induction chemotherapy and azacitidine, and achieved complete and partial responses, respectively. In addition, UBA1 mutations were detected in the 2 MDS patients at Kanazawa University Hospital (cases 3 and 4). Case 3 also underwent unrelated BMT after experiencing cytopenia relapse and inflammatory symptoms during corticosteroid reduction. The clinical characteristics and outcomes of the 4 patients with VEXAS syndrome are summarized in Table 1. Variant allele frequencies (VAFs) of UBA1 mutations ranged from 2% to 71%. The 3 patients who underwent unrelated BMT received fludarabine and busulfan-based conditioning regimens and graft-versus-graft disease (GVHD) prophylaxis with tacrolimus + methotrexate or cyclosporine + methotrexate. All 3 patients achieved neutrophil and platelet engraftment. One patient required systemic corticosteroids for acute skin GVHD. One patient died of idiopathic interstitial pneumonia 5 months after BMT. The other 2 patients were alive without relapse, chronic GVHD, or other complications at 18 and 28 months after BMT. Discussion Our results support the curative potential of allogeneic HSCT for VEXAS syndrome without excessive toxicity. The occurrence of transplant-related mortality due to idiopathic interstitial pneumonia may be related to the reported poor outcome of the p.M41V mutation following non-transplant therapy. The low prevalence of VEXAS syndrome in the current cohort may be due to the late age of onset and the rare progression to advanced MDS. The low VAFs of UBA1 mutations in the 2 patients who responded to chemotherapy before HSCT may indicate the efficacy of chemotherapy in selectively eradicating UBA1 mutant clones. Our rapid, sensitive, and cost-effective screening method for VEXAS syndrome can help optimize treatment strategies for this rare disease in future studies.

Comparison of Autologous, Matched Sibling, and Alternative Donor Stem Cell Transplant Outcomes for Acute Myeloid Leukemia Patients in First Remission: A Propensity Score Matching Study

Introduction Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). Auto-HSCT is more commonly administered in favorable- and intermediate-risk AML with good remission, while MSD-HSCT and AD-HSCT are suggested for patients with high-risk factors. In the present study, we aim to retrospectively compared auto-HSCT with MSD-HSCT and AD-HSCT in de novo AML patients who are in first complete remission (CR1) with favorable or intermediate risk, according to 2022 ELN criteria. Methods We conducted a single-center retrospective comparative analysis, comparing auto-HSCT and allo-HSCT for favorable and intermediate-risk de novo AML in CR1. Patients with secondary AML, acute promyelocytic leukemia, poor-risk AML, those receiving syngeneic HSCT, those not in CR1 before HSCT, or those who achieved CR1 with ≥ 3 cycles of induction chemotherapy were excluded from the study. A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Persistent undetectable MRD (uMRD) was defined as uMRD after one course of chemotherapy without recurrent positive MRD before HSCT, while non-persistent uMRD was characterized by the presence of detectable MRD at least once before HSCT. The variables used for propensity score matching included induction chemotherapy cycles, consolidation chemotherapy cycles, and measurable residual disease (MRD) measurement by flow cytometer before HSCT. A caliper width of 0.2 was used. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Results After applying propensity score matching, a final cohort of 126 patients was available for analysis. This cohort consisted of 42 patients in each group: auto-HSCT, MSD-HSCT, and AD-HSCT. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT (haplo-HSCT). All patients received myeloablative conditioning regimen. There were no significant differences observed in the 3-year overall survival (OS) and disease-free survival (DFS) among the auto-HSCT, MSD-HSCT, and AD-HSCT groups [3-year OS: 79.5% (95% CI, 67.8-93.3%), 83.0% (95% CI, 72.2-95.3%), and 65.7% (95% CI, 50.5-85.5%), respectively; P=0.21. 3-year DFS: 72.6% (95% CI, 59.9-87.9%), 83.0% (95% CI, 72.2-95.3%), and 67.5% (95% CI, 54.2-84.1%), respectively; P=0.32]. The cumulative incidence of 3-year NRM was 2.7% (95% CI, 2.0-12.5%), 7.3% (95% CI, 1.8-17.9%), and 21.9% (95% CI, 10.7-35.6%), respectively (P=0.008). The 1-year probability of OS after relapse was higher in the auto-HSCT group (44.4%; 95% CI, 21.4-92.3%) compared with MSD-HSCT (0.0%) and AD-HSCT (37.5%; 95% CI, 8.4-99.9%) (P=0.0017). The MRD status before HSCT had an impact on DFS (persistent uMRD versus non-persistent uMRD: HR=0.29; 95% CI 0.09-0.94, P=0.04) and relapse (persistent uMRD versus non-persistent uMRD: HR=0.17; 95% CI 0.05-0.66, P=0.01) following auto-HSCT. The subgroup analysis was then performed based on MRD status before HSCT. In patients with uMRD before transplant (n=83), OS was similar across the groups. However, auto-HSCT showed a trend of increased DFS compared to AD-HSCT (HR 2.85, P=0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (n=38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, P=0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first two years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (P=0.015) and AD-HSCT (P<0.001). Conclusions Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.

