Courses Of Induction Chemotherapy Research Articles

Expression of RIPK1 and FADD are associated with chemosensitivity and survival in head and heck squamous cell carcinoma via tanshinone IIA-mediated modulation of the RIPK1-FADD-Caspase 8 complex.

Tanshinone IIA (Tan IIA), a main active ingredient of salvia miltiorrhiza, has a wide range of antitumor effects, while its specific role and mechanism in head and neck squamous cell carcinomas (HNSCC) is not fully understood. Totally 59 primary HNSCC patients underwent two courses of induction chemotherapy before surgery. The association between expression of Fas-Associated Death Domain (FADD) and receptor interacting protein kinase 1 (RIPK1) and chemotherapy resistance and survival were evaluated. The cell counting kit-8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments. The quantitative real-time reverse-transcription polymerase chain reaction, Western blot analysis and flow cytometry were used. FADD and RIPK1 expressions were differentially expressed in Chemosensitive and drug-resistant patients. Furthermore, patients with tumors exhibiting high expression of FADD and RIPK1 had significantly greater risk for chemoresistance and mortality than patients with tumors that had low levels of these proteins. Moreover, Tan IIA reduced the expression of RIPK1 and FADD in HNSCC chemoresistant cell lines, which could increase the chemosensitivity of cisplatin and promote apoptosis. Overexpression of RIPK1 led to attenuation of therapeutic effects of Tan IIA, which were mainly realized through regulation of the RIPK1-FADD-Caspase 8 complex. This study is the first to demonstrate the clinical value and role of FADD and RIPK1 in the treatment of HNSCC. This work establishes the proapoptotic effects of Tan IIA and its potential to enhance chemosensitivity in HNSCC by modulating the RIPK1-FADD-Caspase 8 complex.

Prognostic impact of number of induction courses to attain complete remission in patients with acute myeloid leukemia transplanted with either a matched sibling or human leucocyte antigen 10/10 or 9/10 unrelated donor: An Acute Leukemia Working Party European Society for Blood and Marrow Transplantation study.

For the majority of patients with acute myeloid leukemia (AML) an allogeneic stem cell transplant (SCT) in first complete remission (CR) is preferred. However, whether the number of courses required to achieve CR has a prognostic impact is unclear. It is unknown which factors remain important in patients requiring more than one course of induction to attain remission. This Acute Leukaemia Working Party study from the European Society for Blood and Marrow Transplantation identified adults who received an allograft in first CR from either a fully matched sibling or 10/10 or 9/10 human leucocyte antigen (HLA)-matched unrelated donor (HLA-A, HLA-B, HLA-C, HLA-DR, or HLA-DQ). Univariate and multivariate analyses were undertaken to identify the prognostic impact of one or two courses of induction to attain CR. A total of 4995 patients were included with 3839 (77%) patients attaining a CR following one course of induction chemotherapy (IND1), and 1116 patients requiring two courses (IND2) to attain CR. IND2 as compared to IND1 was a poor prognostic factor in a univariate analysis and remained so in a multivariate Cox model, resulting in an increased hazard ratio of relapse (1.38; 95% confidence interval [CI], 1.16-1.64; p=.0003) and of death (1.27; 95% CI, 1.09-1.47; p=.002). Adverse prognostic factors in a multivariate analysis of the outcomes of patients requiring IND2 included age, FLT3-ITD, adverse cytogenetics, and performance status. Pretransplant measurable residual disease retained a prognostic impact regardless of IND1 or IND2. Initial response to chemotherapy as determined by number of courses to attain CR, retained prognostic relevance even following SCT in CR.

A nationwide phase II study of delayed local treatment for children with high-risk neuroblastoma: The Japan Children's Cancer Group Neuroblastoma Committee Trial JN-H-11.

Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity. Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications. Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n=8; stage 4, n=56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]. This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma.

Serum IgG and IgA level in children with acute lymphoblastic leukaemia and its relation with outcome in induction chemotherapy

Background: Immunosuppression in children with Acute Lymphoblastic Leukaemia (ALL) escalates vulnerability to severe infectious complications which leads to higher morbidity and mortality rates among patients. Immunoglobulins are important part of defence mechanism of the body contributing to the humoral immunity. Of all the immunoglobulins, IgG and IgA represents most common type of antibody in blood circulation and provides most long-lived antibody-based immunity against invading pathogens. In earlier years, studies have shown that, serum immunoglobulins are found to be decreased during chemotherapy and this reduction is related with severe sepsis and death in patients. Early identification of immune status can be much useful for assessment of severity and better risk stratification of the patients. Objective: Evaluation of serum IgG and IgA levels in children with ALL and its relationship with sepsis in induction phase of chemotherapy. Method: This prospective observational study was conducted in the Departments of Paediatric Haematology & Oncology and Department of General Paediatrics, Bangabandhu Sheikh Mujib Medical University, Dhaka. During January 2022 to December 2022, a total 60 paediatric patients of newly diagnosed ALL were included as study population. As control, 30 patients were included in this study from General paediatrics and Paediatric Haematology & Oncology, BSMMU to compare baseline immunoglobulin levels with the study group. Complete history and physical examination of all patients were undertaken, and all prior reports were collected. Serum IgG and IgA level assay was done before starting chemotherapy and at the end of induction chemotherapy in the study group. Patients diagnosed with ALL received chemotherapy modified UK-ALL 2003 protocol. History and data of any event of sepsis, along with the symptoms of complications were taken from all patients during the course of induction chemotherapy. Results: The mean age of the cases were 5.49±3.15 (mean ± SD) years, which ranged from 1.9 to 15 years. Among the cases, 41 patients (68.3%) were male and 19 (31.7%) females. Seven (11.7%) subjects expired during induction chemotherapy. In comparison to the control group the mean IgG level in the study group was lower at baseline and even lower at the end of induction and it was statistically significant (p<0.05). The mean IgG level was low in patients with septic events in comparison with the patients with no septic events. Difference of mean of IgG between septic and aseptic patients was significant only at the end of induction chemotherapy (p<0.05). The mean IgA level was low in study group in comparison with the control group and it was statistically significant (p<0.05) only at the end of induction chemotherapy. The mean IgA level was low in patients with septic events in comparison with the patients with no septic events. Difference of mean of IgA between septic and aseptic patients was significant (p<0.05). Based on the receiver-operator characteristic (ROC) curves of change of S. IgG, with a cut off value 50% decreased from baseline having 68.8% sensitivity and 29.7% specificity for prediction of sepsis. Considering change of S. IgA with a cut off value 50% decreased from baseline having 67.6% sensitivity and 27.5% specificity for prediction of sepsis. Conclusion: In our study, the mean IgG and IgA level of the cases were low in comparison to the control group. The mean IgG and IgA level of the patients were lower who had infectious complications, and it was more marked after induction chemotherapy. Therefore, evaluation of immunoglobulin profiles is recommended to be considered in patients with ALL in further studies.