A Review of FLT3 Kinase Inhibitors in AML.

Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6-8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient's condition and susceptibility.

New Approaches Towards Targeted Therapy for Childhood Neuroblastoma.

Neuroblastoma (NB), comprising around 10% of all childhood neoplasms and 15% of pediatric cancer deaths is a heterogenous disease and can be divided into very low-, low-, intermediate- and high-risk NB. Treatment of very low/low-risk NB is usually based on observation, or surgery alone, whereas intermediate-risk NB is in addition to surgery treated with mild chemotherapy and roughly 80-95% of the patients are cured. In contrast, high-risk NB patients receive multimodal therapy with e.g. induction, consolidation, and maintenance therapy, which can include induction chemotherapy and surgery and in severe cases adding intensive chemotherapy and even autologous stem cell transplantation and radiotherapy. Unfortunately, however this treatment does not cure all patients and around 50% succumb to disease. For this purpose, new treatment options are urgently needed. In this review, we describe the complex molecular heterogeneity of NB, and potential new options for targeted therapy.

Therapeutic strategy aiming at R0 resection for borderline-resectable esophageal squamous cell carcinoma using induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil.

Treatment for borderline resectable (cT3br) esophageal squamous cell carcinoma (SCC) is currently undefined. This study aimed to analyze the outcome of treatment strategies including induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) against T3br esophageal SCC. A total of 32 patients with cT3br esophageal SCC enrolled in this study were treated with two cycles of DCF induction therapy. The overall response rate to DCF induction therapy was 62.5%, while the disease control rate was 93.8% (complete response (CR), three; partial response (PR), 17; stable disease (SD), 10; progressive disease (PD), 2). After DCF induction chemotherapy, 27 patients underwent conversion surgery (CS) and five patients underwent definitive chemoradiotherapy (CRT). Out of 27 patients who underwent CS, 17 underwent transthoracic esophagectomy and 10 underwent thoracoscopic esophagectomy. Anastomotic leakage occurred in five patients (18.5%) and pneumonia in four (14.8%). Recurrent laryngeal nerve paralysis and arrhythmia were observed in two patients (7.4%). The R0 resection rate was 81.5%. Among the five patients who underwent definitive CRT, only one patient (20.0%) achieved CR. Two patients (40.0%) had PR and two (40.0%) had PD. Salvage esophagectomy was performed in one patient after definitive CRT. The 1-, 3-, and 5-year overall survival rates were 75.0, 50.6, and 46.4%, respectively, whereas the 1-, 3-, and 5-year disease-free survival rates were 54.9, 38.8, and 38.8%, respectively. DCF induction therapy and subsequent CS or definitive CRT are promising treatment strategies for cT3br esophageal SCC.

T1-2N1M0 nasopharyngeal carcinoma chemotherapy or not: A retrospective study.

Radiotherapy (RT) combined with chemotherapy is the standard treatment for T1-2N1M0 nasopharyngeal carcinoma (NPC) based on conventional radiotherapy. However, intensity-modulated radiotherapy (IMRT) has narrowed the treatment gap between RT and chemoradiotherapy. Thus, this retrospective study aimed to compare the efficacy of RT and chemoradiotherapy (RT-chemo) in treating T1-2N1M0 NPC in the IMRT era. From January 2008 to December 2016, 343 consecutive patients with T1-2N1M0 NPC in two cancer centers were included. All patients received RT or RT-chemo, chemotherapy including induction chemotherapy (IC) + concurrent chemoradiotherapy (CCRT), CCRT, or CCRT + adjuvant chemotherapy (AC). The number of patients who received RT, CCRT, IC + CCRT, and CCRT + AC was 114, 101, 89, and 39. The survival rates were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariable analysis was performed to identify valuable prognostic factors. The median follow-up time for survivors was 93 (range: 55-144) months. The 5-year overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) for the RT-chemo and RT groups were 93.7%, 88.5%, 93.8%, 93.8% and 93.0%, 87.7%, 91.9%, 91.2%, respectively (P>0.05 for all outcomes). No significant survival differences were found between the two groups. The T1N1M0 or T2N1M0 subgroup analysis showed that treatment outcomes had no significant differences between the RT and RT-chemo groups. After adjusting for various factors, treatment mode was not identified as an independent prognostic factor for all survival rates. In this study, outcomes of T1-2N1M0 NPC patients treated by IMRT alone were comparable to chemoradiotherapy, supporting the omission or postponement of chemotherapy.

Total Neoadjuvant Therapy in Rectal Cancer: Multi-center Comparison of Induction Chemotherapy and Long-Course Chemoradiation Versus Short-Course Radiation and Consolidative Chemotherapy

BackgroundTotal neoadjuvant therapy for locally advanced rectal cancer may include induction chemotherapy and chemoradiation or short-course radiotherapy and consolidative chemotherapy. MethodsPatients with clinical stage 2 or 3 rectal cancer who received induction chemotherapy followed by long-course chemoradiation at the University of Colorado (2016–2020) or short-course radiotherapy followed by consolidative chemotherapy at Washington University (2017–2020) were assessed. ResultsEighty-four patients received induction chemotherapy and chemoradiation and 83 received short-course radiotherapy and consolidative chemotherapy. Among patients with complete re-staging evaluation, clinical complete response rates were similar, 49% (18/37) and 53% (44/83), respectively (p = 0.659). In the induction chemotherapy and chemoradiation group, 80% (n = 67) underwent surgery and 28% (n = 19) achieved a pathologic complete response. In the short-course radiotherapy and consolidative chemotherapy group, 44 (53%) patients underwent surgery and 11% (n = 5) had a pathologic complete response. Overall, a complete response was observed in 43% (n = 36) of patients who received induction chemotherapy and chemoradiation compared to 53% (n = 44) who received short-course radiotherapy and consolidative chemotherapy (p = 0.189). Perioperative outcomes were similar in patients who received induction chemotherapy and chemoradiation compared to short-course radiotherapy and consolidative chemotherapy: intraoperative complications (2% vs 7%), complete mesorectal specimen (85% vs 84%), anastomotic leak (9% vs 7%), organ/space infection (9% vs 5%), readmission (19% vs 21%), and reoperation (8% vs 9%), respectively (all p > 0.05). ConclusionsIn patients with clinical stage 2 or 3 rectal cancer, total neoadjuvant therapy with either induction chemotherapy and chemoradiation or short-course radiotherapy followed by consolidative chemotherapy were associated with similar perioperative morbidity and complete response rates.

Survival impact of unexpected N2 in stage IIIB/N2 non-small cell lung cancer patients.

We investigated the effect of unexpected N2 on survival in stage IIIB/N2 cases. We retrospectively analyzed 1803 non-small cell lung cancer patients between 2010 and 2016. There were 89 patients (4.9%) with unexpected N2 (pathological (p) IIIB/N2 group), whereas 49 patients (2.7%) with cN2 (clinical (c) IIIB/N2 group). Although pIIIB/N2 group underwent surgery followed by adjuvant therapy, the cIIIB/N2 group of patients had multimodality treatment including induction chemotherapy ± radiotherapy followed by surgery. The five-year overall survival (OS) for all patients was 36.0% [median survival time (MST) 27.9 months], and disease-free survival (DFS) was 28.9% (MST, 18.2 months). The OS was 39.6% (MST: 34.4 months) and the median DFS time was 31.1% (Median: 23.1 months) in the pIIIB/N2 group, whereas it was 29.2% (MST: 23.0 months) for OS and 22% (median: 12.4 months) for DFS in the cIIIB/N2 group. There were no significant OS and DFS differences between the pIIIB/N2 group and the cIIIB/N2 group (p = 0.124 and p = 0.168, respectively). In stage IIIB/N2 cases, the fact that N2 could not be detected preoperatively with minimally invasive or invasive methods and was detected in the pathological examination after surgery does not provide a survival advantage.

Which future for de-intensified treatments in HPV-related oropharyngeal carcinoma?

The development of deintensified therapies aiming at reducing the treatment-related toxicity while not impairing the outcome is an unmet need in HPV+ oropharyngeal carcinoma patients. Several deintensification approaches have been explored in this setting, including induction chemotherapy with reduced chemoradiation dose in responding pts. The findings of the studies conducted so far show that the available deescalated therapy should be based on the disease risk profile. At present, we still lack robust high level data to infer that the cited interventions are equivalent or superior to standard of care treatments. However, literature data suggest that approximately 70% of low-risk patients might receive a deintensified approach by including either surgery or induction chemotherapy. In the context of high-risk disease, more than 80% of patients may undergo a deintensified loco-regional treatment by neoadjuvant systemic therapy. Epidemiological data suggest that in the next decades, most of the HPV-related OPSCC patients will be made of old and possibly frail individuals. However, this patient population was excluded from most of the studies conducted so far. Therefore, there is a strong need for clinical trials to define risk-based deescalation strategies in this population and in younger patients as well.