Postinduction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission

AbstractSelection of patients with NPM1-mutated acute myeloid leukemia (AML) for allogeneic transplant in first complete remission (CR1-allo) remains controversial because of a lack of robust data. Consequently, some centers consider baseline FLT3–internal tandem duplication (ITD) an indication for transplant, and others rely on measurable residual disease (MRD) status. Using prospective data from the United Kingdom National Cancer Research Institute AML17 and AML19 studies, we examined the impact of CR1-allo according to peripheral blood NPM1 MRD status measured by quantitative reverse transcription polymerase chain reaction after 2 courses of induction chemotherapy. Of 737 patients achieving remission, MRD was positive in 19%. CR1-allo was performed in 46% of MRD+ and 17% of MRD− patients. We observed significant heterogeneity of overall survival (OS) benefit from CR1-allo according to MRD status, with substantial OS advantage for MRD+ patients (3-year OS with CR1-allo vs without: 61% vs 24%; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.24-0.64; P < .001) but no benefit for MRD− patients (3-year OS with CR1-allo vs without: 79% vs 82%; HR, 0.82; 95% CI, 0.50-1.33; P = .4). Restricting analysis to patients with coexisting FLT3-ITD, again CR1-allo only improved OS for MRD+ patients (3-year OS, 45% vs 18%; compared with 83% vs 76% if MRD-); no interaction with FLT3 allelic ratio was observed. Postinduction molecular MRD reliably identifies those patients who benefit from allogeneic transplant in first remission. The AML17 and AML19 trials were registered at www.isrctn.com as #ISRCTN55675535 and #ISRCTN78449203, respectively.

Neoplasia-related and treatment-induced lymphopenia: impact on the outcome of chemoradiotherapy in laryngeal cancer

Introduction The role of the immune system in the efficacy of radiotherapy (RT) has been well established. We examined the role of neoplasia-related and treatment-induced lymphopenia in the outcome of RT or chemoradiotherapy (CRT) in squamous cell laryngeal cancer. Materials and Methods We retrospectively analyzed a series of 135 laryngeal carcinomas treated with radical or postoperative RT/CRT. Six lymphocyte-related variables were defined and examined: i. lymphocyte counts (LCs) before a brief course of induction chemotherapy, ii. pre-RT LCs, iii. post-RT LCs, iv. pre-RT neutrophil/lymphocyte ratio (N/L), v. pre-RT monocyte/lymphocyte ratio (M/L), and vi. pre-RT platelet/lymphocyte ratio (Pt/L). Results RT and CRT resulted in a significant decrease of LCs at the end of therapy, and this was significantly more prominent in patients treated with radical intent and neck irradiation (median LC nadir 810/μl vs. 1250/μl; p = .0003). Induction chemotherapy did not intensify the lymphotoxic effect of RT. LCs lower than the 33rd percentile before RT (<1718/μl) and after RT (<720/μl) were significantly linked to poor locoregional progression-free survival (LRFS; p = .02 and p = .08, respectively) and disease-specific overall survival (OS; p = .02 and p = .03, respectively). This was also confirmed multivariate analysis (LRFS: p = .006/HR = 2.41 and p = .08/HR = 1.76, respectively; OS: p = .001/HR = 3.06 and p = .02/HR = 2.07, respectively). High pre-RT N/L, M/L, and Pt/L ratios were also of ominous prognostic relevance. Conclusions Both neoplasia-related and RT-induced lymphopenia define the outcome of RT in terms of locoregional failure, incidence of metastasis, and, finally, disease-specific survival of patients with laryngeal cancer. Restoration of pre-RT lymphopenia and protection of peripheral lymphocytes during RT emerge as critical issues that demand therapeutic interventions to maximize the efficacy of RT/CRT in patients with laryngeal cancer.

A case of perioperative artificial pancreas therapy for a patient with esophageal cancer with type 1 diabetes.

A 72-year-old female with type 1 diabetes, a history of interstitial pneumonia, and diabetic ketoacidosis was admitted to our hospital with dysphagia. Endoscopy revealed a circumferential neoplastic lesion in the upper to middle esophagus, and a biopsy revealed squamous cell carcinoma. Computed tomography revealed invasion of the left main bronchus, and induction chemotherapy was initiated with a diagnosis of unresectable locally advanced esophageal cancer. After one course of induction chemotherapy, the tumor size reduced, bronchial invasion improved, and thoracoscopic esophagectomy was performed. During surgery and until 3days after surgery, the patient's blood glucose level was controlled using an artificial pancreas, and the target blood glucose range was set at 140-180mg/dL. On the fourth postoperative day, the patient was managed using a sliding scale. Mean blood glucose was 186.7 ± 70.0mg/dL for 3days before surgery, 190.5 ± 25.0mg/dL during artificial pancreas therapy from the surgery to the next day, 169.8 ± 22.0mg/dL during artificial pancreas therapy on the second to third postoperative days, and 174.5 ± 25.0mg/dL during sliding scale therapy for 4-15days after surgery. No hypoglycemia or ketoacidosis was noted.

The Efficacy of Modified Melphalan and Busulfan-Based Conditioning Regimen for Autologous-HSCT in Low-Risk and Intermediate-Risk AML Patients

Abstract: Background: Treatment options for patients with low-risk and intermediate-risk acute myeloid leukemia (AML) patients (non-M3) who achieved complete response (CR) after one course of induction chemotherapy include consolidation chemotherapy, autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Compared with chemotherapy, auto-HSCT could significantly reduce relapse rate, as was associated with significantly lower transplant-related mortality compared with allo-HSCT, but relapse rate was relatively high. The selection of conditioning regimen was crucial to reduce relapse rate after transplantation. In this study, we made refinements in the conditioning regimen with two alkylating agents, namely MCBA (the combination of melphalan, cladribine, busulfan, and cytarabine). We aim to investigate the efficacy of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. Methods: This prospective multi-center clinical trial was conducted in 5 tertiary hospitals in China, and enrolled low-risk and intermediate-risk AML patients (non-M3) who achieved CR after one course of induction chemotherapy, followed by 1-3 courses of high-dose cytarabine consolidation chemotherapy, and underwent auto-HSCT from May 2021 to June 2023 (ChiCTR Registration ID: ChiCTR2200056167). The MCBA conditioning regimen consists of melphalan 70mg/m 2/d, day -6~-5, cladribine 5mg/m 2/d, day -4~-2, busulfan 3.2mg/kg/d, day -8~-7, cytarabine 2g/m 2/d, day -4~-2. Results and Discussion: This study included a total 21 AML patients, 14 males, 7 females, with median age 41 years (ranged 20-56 years). There were 8 of low-risk and 13 of intermediate-risk. The median infused mononuclear cell and CD34+ cell counts were 12.22×10 8/kg (ranged 1.79-34.68×10 8/kg) and 2.28×10 6/kg (ranged 1.05-17.15×10 6/kg) respectively. Neutrophil and platelet engraftment were achieved in all patients, with a median time of 13 days (ranged 11-27 days) and 32 days (ranged 12-150 days) respectively. On the day of reconstitution, all patients exhibited good responses, including hematologic CR and minimal residual disease (MRD) negativity rates of 100%. 11 (52.4%) patients received maintenance therapy after auto-HSCT, with a median time of 3.5 months (ranged 1-9 months). Azacytidine, venetoclax or geritinib were the main maintenance therapies. With a median follow-up of 306 days（ranged 43-798 days）, the estimated 1-year overall survival (OS) and 1-year disease-free survival (DFS) were 80.4±13.4% and 70.9±12.8%, respectively. 4 patients relapsed within 1year, and the median time from HSCT to relapse was 240 (101-314) days. The probability of relapsed rate was 29.1±12.8%. Mucositis was the main reported regimen-related toxicity, mostly were mild and well tolerated. Severe mucositis included grade Ⅱ liver damage (4.8%), grade Ⅱ oral mucositis (4.8%) and grade Ⅲ-Ⅳ diarrhea (9.5%), respectively. Conclusion: The preliminary data demonstrated the efficiency of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. The regimen-related toxicity was well tolerated.

Outcomes for Children with High Risk Acute Myeloid Leukemia on the Myechild 01 International Phase III Clinical Trial