Clinical feasibility of combining intraoperative electron radiation therapy with minimally invasive surgery: a potential for electron-FLASH clinical development

BackgroundLocal cancer therapy by combining real-time surgical exploration and resection with delivery of a single dose of high-energy electron irradiation entails a very precise and effective local therapeutic approach. Integrating the benefits from minimally invasive surgical techniques with the very precise delivery of intraoperative electron irradiation results in an efficient combined modality therapy.MethodsPatients with locally advanced disease, who are candidates for laparoscopic and/or thoracoscopic surgery, received an integrated multimodal management. Preoperative treatment included induction chemotherapy and/or chemoradiation, followed by laparoscopic surgery and intraoperative electron radiation therapy.ResultsIn a period of 5 consecutive years, 125 rectal cancer patients were treated, of which 35% underwent a laparoscopic approach. We found no differences in cancer outcomes and tolerance between the open and laparoscopic groups. Two esophageal cancer patients were treated with IOeRT during thoracoscopic resection, with the resection specimens showing intense downstaging effects. Two oligo-recurrent prostatic cancer patients (isolated nodal progression) had a robotic-assisted surgical resection and post-lymphadenectomy electron boost on the vascular and lateral pelvic wall.ConclusionsMinimally invasive and robotic-assisted surgery is feasible to combine with intraoperative electron radiation therapy and offers a new model explored with electron-FLASH beams.

Advanced Nasopharyngeal Carcinoma: Current and Emerging Treatment Options.

Nasopharyngeal carcinoma (NPC) has seen improved treatment outcomes and a decrease in incidence worldwide in recent years due to developments in medicine and improved public health. However, 70% of cases are still diagnosed at advanced stages and these advanced NPC cases show a poor prognosis. Reports on current and future treatment in advanced NPC are summarized. Chemoradiotherapy is the mainstay of treatment for advanced NPC. The administration of platinum agents as a concurrent drug and intensity modulated radiotherapy (IMRT) is the most appropriate irradiation method, and is associated with high local control rates. For induction and adjuvant chemotherapy, platinum-based two- or three-drug combination chemotherapy is recommended. The tumour volume, plasma Epstein-Barr virus (EBV)-DNA levels, and the tumour site are used to determine the indication for adjuvant and neo-adjuvant chemotherapy. The tolerability of induction chemotherapy is controversial, and the indications and timing should be carefully considered in each case. Chemotherapy is used for patients with distant metastasis. Gemcitabine/cisplatin is the first-line regimen. The efficacy of immune checkpoint inhibitor (ICI) treatment has recently been reported for NPC and, as in other areas of the head and neck, it is expected to be effective for patients with recurrent/distant metastasis. Trials are underway for various uses of ICIs, including induction chemotherapy, postoperative treatment, and use in combination with chemoradiotherapy. Immunotherapy for NPC, an EBV-associated cancer, has been reported to have some efficacy with immunotherapy used in other EBV-associated cancers. Immunotherapy may be introduced for NPC in the future, depending on the results of clinical trials. Future changes in the treatment of NPC are expected to include risk classification based on plasma EBV-DNA levels and the development of personalized treatment with individual selection of timing and type of therapy.

Single-Center 20-Year Experience in Surgical Treatment of Malignant Pleural Mesothelioma.

Objectives: We examined a series of malignant pleural mesothelioma (MPM) patients who consecutively underwent surgery in our institution during the last 20 years. Across this period, we changed our surgical approach to MPM, adopting extended pleurectomy and decortication (eP/D) instead of extrapleural pneumonectomy (EPP). In this study, we compare the perioperative outcomes and long-term survival of patients who underwent EPP vs. eP/D. Methods: A retrospective analysis was carried out of all the MPM patients identified from our departmental database who underwent EPP or P/D from 2000 to 2021. Clavien–Dindo criteria was adopted to score postoperative complications, while Kaplan–Meier methods and a Cox multivariable analysis were used to perform the survival analysis. Results: Of 163 patients, 78 (48%) underwent EPP and 85 (52%) eP/D. Induction chemotherapy was significantly administrated more often in the eP/D group (88% vs. 51%). Complete trimodality treatment including induction chemotherapy, radical surgery, and adjuvant radiotherapy was administered in 74% of the eP/D group versus 32% of the EPP group (p < 0.001). The postoperative morbidity rate was higher in the eP/D group (54%) compared to the EPP group (36%) (p = 0.02); no statistically significant differences were identified concerning major complications (EPP 43% vs. eP/D 24%, p = 0.08). No statistical differences were identified in 30-day mortality, 90-day mortality, median disease-free, and overall survival statistics between the two groups. The Cox multivariable analysis confirmed no induction chemotherapy (HR, 0.5; p = 0.002), RDW (HR, 1.08; p = 0.02), and the presence of pathological nodal disease (HR, 1.99; p = 0.001) as factors associated with worse survival in the entire series. Conclusions: Our data support that eP/D is a well-tolerated procedure allowing the implementation of a trimodality strategy (induction chemotherapy, surgery, and radiotherapy) in most MPM patients. When eP/D is offered in this setting, the oncological results are comparable to EPP. To obtain the best oncological results, the goal of surgical resection should be macroscopic complete resection (R0) in carefully selected patients (clinical N0).