Background: Outcomes for pediatric acute myeloid leukemia (AML) remain disappointing, particularly for patients with poor risk cytogenetic/molecular genetic abnormalities and those who fail to achieve complete remission following course 1 of induction chemotherapy. Despite upfront allogeneic hematopoietic stem cell transplantation (HSCT) for these patients, high rates of relapse persist. The optimal approach to chemotherapy intensification and timing of HSCT for high risk (HR) patients remains unknown, with variable approaches employed by cooperative trial groups. Methods: The MyeChild 01 international phase III trial (NCT02724163) in children with de novo AML allocated patients up to 3 doses of gemtuzumab ozogamicin (GO 3mg/m 2/dose) during the first course of induction chemotherapy (mitoxantrone 12 mg/m2/dose x4; cytarabine 100 mg/m2/dose x20). Patients classified as HR after course 1 received FLA-Ida for course 2 followed by allogeneic HSCT. If required, a third course of bridging therapy (FLA) was given prior to HSCT. HR patients in MyeChild 01 included those with NUP98 fusions, selected KMT2A fusions ( KMT2A::MLLT10, KMT2A::MLLT4, KMT2A::AFF1, KMT2A::ABI1), CBFA2T3::GLIS2, DEK::NUP214, MECOM ( EVI1) rearrangements and all 12p abnormalities including MNX1::ETV6, in addition to the traditional HR abnormalities -7, -5/del(5q) and FLT3-ITD (without concurrent good risk abnormalities, including NPM1 mutations). Patients with induction failure after course 1 (≥ 5% blasts confirmed by flow) and those with non-HR cytogenetics/molecular genetics who remained MRD positive after course 2 (intermediate risk cytogenetics) or 3 (good risk cytogenetics) were also classified as HR. Here, we report the estimated 2-year outcomes for patients assigned HR post course 1 who received mitoxantrone and cytarabine and at least 1 dose of GO during course 1 (MA-GO). Outcomes of trial randomisations (1 vs 2 or 3 GO doses; consolidation for standard risk patients; HSCT conditioning) will be reported separately. Results: Of 749 patients enrolled at initial diagnosis, 183 received MA-GO during course 1 and were assigned HR post course 1. Of these, 172 (94%) patients had poor risk cytogenetic/molecular genetics, of which 32 also failed to achieve CR. Additionally, 11 (6%) patients did not have poor risk cytogenetic/molecular genetics but failed to achieve CR with MA-GO and thus were assigned to the HR group. Post course 1, 140 (77%) of these HR patients achieved CR/CRi, with 102/155 (66%) patients with evaluable samples achieving MRD negativity post course 1. Following course 1, 174 (95%) remained on trial and received FLA-Ida as course 2 and 163 patients (89%) proceeded to HSCT, 55 on trial and 108 following discontinuation from the trial. Estimated event-free survival (EFS) and overall survival (OS) at 2 years was 62% (95% CI: 56-70%) and 71% (64-78%) respectively (Figure 1 &amp; 2). Estimated cumulative incidence of relapse (CIR) and death in remission at 2 years was 26% (19-33%) and 7% (3-11%) respectively. For HR patients who received MA-GO in course 1, on trial FLA-Ida as course 2 and on or off trial HSCT (n = 156), 2 year estimated outcomes were EFS 69% (62-77%), OS 77% (70-85%) and CIR 24% (17-32%). The most common cytogenetic/molecular genetic abnormalities were rearrangements of KMT2A (50/183, 27%), with KMT2A::MLLT10 predominating (70%). FLT3-ITD (19%), NUP98 fusions (14%), -7 (13%), abn(12p) (11%), del(5q) (8%) and CBFA2T3::GLIS2 (6%) accounted for the majority of other abnormalities with outcomes varying by subtype. Collectively, KMT2A-rearranged patients had EFS and OS of 68% (55-83%) and 71% (59-86%) respectively and CIR of 26% (12-40%). For FLT3-ITD, the EFS and OS was 75% (62-92%) and 83% (69-99%) respectively with a CIR of 14% (1-26%). Of the 25 patients with a NUP98 fusion, 17 (68%) were NUP98::NSD1. The EFS and OS for patients with NUP98 fusions was 71% (55-92%) and 96% (88-100%) respectively with CIR 25% (1-48%). Conclusions: Two intensive courses of induction chemotherapy, including GO and mitoxantrone in course 1 and FLA-Ida in course 2, consolidated with allogeneic HSCT, appears to be an effective approach for most HR patients. 2 year estimated outcomes for HR patients compare favourably to recent trials of GO in pediatric AML, with particularly encouraging data for patients with KMT2A-r and FLT3-ITD.

Myelodysplasia-Related Gene Mutations for NGS-Based MRD Assessment in Acute Myeloid Leukemia

Introduction: Measurable residual disease (MRD) plays an increasing role for treatment management of AML patients. While next-generation-sequencing (NGS) based MRD assessment can be well standardized, there is uncertainty about the type of gene mutations that associate with prognosis and are useful for MRD assessment. The 2022 ELN recommendations assign patients with at least one mutation in the genes ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 or ZRSR2 to the subgroup of myelodysplasia-related gene mutations (MRGM), which is associated with poor prognosis. We aimed to define the prognostic effect of MRD after induction chemotherapy in AML patients with MRGM using MRG mutations for MRD assessment by NGS. Methods: We retrospectively collected bone marrow and peripheral blood samples from AML patients in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after one to two cycles of 7+3-based standard induction chemotherapy (IC) with at least one MRGM detected at diagnosis by myeloid panel sequencing covering 48 AML associated genes. Patients treated with one course of IC were included if they proceeded to allogeneic hematopoietic cell transplantation (alloHCT) already after one cycle. Molecular MRD status was assessed using targeted NGS and bioinformatics error-correction with 0.01% sensitivity as described before using only MRGM as MRD markers. Results: MRD was assessed on 104 adult newly-diagnosed AML patients (median age 58.6) with a total of 166 MRGM, resulting in a median of one MRGM per patient (range 1-4). 43 (41.3%) patients had secondary or therapy-related AML and 20 (19.2%) had myelodysplasia-related cytogenetic abnormalities. 68 (65.4%) patients were MRD positive for at least one MRGM after one (18 patients (17.3%)) or two (86 patients (82.7%)) cycles of intensive chemotherapy, while 36 (34.6%) became MRD negative. Measured variant allele frequencies (VAF) of positive samples ranged from 0.02-43.1% (median VAF 1.34%).MRD positive patients were older and more likely to be male compared to MRD negative patients, while cytogenetic risk, WBC count, Hgb, platelet count and ECOG status at diagnosis were similar to MRD negative patients. 53 (77.9%) MRD positive and 23 (63.9%) MRD negative patients underwent alloHCT in first CR/CRi.Median follow-up was 3.35 years. OS (P = 0.92), RFS (P = 0.99) and CIR (P = 0.98) were similar in MRD positive (at least one MRGM detectable) and negative (no MRGM detectable) patients (Figure 1). OS, RFS and CIR were also similar between MRD positive and negative patients, when MRD negativity was defined by conversion of at least one MRGM to negativity (55 (52.9%) MRD positive, 49 (47.1%) MRD negative), and when ASXL1 was excluded from the analysis. As variants with VAF &amp;gt;5% in CR/CRi samples may indicate clonal hematopoiesis, we excluded all variants with VAF &amp;gt;5% and repeated the analysis with the 88 (84.6%) remaining patients. Again, OS, RFS and CIR were similar for MRD positive and negative patients. We next reasoned that reduction of VAF correlates with the sensitivity of leukemic cells and possibly with depth of remission and long-term outcome. The fold-reduction of VAFs from diagnosis to the time of MRD analysis was calculated for all variants. For patients with several MRGMs, the variant with the largest fold-reduction was considered including undetectable variants. Patients with more or less than a 2-log, 3-log or 4-log reduction (log 10) had similar OS, RFS and CIR, respectively. Evaluating each MRGM individually, only RUNX1-MRD associated with RFS and by trend CIR (comparing MRD positive to negative patients for OS, HR 3.41, 95% CI 0.43-26.82, P = 0.24; RFS, HR 4.37, 95% CI 1.07-17.79, P = 0.04; CIR, HR 3.30, 95% CI 0.79-13.82, P = 0.1). Conclusion: 65.4% of AML-MRGM patients in CR/CRi remained MRD positive when MRGMs were used for MRD assessment by NGS. MRD positivity was associated with age above 60 years and male sex.Using all MRG mutations for MRD assessment at a threshold of 0.01% or by various degrees of log-reduction was not predictive of outcome after intensive induction chemotherapy. This limits the number of potential MRD markers for NGS analysis before alloHCT, although individual markers like RUNX1 may be of prognostic value.

Early Peripheral Blood Blast Clearance As a Prognostic Marker for Early Treatment Response in Pediatric Acute Myeloid Leukemia

Background and Significance The cure rate of pediatric acute myeloid leukemia (AML) has improved significantly; however, relapses still occur in up to 30% of the total patient population in high-income countries (HICs), and in an even higher percentage of patients in low- and middle-income countries (LMICs). Early treatment response, cytogenetics and minimal residual disease (MRD) are well-known prognostic factors for treatment outcome; however, sophisticated techniques for identifying prognostic factors are often lacking in LMICs, and are sometimes unsuccessful in HICs. Early treatment response assessed by a bone marrow (BM) aspirate on day 15 or day 22 (D22) (depending on the applicable protocol) after initiation of chemotherapy is a known prognostic factor for outcome in patients with pediatric AML, but does not allow modifications of the first induction chemotherapy course (Creutzig 2014, Abrahamsson 2011, Kern 2003). In both pediatric acute lymphoid leukemia (ALL) and adult AML, early peripheral blood blast clearance (PBBC) is a known early indicator of treatment response (Manabe 2008, Arellano 2012), whereas to the best of our knowledge, this has not yet been reported in pediatric AML. In this study, we evaluated the significance of time to complete PBBC, and rate of PBBC after initiation of chemotherapy, in relation to disease status in BM D22, as measure of early treatment response that has prognostic significance. Study Design and Methods Pediatric patients with AML, aged 0-18 years, that were treated according to the NOPHO-DBH AML-2012 protocol were included. The first 5 days of induction therapy consisted of etoposide, followed by 7 days of low-dose cytarabine and mitoxantrone or liposomal daunorubicin. Peripheral blood (PB) was assessed by morphology at the time of diagnosis, daily in the first week, and thrice weekly until D22 or until occurrence of complete clearance of blasts. BM D22 was assessed by morphology and flow cytometry. A receiver operating characteristic (ROC) analysis was performed to evaluate the predictive power of days from starting chemotherapy to complete PBBC. The correlation between time to complete PBBC and BM D22 results was analyzed using a logistic regression model. Multivariable logistic regression models were applied for the association after adjusting for effects of other covariates. Rate of PBBC was defined as the percentage of the absolute PB blast count on the day of diagnosis that cleared with each day of therapy, on average, until D22 or the day of complete PBBC. Results In total, 319 patients were included, out of whom 241 were eligible for analysis, and 78 not eligible due to missing or incomplete data. Day 9 after initiation of chemotherapy was identified as the most discriminating cut-off point for predicting BM D22 response. Patients were categorized into early PBBC (≤9 days; n=159) and delayed PBBC (&amp;gt;9 days; n=82) groups. Early PBBC was associated with having &amp;lt;5% AML cells in BM D22 as assessed by both morphology (OR 3.11; P=0.005) and flow cytometry (OR 2.73; P=0.041). Early PBBC also showed a much lower likelihood of having &amp;gt;15% AML cells in BM D22 by morphology (OR 0.08; P=0.002). None of the early PBBC patients had &amp;gt;15% AML cells in BM D22 by flow cytometry. For 217 patients (selection due to missing data [n=24]), the rate of PBBC could be calculated, and a discriminative cut-off value of 11% was identified. Patients were categorized into high rate of PBBC (&amp;gt;11%; n=132) and low rate of PBBC (≤11%; n=85). High rate of PBBC was associated with having &amp;lt;5% AML cells in BM D22 by flow cytometry (OR 4.30; P=0.007) and negative MRD status (OR 2.02; P=0.004), while also showing a strong association with a lower likelihood of &amp;gt;15% AML cells in BM D22 (OR 0.11; P=0.007) by morphology. None of the high rate PBBC patients had &amp;gt;15% AML cells in BM D22 by flow cytometry. Conclusion Both early complete PBBC and rate of PBBC after initiation of chemotherapy holds promise as prognostic marker for clinical outcome in pediatric AML, as it correlates significantly with BM D22 response. These findings may offer an early and easily accessible prognostic factor, particularly beneficial for LMICs, as well as for patients with unsuccessful MRD analyses.