Prognostic value of tumor-infiltrating CD163+macrophage in patients with metastatic gastric cancer undergoing multidisciplinary treatment

BackgroundThe multidisciplinary treatment including induction chemotherapy plus conversion surgery (CS) has attracted attention as a new strategy to improve the outcome of metastatic gastric cancer (MGC). However, it is unclear which patients achieve a good response to chemotherapy and successful CS. Tumor-infiltrating immune cells (TIICs) have been reported to be both prognostic and predictive biomarkers not only in immunotherapy but also in chemotherapy in many cancer types. However, there have been no reports on the usefulness of TIICs as biomarkers in conversion surgery for MGC. The aim of the present study was to evaluate the association between the TIICs and treatment outcome for the multidisciplinary treatment in MGC.MethodsWe retrospectively analyzed 68 MGC patients who received docetaxel plus cisplatin plus S-1 (DCS) therapy between April 2006 and March 2019 in our institute. The number of tumor-infiltrating CD4+, CD8+, Foxp3+lymphocytes, CD68+, CD163+macrophages in pre-treatment endoscopic biopsy samples were evaluated to investigate their predictive value for multidisciplinary treatment.ResultsFifty patients underwent CS following DCS therapy (CS group), whereas 18 patients underwent DCS therapy alone (non-CS group). The median survival time (MST) of CS group was 33.3 months, which was significantly longer than the MST of 9.0 months in non-CS group (p < 0.01). The number of CD163+macrophages was extracted as an independent prognostic factor for overall survival in all patients. There were more cases of high infiltration of CD163+macrophages in non-CS group than in CS group. Furthermore, in CS group, pathological responders to DCS therapy showed low infiltration of CD163+ macrophages, and high infiltration of CD8+lymphocyte. CD163 low group showed a significant prolonged survival compared with CD163 high group in patients who underwent CS (p = 0.02).ConclusionsThe pre-treatment CD163+macrophages infiltration would be a pivotal biomarker for predicting prognosis and pathological response to multidisciplinary treatment among TIICs in MGC.Thus, for patients with low CD163+macrophage infiltration in pre-treatment biopsy sample, diagnostic imaging should be performed frequently during chemotherapy to avoid missing the optimal timing for CS, and CS should be aggressively considered as a treatment option if curative resection is deemed feasible.

Surgical stage in sequential therapy of unresectable oral cancer T3-4bN0-3M0: evaluation of treatment results

Introduction. Unresectable oral cancer is an urgent and complex problem in modern oncology. Annually, the proportion of patients with stage III–IV is 35 %, and the one-year mortality rate for this pathology reaches 32 %. Patients with advanced oral tumors usually have a negative prognosis and treatment tactics are limited to radiation therapy (RT), chemoradiation therapy, or sequential therapy, including induction chemotherapy (CT). Polymodal therapy for oral cancer is of particular interest in the treatment of pathology in this area.The study objective – to analyze the results of sequential treatment, including induction CT followed by RT and induction CT followed by surgery and RT in patients with unresectable oral cancer (T3–4bN0–3M0).Materials and methods. This retrospective study included 30 patients (11 women and 19 men) with primary non-resectable squamous cell carcinoma of the oral cavity (T3–4bN0–3M0) who received 2–3 courses of induction chemotherapy (CT) with DCF (docetaxel, cisplatin, 5-fluorouracil). Mean patients’ age was 61.2 years. The first treatment stage included induction CT according to the following scheme: docetaxel (75 mg/m2 /day on day 1) + cisplatin (75 mg/m2 /day on day 1) + 5-fluorouracil (1000 mg/m2 /day on days 1–4) repeated every 21 days. Study participants were divided into 2 groups according to their objective response to CT. Patients with resectable residual tumors have undergone surgery (after induction CT) followed by radical radiation therapy (RT) (induction CT + surgery + RT). Patients with non-resectable residual tumors/no objective response/no complete response after induction CT have undergone radical RT (induction CT + RT).Results. The objective response rate (ORR) to induction CT was 66.6 % (20 / 30). Five out of thirty patients (16.7 %) received no subsequent therapy: 3 individuals developed grade III–IV adverse events, while 2 individuals had progressive disease. One-third of patients (10 / 30; 33.3 %) had surgery followed by RT. Half of patients (15 / 30; 50 %) received RT after induction CT. The two-year relapse-free survival rates in the groups of induction CT + surgery + RT and induction CT + RT was 14 and 16 %, respectively (p = 0.49). The two-year overall survival rates in the same groups were 44 and 38 %, respectively (р = 0.74).Conclusion. Resectability was achieved in 33.3 % (10 / 30) of patients with initially unresectable oral cancer after induction CT. A sequential therapy regimen, including a surgical stage after induction CT, did not demonstrate a statistically significant increase in overall and disease-free survival rates. Sequential multimodal treatment of common oral cancers has some potential, but requires further study to assess its significance.