Expression and Prognostic Impact of HK2 in Bone Marrow of Patients with Newly Diagnosed Acute Myeloid Leukemia

To detect the expression level of HK2 gene in the bone marrow of newly diagnosed patients with acute myeloid leukemia (AML) and investigate its influence on the clinical characteristics and prognosis. The expression level of HK2 gene in the bone marrow of 90 newly diagnosed patients with AML that accompanying clinical characteristics and survival status were detected by RT-qPCR, and compared with 18 allogeneic hematopoietic stem cell transplantation (allo-HSCT) donors. The Chi-square test, Kaplan-Meier survival analysis, and Cox proportional hazards regression model were used to analyze the correlation of HK2 expression level with clinical characteristics and prognosis. Compared with allo-HSCT donors, the HK2 expression was significantly increased in newly diagnosed AML patients (P <0.01). Compared with patients with total response (OR, complete response + complete response with incomplete hematologic recovery) after 2 courses of induction chemotherapy, the expression of HK2 in patients without OR was significantly increased (P <0.05). There was a significant difference in the relative expression of HK2 between patients with and without OR after 2 courses of induction therapy (P <0.001). The median survival time of patients with high expression of HK2 was significantly shorter than that of patients with low expression of HK2 (P <0.05). The multivariate Cox proportional hazards regression analysis showed that prognostic stratification, the expression level of HK2, and whether two courses of induction therapy achieved OR were independent factors affecting the prognosis of AML patients (P <0.05). Compared with allo-HSCT donors, the expression level of HK2 gene is increased in the bone marrow of newly diagnosed AML patients. The prognosis of patients with high expression of HK2 is poor. The expression level of HK2 is an independent factor affecting the prognosis of AML patients.

A RARE CASE OF BILATERAL SPONTANEOUS TENSION PNEUMOTHORAX IN A PATIENT WITH MUCORMYCOSIS

Mucormycosis is an invasive fungal infection seen in immunocompromised hosts. Here a rare case of mucormycosis with pulmonary involvement followed by bilateral spontaneous tension pneumothorax is described. Bilateral spontaneous tension pneumothorax is a rare and fatal condition. We present a case of 3 years old child, diagnosed case of acute Leukemia. During the course of induction chemotherapy, he was hospitalized with fever and diarrhea. He was being managed on lines of neutropenic colitis. During the hospital stay, the child developed sudden respiratory distress and seizures. Chest X-ray showed bilateral spontaneous tension pneumothorax. Immediate bilateral chest tubes insertions were done. He was also electively intubated. After successful lung expansion, the trial of weaning off the ventilator was given and patient was successfully extubated. CT Thorax after lung re-expansion showed few pneumatoceles with no bronchopleural fistulous communication. CT Brain and para nasal sinuses showed fungal rhinosinusitis with intracranial extension. Nasal endoscopy and debridement of necrotic tissue was done. Tissue cultures showed the growth of mucor species. The patient was also started on amphotericin B that was later changed to Posaconazole. He responded well to anti-fungal treatment and there was no recurrence of pneumothorax. Keywords: Mucormycosis, Tension pneumothorax, Bronchopulmonary fistula

Soluble Programmed Death-Ligand 1 (sPD-L1) as a Promising Marker for Head and Neck Squamous Cell Carcinoma: Correlations With Clinical and Demographic Characteristics.

Background and objective Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer type that affects the mucosal lining of the upper aerodigestive tract. Soluble programmed death-ligand 1 (sPD-L1)is a significant factor in hindering T cells' function, which prevents cancer cells from being detected by the immune system. This means that sPD-L1 is an essential component in the immune evasion of cancer. This study aimed to explore the potential of sPD-L1 as a prognostic biomarker for patients with HNSCC undergoing concurrent chemotherapy and radiation therapy. Methodology The study included 106 patients with locally advanced HNSCC who received three courses of induction chemotherapy followed by concurrent chemoradiation and 60 healthy subjects as controls. sPD-L1 levels were measured using anenzyme-linked immunosorbent assay (ELISA) kit, and the cutoff value was determined based on receiver operating characteristic (ROC) curve analysis. Results The results showed that sPD-L1 levels were significantly higher in HNSCC patients compared to healthy controls, with a cutoff value of 31.51 pg/mL. Higher sPD-L1 levels were associated with poorer overall survival rates. Conclusions These findings suggest that sPD-L1 may serve as a valuable prognostic biomarker for HNSCC patients undergoing concurrent chemotherapy and radiation therapy. The study highlights the importance of exploring new biomarkers and therapeutic strategies for HNSCC to improve patient outcomes and reduce morbidity and mortality rates associated with this disease.

Reduction rate of monoclonal protein as a useful prognostic factor in standard-risk group of newly diagnosed multiple myeloma.

Multiple myeloma (MM) is a common hematologic malignancy that originates from a malignant clone of plasma cells. Solitary plasmacytoma, history of diabetes, and platelet count are considered as prognostic factors for MM. But some patients are still associated with much worse outcomes without any prognostic predictors. This study aimed to observe the reduction rate of monoclonal protein (M protein) after the first and fourth chemotherapy cycles, which is considered as a new prognostic factor for progression-free survival (PFS) in standard-risk group of newly diagnosed MM patients. To investigate the reduction rate of M protein after first and fourth cycle chemotherapy as a useful prognostic factor. A total of 316 patients diagnosed with MM for the first time between 2010 and 2019 at the Lishui Municipal Central Hospital were included. All patients were diagnosed according to the National Comprehensive Cancer Network (NCCN) 2020.V1 diagnostic criteria. The risk assessment was performed by the Mayo Stratification for Macroglobulinemia and Risk-Adapted Therapy guidelines. After diagnosis, 164 patients were evaluated and underwent treatment with four to eight courses of continuous induction chemotherapy. The patients with no response after induction treatment were administered additional therapy following the NCCN 2020.V1 criteria. The following baseline data from the patients were collected: Gender, age at diagnosis, Durie-Salmon stage, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, catabolite activator protein, albumin/globulin ratio, lactate dehydrogenase, translocation (t)(6;14), t(11;14), maintenance regimen, total cholesterol (TC), triglyceride, and phosphorous. All baseline data and the reduction rate of M protein after each chemotherapy cycle from the first to fourth were assessed by univariate analysis. The factors influencing the overall survival and PFS were then assessed by multivariate analysis. We found the first cycle (C1) reduction rate and the fourth cycle (C4) reduction rate as predictors of PFS. Then, PFS was compared between patients with a C1 reduction rate of M protein of ≥ 25% vs < 25% and ≥ 50% vs < 50%, and between patients with a C4 reduction rate of ≥ 25% vs < 25%, ≥ 50% vs < 50%, and ≥ 75% vs < 75%. Multivariate analysis revealed age [hazard ratio (HR): 1.059, 95% confidence interval (95%CI): 1.033-1.085, P ≤ 0.001], International Staging System stage (HR: 2.136, 95%CI: 1.500-3.041, P ≤ 0.001), autotransplantion (HR: 0.201, 95%CI: 0.069-0.583, P = 0.019), TC (HR: 0.689, 95%CI: 0.533-0.891, P = 0.019), C1 reduction rate (HR: 0474, 95%CI: 0.293-0.767, P = 0.019), and C4 reduction rate (HR: 0.254, 95%CI: 0.139-0.463, P = 0.019) as predictors of PFS. The Kaplan-Meier survival analysis and the log-rank tests revealed that a higher reduction rate of M protein after first cycle (≥ 50%) and fourth cycle (≥ 75%) chemotherapy was associated with a longer PFS than the lower one. Higher reduction rates of M protein after the first and fourth chemotherapy cycles can act as advantageous prognostic factors for PFS in standard-risk group of MM patients during initial diagnosis.

Invasive mucorales sinusitis in a young patient with Emberger syndrome and newly diagnosed AML: A case report and literature review of invasive fungal infections in GATA2 deficiency.

Germline pathogenic variants (PVs) in the gene encoding the GATA2 transcription factor can result in profound reductions of monocytes, dendritic cells, natural killer cells and B cells. GATA2 PVs are associated with an increased risk of myeloid malignancies and a predisposition to nontuberculous mycobacterial and human papillomavirus infections. Additionally, invasive fungal infections (IFIs) have been reported in individuals with GATA2 PVs, even in the absence of myeloid malignancies. In this report, we present the case of a 40-year-old man with Emberger syndrome (GATA2 mutation, recently diagnosed acute myeloid leukaemia [AML] and history of lymphedema with hearing loss) who developed Mucorales sinusitis while receiving his first course of remission induction chemotherapy. Additionally, we review the literature on all published cases of proven IFIs in patients with GATA2 PVs. Clinicians should be aware that patients with GATA2 PVs could be vulnerable to opportunistic IFIs, even in the absence of AML and antineoplastic therapy. Furthermore, the distinctly unusual occurrence of mucormycosis during the first course of induction chemotherapy for AML in our patient indicates that patients with germline GATA2 PVs receiving induction chemotherapy for AML might be at high risk for early onset of IFIs due to aggressive, opportunistic moulds.

Azacitidine Post-Remission Therapy for Elderly Patients with AML: A Randomized Phase-3 Trial (QoLESS AZA-AMLE).