Induction Chemotherapy Followed by Pleurectomy Decortication and Hyperthermic Intraoperative Chemotherapy (HITHOC) for Early-Stage Epitheliod Malignant Pleural Mesothelioma-A Prospective Report.

Malignant pleural mesothelioma (MPM) is an aggressive disease with poor prognosis and the current treatment for early-stage MPM is based on a multimodality therapy regimen involving platinum-based chemotherapy preceding or following surgery. To enhance the cytoreductive role of surgery, some peri- or intra-operative intracavitary treatments have been developed, such as hyperthermic chemotherapy, but long-term results are weak. The aim of this study was to report the post-operative results and mid-term outcomes of our multimodal intention-to-treat pathway, including induction chemotherapy, followed by surgery and Hyperthermic Intraoperative THOracic Chemotherapy (HITHOC) in the treatment of early-stage epithelioid MPM. Since 2017, stage I or II epithelioid MPM patients have been inserted in a surgery-based multimodal approach comprising platinum-based induction chemotherapy, followed by pleurectomy and decortication (P/D) and HITHOC with cisplatin. The Kaplan–Meier method was used to estimate overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). During the study period, n = 65 patients affected by MPM were evaluated by our institutional Multidisciplinary Tumour Board; n = 12 patients with stage I-II who had no progression after induction chemotherapy underwent P/D and HITHOC. Post-operative mortality was 0, and complications developed in n = 7 (58.3%) patients. The median estimated OS was 31 months with a 1-year and 3-year OS of 100% and 55%, respectively. The median PFS was 26 months with 92% of a 1-year PFS, whereas DFS was 19 months with a 1-year DFS rate of 83%. The multimodal treatment of early-stage epithelioid MPM, including induction chemotherapy followed by P/D and HITHOC, was well tolerated and feasible with promising mid-term oncological results.

Prognostic Factors and Survival Outcomes in Blast Transformed Chronic Myelomonocytic Leukemia: A Mayo Clinic-MD Anderson Cancer Center Study of 171 Cases

Background:Blast transformed (BT) chronic myelomonocytic leukemia (CMML); defined by ≥20% blood or bone marrow (BM) blasts, occurs in 15-30% of patients and is a major cause of mortality. Reported risk factors include high risk karyotype, circulating blast count, circulating immature myeloid cells (IMC), CMML morphological subtype, and the presence of ASXL1 mutations. In the current study, we reviewed consecutive cases of BT CMML from the Mayo Clinic, MN, and the MD Anderson Cancer Center, Texas, USA, with the intent to examine i) prognostic factors, ii) survival trends, and iii) treatment outcomes.Methods:Diagnoses of CMML and BT-CMML were according to the 2016 WHO criteria. Treatment response in BT-CMML patients was assessed according to standard AML response criteria. Statistical analyses considered clinical and laboratory data collected at the time of BT. Survival was calculated from the date of BT to the date of death or last contact.Results:171 cases of BT CMML were identified from the Mayo Clinic (n=84) and MDACC (n=87). The median age at BT was 69 years and 64% were male. Eight one (49%) had received prior hypomethylating agent (HMA) therapy (Decitabine 50, 5-azacitidine 31), with 30% having achieved a complete remission (CR) prior to BT. CMML patients that received prior HMA therapy were more likely to have thrombocytopenia (p=0.03), higher LDH levels (p=0.007), lower frequency of TET2 mutations (p=0.04) and higher risk stratification by the Mayo prognostic model (p=0.009). The two institutional cohorts were comparable with regards to variables, both at CMML diagnosis and BT.Patient characteristics at time of BT: The median time from CMML diagnosis to BT was 12 months (range, 1-36). At BT, 16 (10%) presented with extramedullary disease, 81 (63%) with an abnormal karyotype, 41 (34%) with cytogenetic clonal evolution, with the following mutational distribution; TET2 50%, ASXL1 39%, NRAS 39%, FLT3 ITD 20%, NPM1 6%, RUNX1 6%, and 5% each for IDH1/2, EZH2 and JAK2 . Molecular clonal evolution was seen in 4 (22%) of 18 evaluable cases.Survival trends: After a median follow-up of 4.4 months (range 0-122), 141 (82%) deaths were recorded. Median overall survival (OS) was 6 months with 1- and 3-year survival rates of 25% and 9%, respectively; survival trends were similar (p=0.4) for patients diagnosed prior to and after the year 2006 (figure 1A).Treatment and response rates: Specific treatment for BT-CMML was documented in 157 cases and included induction chemotherapy (n=61), induction chemotherapy followed by stem cell transplant (HCT, n=18), HCT alone (n=3), HMA (n=18), novel therapeutic agents (n=18), and best supportive care (BSC, n=39). Treatment response was assessable in 113, including 76 treated with induction chemotherapy, 18 with HMA and 16 with novel therapeutics; with respective CR rates of 24%, 0% and 41%; with an additional 24%, 16% and 16% of patients achieving CR with incomplete blood count recovery (CRi), with a survival similar to those with CR (figure 1B). HCT was reported in 25 patients, 17 myeloablative and 8 reduced intensity, with a median OS of 7 months.Predictors of survival in BT-CMML: In univariate analysis of variables recorded at time of BT, risk factors adversely impacting survival included older age, lower hemoglobin, PB blast %, adverse cytogenetics at BT, prior exposure to HMA, not receiving induction chemotherapy, not achieving CR or CRi and not receiving HCT; all of these risk factors remained significant when analysis was adjusted for age. In multivariable analysis, lack of prior HMA exposure (p=0.001, HR 5.1; 95% CI 1.9-14.1) and the achievement of CR/CRi (p=0.02, HR 1.4; 95% CI 1.2-3.4) remained significant while HCT lost its significance (p=0.09). Gene mutations, including FLT3 ITD, cytogenetic and molecular clonal evolution at the time of BT did not impact survival. The 3-year survival rates for BT patients receiving induction chemotherapy, induction chemotherapy followed by HCT, HMA, novel agents and BSC were 8%, 20%, 12%, 3% and 0% respectively (figure 1C).Conclusions: Survival in patients with BT- CMML is dismal (≈6 months) and is adversely impacted by prior exposure to HMA and by the failure to achieve CR/CRi. After BT, the use of HMA therapy is largely ineffective (0% CR), with intensive therapies such as induction chemotherapy with or without HCT, failing to achieve durable remissions. [Display omitted] DisclosuresJabbour:Amgen: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda Oncology: Research Funding. Kantarjian:Amgen: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding.