This phase-3 randomized multicenter trial evaluated the efficacy of subcutaneous azacitidine (AZA) post-remission therapy vs. best supportive care (BSC) in elderly acute myeloid leukemia (AML) patients. The primary endpoint was the difference in disease-free survival (DFS) from complete remission (CR) to relapse/death. Patients with newly diagnosed AML aged ≥61 years received two courses of induction chemotherapy ("3+7" daunorubicin and cytarabine) followed by consolidation (cytarabine). At CR, 54 patients were randomized (1:1) to receive BSC (N = 27) or AZA (N = 27) at a dose of 50 mg/m2 for 7 days every 28 days and the dose increased after the 1st cycle to 75 mg/m2 for a further 5 cycles, followed by cycles every 56 days for 4.5 years. At 2 years, median DFS was 6.0 (95% CI: 0.2-11.7) months for patients receiving BSC vs. 10.8 months (95% CI: 1.9-19.6, p = 0.20) months for AZA. At 5 years, DFS was 6.0 (95% CI: 0.2-11.7) months in the BSC arm vs. 10.8 (95% CI: 1.9-19.6, p = 0.23) months in the AZA arm. Significant benefit was afforded by AZA on DFS at 2 and 5 years in patients aged >68 years (HR = 0.34, 95% CI: 0.13-0.90, p = 0.030 and HR = 0.37, 95% CI: 0.15-0.93, p = 0.034, respectively). No deaths occurred prior to leukemic relapse. Neutropenia was the most frequent adverse event. There were no differences in patient-reported outcome measures between study arms. In conclusion, AZA post-remission therapy was found to provide benefit in AML patients aged >68 years.

Results of complex treatment of patients with locally advanced squamous cell carcinoma of the paranasal sinuses and nasal cavity using induction chemotherapy

Introduction. About 600 new cases of malignant neoplasms of the paranasal sinuses and nasal cavity are detected annually in Russia. To date, there are no randomized trials to determine the optimal treatment algorithm for this group of patients. Data on the use of induction chemotherapy in squamous cell carcinoma of sino-nasal tract are limited to a small series of clinical observations and, often, are retrospective in nature.Aim. Evaluation of the effectiveness of induction chemotherapy in patients with locally advanced squamous cell carcinoma of the paranasal sinuses and nasal cavity.Materials and methods. Since 2012, 22 patients with locally advanced cancer of the paranasal sinuses and nasal cavity have been treated in our center, who underwent 3-component induction chemotherapy according to the TPF protocol. Evaluation of the effectiveness of treatment was carried out according to the criteria of Response evaluation criteria in solid tumors 1.1 (RECIST 1.1). Patients with a decrease in the tumor size by 30 % or more, were followed by radiation therapy in doses of 66–70 Gy. Patients with a residual tumor underwent surgery after the end of chemoradiotherapy.Results. In 21 patients available for analysis, overall response rate after induction chemotherapy was 71 %: complete response was registered in 3 (14 %) patients, partial response in 12 (57 %), stable disease in 4 (19 %). Progression disease after 3 courses of induction chemotherapy was detected in 2 (10 %) patients.Conclusions. Thus, induction chemotherapy in patients with squamous cell carcinoma of sino-nasal tractseems to be a promising direction for investigation, that can significantly improve the long-term results of treatment of this category of patients and help to avoid of disabling surgery in some of them.

Efficacy and safety of different radiotherapy doses in neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A retrospective study.

This study aims to compare the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) with different radiotherapy doses (45Gy and 50.4Gy) in patients with locally advanced rectal cancer (LARC). Herein, 120 patients with LARC were retrospectively enrolled between January 2016 and June 2021. All patients underwent two courses of induction chemotherapy (XELOX), chemoradiotherapy, and total mesorectum excision (TME). A total of 72 patients received a radiotherapy dose of 50.4 Gy, while 48 patients received a dose of 45 Gy. Surgery was then performed within 5-12 weeks following nCRT. There was no statistically significant difference between the baseline characteristics of the two groups. The rate of good pathological response in the 50.4Gy group was 59.72% (43/72), while in the 45Gy group achieved 64.58% (31/48) (P>0.05). The disease control rate (DCR) in the 50.4Gy group was 88.89% (64/72), compared to 89.58% (43/48) in the 45Gy group (P>0.05). The incidence of adverse reactions for radioactive proctitis, myelosuppression, and intestinal obstruction or perforation differed significantly between the two groups (P<0.05). The anal retention rate in the 50.4Gy group was significantly higher in contrast to the 45Gy group (P<0.05). Patients receiving a radiotherapy dose of 50.4Gy have a better anal retention rate but also a higher incidence of adverse events such as radioactive proctitis, myelosuppression, and intestinal obstruction or perforation, and a comparable prognosis to patients treated with a radiotherapy dose of 45Gy.

The trace that is valuable: serum copper and copper to zinc ratio for survival prediction in younger patients with newly diagnosed acute myeloid leukaemia

PurposeNo data on predicting the survival of AML patients based on the level of trace elements in the serum have been presented to date. The aims of this prospective cohort study were as follows: (i) to evaluate the serum Cu and Zn levels in people from Northeast China, (ii) to assess the association between the serum Cu level (SCL) and Cu to Zn ratio (SCZR) and clinical and nutrition data, and (iii) to investigate the predictive values of the SCL and SCZR in newly diagnosed de novo AML patients.MethodsA total of 105 newly diagnosed AML patients and 82 healthy controls were recruited. The serum Cu and Zn levels were determined by inductively coupled plasma spectrometry. The associations of SCL and SCZR with the survival of these AML patients were assessed by Cox proportional hazards models.ResultsBoth SCL and SCZR were positively related to the blast percentage of bone marrow and C-reactive protein, negatively related to albumin level and CEBPA double mutation and were significantly associated with worse overall survival and disease-free survival. Meanwhile, patients with higher SCL had worse CTCAE levels, and patients with higher SCZR showed less complete remission during the first course of induction chemotherapy. Moreover, higher SCZR was positively associated with ELN risk stratification, and was negatively associated with haemoglobin level and prognostic nutritional index (PNI).ConclusionThe SCL and SCZR are associated with long-term survival in patients with newly diagnosed AML undergoing intensive induction and may serve as important predictive biomarkers.