Nasopharyngeal carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Nasopharyngeal carcinoma (NPC) is a rare pediatric tumor. Collaborative studies performed over the last decades showed improved results compared to historical data, but standardized guidelines for diagnosis and management of pediatric NPC are still unavailable. This study presents a European consensus guideline for the diagnosis and treatment of pediatric NPC developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT). Main recommendations include induction chemotherapy with cisplatin and 5-flurouracil, concomitant chemoradiotherapy in advanced disease, and to consider maintenance treatment with interferon beta (IFN-β) for selected high-risk patients. Dose adjustments of radiotherapy based on response to induction chemotherapy may decrease the rates of long-term treatment-related complications that affect most of the survivors.

Children Diagnosed with Acute Leukemia of Ambiguous Lineage (ALAL) Benefit from Acute Myeloid Leukemia (AML) Treatment Protocols: A Retrospective Analysis from a Single Center

Background:Acute Leukemia of Ambiguous Lineage (ALAL) is a very rare type of leukemia, comprising 2%-5% of Acute Leukemias (AL). There is a lack of a uniform definition, with two different classification systems used (EGIL and WHO 2008/2016), making the optimal chemotherapy approach undetermined. Patients and Methods:The medical records of newly diagnosed ALAL patients (BAL based on the EGIL criteria or ALAL based on the 2008/2016 WHO criteria), who were admitted to our hospital from January 2012 to August 2020, were retrospectively reviewed. Patients characteristics including age, sex, blood count, blasts in bone marrow and peripheral blood, morphology, immunophenotyping, and cytogenetic/molecular studies were obtained. Treatment methods and outcome data including induction chemotherapy, complete remission (CR), relapse, use of Hematopoietic Stem Cell Transplantation (HSCT) in first CR (CR1), and death were reviewed. Results:Among a total of 168 newly diagnosed patients with AL, 7 (4.17%) patients (5 male &amp; 2 female), fulfilled prerequisites of ALAL/MPAL. The median age at diagnosis was 5 years (range 1-14 years). Distinct dimorphic lymphoid and myeloid (monocytic) blast populations were present in one case with bilineal leukemia, as well as in two cases of biphenotypic leukemia. The remaining cases had morphologic and cytochemical features of Acute Myeloid Leukemia (AML), French-American-British (FAB): M1, M5 subtypes in two cases and Acute Lymphoblastic Leukemia (ALL) FAB L1-L2 subtype in one case. One case presented with early switch of lineage from ALL at diagnosis to AML M5 at the end of induction treatment. The AML directed regimen was associated with better complete remission rate at the end of induction treatment (CR 100%) compared to the ALL directed regimen (CR 0%). It is of note that the two patients that failed to achieve CR with ALL directed chemotherapy did respond to the AML induction treatment. Six patients underwent HSCT in CR1. One patient relapsed and underwent HSCT in CR2, but succumbed due to treatment related mortality during the transplantation period. At a median follow-up of 3.7 years (range 1-8 years) the 5-year overall survival (OS) and the event free survival (EFS) were 80% and 60%, respectively. Conclusions:Considering that ALAL is a very rare leukemia, the optimal treatment approach remains a dilemma for many clinicians. Although patient numbers are small and follow-up periods are short, the use of AML treatment protocols for ALAL appears to be promising and efforts need to be made on an international collaborative scale. Disclosures Kattamis: Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Vertex:Membership on an entity's Board of Directors or advisory committees;Genesis Pharma SA:Membership on an entity's Board of Directors or advisory committees;Apopharma/Chiesi:Honoraria, Speakers Bureau;Celgene/BMS:Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Ionis:Membership on an entity's Board of Directors or advisory committees;Agios:Consultancy;Vifor:Membership on an entity's Board of Directors or advisory committees.

High MYC Protein Expression in MDS Is Associated with Early Transformation to AML

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is shown to be associated with dismal clinical outcomes and there remains a pressing need for new therapeutic strategies to improve survival outcomes. It is also important to identify targetable markers that could predict an earlier AML transformation from preexisting MDS. Our recent studies demonstrated that high expression level of MYC oncoprotein is associated inferior survival outcome in AML-MRC patients and that MYC plays an oncogenic role by epigenetic regulation of hydroxylation of 5-methylcytosine. However, the role of MYC in MDS to AML progression remain to be answered. Here, we investigated MYC protein expression levels in bone marrow (BM) specimens of patients with preexisting MDS and their subsequent AML-MRC specimens to determine whether increased MYC expression is associated with early AML progression. We retrospectively identified 32 patients with histologically confirmed AML-MRC evolving from MDS and evaluated MYC protein levels in BM biopsy specimens at the time of initial MDS diagnosis and at the time of disease transformation to AML-MRC, respectively. Clinical data including age at diagnosis, gender, CBC with differential count, cytogenetics, somatic mutations common in myeloid disease, blasts count, and IPSS were extracted at the time of MDS and AML-MRC diagnosis. MYC expression was assessed by immunohistochemistry on 4-5µm tissue sections. Deparaffinized slides were stained with anti-MYC antibody (clone Y69, Roche Diagnostics) using a Ventana Benchmark automated system. MYC expression was scored independently by two hematopathologists and categorized as low vs. high as previously described. The cut-off for high MYC expression is ≥5% positive cells. The MDS-to-AML progression free survival (PFS) and overall survival (OS) were calculated from the date of MDS diagnosis and outcomes were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0. Among 32 patients, 69% (n=22) and 31% (n=10) patients had low and high MYC expression at MDS diagnosis (Table 1). The median age was 67.9 (33.5-78.7) and 61.1 (38.9-73.4) and the % of MYC positive blasts were 1% (range, 0-4.5) and 17.5% (range, 5-27.5) in low and high MYC groups, respectively, at the time of MDS diagnosis. There was no statistical difference in BM blast counts between low vs. high MYC groups (median 5% vs. 7.5%, p=0.4951). IPSS risk assessment in a total of 26 patients (19 in low MYC and 7 in high MYC) showed that 9% (n=2), 27% (n=6), 32% (n=7), and 18% (n=4) in low MYC group and 0% (n=0), 20% (n=2), 20% (n=2), and 30% (n=3) in high MYC groups had low, intermediate-I, intermediate-II, and high risk at the time of MDS diagnosis (Table 1). A total of 84% (86% [n=19] in low MYC and 80% [n=8] in high MYC) patients received treatments for MDS; ESA in 16% (n=5), hypomethylating agents in 81% (n=26), and Revlimid in 16% (n=5) (Table 1). Allogeneic stem cell transplant (allo-SCT) was performed in 12.5% (n=4) patients (n=3, low MYC; n=1, high MYC). Following AML progression, a total of 91% (n=29) patients received treatment for AML including induction chemotherapy (n=18), hypomethylating agents (n=7), and other therapies including trial (n=4) (Table 1). In the univariate analyses, patients with low MYC expression had significantly longer MDS-to-AML PFS (median 15.8 vs. 7.25 months, HR=0.1745, 95%CI=0.0591-0.5157, p=0.0016) (Figure 1), however, there was no OS difference between two groups (4.32 vs. 2.35 years, HR=0.5131, 95%CI=0.1064-2.475, p=0.6909). In a multivariate Cox model (adjusting for IPSS, age, front-line therapy, gender, allo-SCT, and MYC level), high MYC expression (HR=3.939, 95%CI=1.107-14.012, p=0.034) and IPSS risk (HR=1.903, 95%CI=1.139-3.181, p=0.014) were significant factor for MDS-to-AML PFS. In conclusion, high MYC expression at the MDS stage was associated with shorter time to AML progression, indicating that MYC plays an oncogenic role in MDS to AML transformation. Although our findings need further validation by prospective studies with greater sample size, our results support a combination treatment of hypomethylating agents with novel agents targeting MYC or/and its downstream pathways and warrant further study to identify underlying mechanisms of MYC-driven MDS to AML progression. Disclosures Talati: Pfizer: Honoraria; Astellas: Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; AbbVie: Honoraria. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Komrokji:JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy.