Multidrug Chemotherapy Research Articles

Longitudinal Health-Related Quality of Life Among Patients With High-Risk Pediatric Hodgkin Lymphoma Treated on the Children's Oncology Group AHOD 1331 Study.

PURPOSEThere have been no previous longitudinal assessments of health-related quality of life (HRQoL) during treatment for pediatric Hodgkin lymphoma (HL). The addition of brentuximab vedotin (BV) to a multidrug chemotherapy backbone demonstrated superior efficacy to standard chemotherapy for patients with pediatric high-risk HL in the AHOD 1331 trial. However, the impact on HRQoL is unknown.PATIENTS AND METHODSAfter treatment random assignment, 268 participants older than 11 years were enrolled in a prespecified, longitudinal, patient-reported outcomes substudy. HRQoL was assessed using the seven-item Child Health Ratings Inventories (CHRIs)-Global scale before treatment (T1) and at cycle 2 (T2), cycle 5 (T3), and end of treatment (T4). A clinically meaningful increase in HRQoL was considered 7 points on the CHRIs-Global. Multivariable linear regression estimated associations between demographic/clinical variables and HRQoL at T1. Linear mixed models estimated changes in HRQoL across the treatment arm.RESULTSParticipant characteristics were balanced by treatment arm. Ninety-three percent of participants completed the CHRIs at T1, 92% at T2, 89% at T3, and 77% at T4. At T1, female sex and fever (P < .05) were each associated with worse HRQoL. By T2, participants in the BV arm experienced a statistically and clinically significant improvement in HRQoL (β = 7.3 [95% CI, 3.2 to 11.4]; P ≤ .001), which was greater than the change in the standard arm (difference in change β = 5.1 [95% CI, -0.2 to 10.3]; P = .057). The standard arm did not experience a statistically or clinically significant increase in HRQoL until T4 (β = 9.3 [95% CI, 4.7 to 11.5]; P < .001).CONCLUSIONThese data demonstrate successful collection of serial HRQoL from youth with high-risk pediatric HL and improvement in HRQoL over the course of initial therapy, sooner and to a greater extent in the group receiving the novel agent BV.

New Biomarkers to Define A Biological Borderline Situation for Pancreatic Adenocarcinoma - Results of An Ancillary Study of the PANACHE01-PRODIGE48 Trial.

To investigate in patients treated for a resectable pancreatic ductal adenocarcinoma (PA), the prognostic value of baseline CA19-9 and circulating tumour DNA (ctDNA) for overall survival (OS), to improve death risk stratification, based on a planned ancillary study from PANACHE01-PRODIGE 48 trial. Biological borderline situation that was first used by the MD Anderson, became a standard practice following the international consensus conference in 2016 to manage PA. Regarding the risk of systemic disease especially in the setting of "markedly elevated" CA19-9, neoadjuvant therapy is advised to avoid unnecessary surgery, with risk of early recurrence. To best define biological borderline situations, new biomarkers are needed. Characteristics at diagnosis and OS were compared between patients with or without ctDNA status available. OS was estimated with Kaplan Meier method and compared with log-rank test. Restricted cubic spline approach was used to identify optimal threshold for biological parameters for death risk stratification. Univariate and multivariate Cox proportional hazard models were estimated to assess the association of ctDNA status and other parameters with OS. Among the 132 patients from the primary population for analysis in the PANACHE01 -PRODIGE 48 trial, 92(71%) were available for ctDNA status at diagnosis. No selection bias was identified between patients with or without ctDNA status. 14 patients (15%) were ctDNA+ and exhibited a higher risk for death (P=0,0188; HR95% CI: 2.28 (1.12-4.63). In the 92 patients with ctDNA status available among the others parameter analysed only CA19-9 was statically associated with OS in univariate analysis. Patients with log of CA19-9 equal or superior to 4.4 that corresponds to a CA19-9 of 80 UI/mL were identified at higher risk for death (P=0,0143; HR95% CI: 2.2 (1.15-4.19). In multivariate analysis CA19-19 remained independently associated with OS (p-value=0.0323). When combining the two biomarkers, median OS was of 19.4 (IC 95% 3.8-Not reached) months, 30.2 (IC 95% 17.1-NR) months and not reached (IC 95% 39.3-NR) for "CA19-9 high and ctDNA+ group", "CA19-9 high or ctDNA+ group", and "CA19-9 low and ctDNA- group", respectively (logrank P=0,0069). Progress in the management of potentially operable PA remains limited, relying solely on strategies to optimize the sequence of complete treatment, based on modern multidrug chemotherapy (FOLFIRINOX, GemNabPaclitaxel) and surgical resection. The identification of risk criteria, such as the existence of systemic disease, is an important issue, currently referred to as "biologic borderline disease". Few data, particularly from prospective studies, allow us to identify biomarkers other than CA19-9. Combining ctDNA to CA19-9 could be of interest to best define biological borderline situations in PA.

Respiratory insufficiency after brain metastasectomy for extraskeletal Ewing sarcoma in an adult patient with mucopolysaccharidosis type II: a case report.

Mucopolysaccharidosis is a rare lysosomal storage disease caused by deficiencies in enzymes involved in the degradation of glycosaminoglycans. We report the case of an adult with mucopolysaccharidosis type II who developed respiratory insufficiency after brain metastasectomy for extraskeletal Ewing sarcoma. This report describes the case of a 35-year-old man with a mass on the left chest wall for 3months. Magnetic resonance imaging and computed tomography revealed a large mass on the chest wall. Positron emission tomography revealed multiple metastatic lesions in the lungs, ribs, and sternum. A needle biopsy specimen confirmed extraskeletal Ewing sarcoma, and the fusion gene EWS-FLI1 was positive. Subsequently, multidrug chemotherapy was administered. During radiotherapy for the primary lesion, progressive convulsions occurred suddenly. Computed tomography of the brain revealed metastasis in the frontal lobe. Brain metastasectomy was scheduled; however, endotracheal intubation was not possible because of the deformity of the glottis, and emergency tracheostomy was performed. Thereafter, granulation tissue proliferated in reaction to the tracheostomy cannulae in the trachea, and respiratory insufficiency persisted. Because of the rapid growth of an intrathoracic recurrent tumor, the patient passed away 2months after brain surgery. This is the first report of sarcoma in a patient with mucopolysaccharidosis. Respiratory management is difficult in patients with mucopolysaccharidosis, especially under general anesthesia. Orthopedic surgeons should be aware that surgical planning must be performed carefully when soft tissue sarcomas occur in patients with mucopolysaccharidosis.

Effectiveness and safety of primary prophylaxis with G-CSF for patients with Ewing sarcomas: a systematic review for the Clinical Practice Guidelines for the Use of G-CSF 2022 of the Japan Society of Clinical Oncology.

Multidrug chemotherapy for Ewing sarcoma can lead to severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, "Does primary prophylaxis with G-CSF benefit chemotherapy for Ewing sarcoma?" and CQ #2, "Does G-CSF-based intensified chemotherapy improve Ewing sarcoma treatment outcomes?". A comprehensive literature search was conducted in PubMed, Cochrane Library, and Ichushi web databases, including English and Japanese articles published from 1990 to 2019. Two reviewers assessed the extracted papers and analyzed overall survival (OS), febrile neutropenia (FN) incidence, infection-related mortality, quality of life (QOL), and pain. Twenty-five English and five Japanese articles were identified for CQ #1. After screening, a cohort study of vincristine, ifosfamide, doxorubicin, and etoposide chemotherapy with 851 patients was selected. Incidence of FN was 60.8% with G-CSF and 65.8% without; statistical tests were not conducted. Data on OS, infection-related mortality, QOL, or pain was unavailable. Consequently, CQ #1 was redefined as a future research question. As for CQ #2, we found two English and five Japanese papers, of which one high-quality randomized controlled trial on G-CSF use in intensified chemotherapy was included. This trial showed trends toward lower mortality and a significant increase in event-free survival for 2-week interval regimen with the G-CSF primary prophylactic use compared with 3-week interval. This review indicated that G-CSF's efficacy as primary prophylaxis in Ewing sarcoma, except in children, is uncertain despite its common use. This review tentatively endorses intensified chemotherapy with G-CSF primary prophylaxis for Ewing sarcoma.

Liposomal mitoxantrone-based multidrug chemotherapy as a bridge to allogeneic hematopoietic stem cell transplantation in relapsed/refractory acute lymphoblastic leukemia (ALL) after immunotherapy failure: a case report

Acute lymphoblastic leukemia (ALL) represents a malignancy involving early-stage differentiated lymphoid cells that invade the bone marrow, blood, and extramedullary sites. First-line treatment spans 2–3 years with induction, consolidation, intensification, and long-term maintenance phases. Relapsed/refractory (R/R) ALL typically carries an adverse prognosis, and there is currently no standard of care for this disease. Here, we present a case of R/R ALL that responded effectively to liposomal mitoxantrone-based multidrug chemotherapy, resulting in a rapid complete response after 35 days of therapy. Subsequently, the patient was successfully treated with allo-HSCT. At 5 months follow-up, the patient was alive and leukemia-free. Additionally, no severe adverse events were recorded during liposomal mitoxantrone treatment or hospitalization for allo-HSCT. Given the encouraging efficacy and the manageable adverse events observed in our case, liposomal mitoxantrone-based multidrug chemotherapy should be further explored as a bridge to allo-HSCT in patients with R/R ALL.

Pathologic Response Rates in Patients with Gastric Cancer Following FLOT Neoadjuvant Chemotherapy

Background: Gastric adenocarcinoma is among the most prevalent cancers associated with a high mortality rate. The multidrug neoadjuvant chemotherapy administered before and after surgery has attracted attention as a beneficial standard of care for managing this malignancy. Objectives: This study assessed the pathologic response of patients with gastric cancer who were treated with fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). Methods: Patients with pathologically confirmed gastric adenocarcinoma without distant metastases were enrolled in this retrospective cohort study conducted at Imam Reza and Ghaem hospitals in Mashhad. Data regarding demographics, tumor status, treatment toxicity, and pathology results were collected using a predesigned questionnaire after four cycles of FLOT neoadjuvant chemotherapy. SPSS-26.0 was utilized to analyze the data, and a significance level of P &lt; 0.05 was applied. Results: We evaluated data from 53 cases with a mean age of 51.1 ± 9.7 years. Diffuse adenocarcinoma was the most common finding in histology (54.7%). Pathologic complete response was observed in 16 (30.2%) patients. Most (69.8%) patients received only 7 out of 8 planned cycles. Concerning surgical margin, 46 (86.8%) patients achieved R0 tumor resection. Pathologic complete response was not significantly linked with age (P = 0.91), sex (P = 0.65), performance status (P = 0.2), tumor histology (P = 0.14), tumor grading (P = 0.07), tumor location (P = 0.8), and the number of neoadjuvant chemotherapy cycles (P = 0.9). Conclusions: Our findings demonstrated the relative clinical efficacy of neoadjuvant chemotherapy with the FLOT regimen administered before and after surgery. However, due to chemotherapy-related side effects, patients may not adhere to all eight prescribed cycles of chemotherapy.

Outcome of serial cardiac evaluations during doxorubicin-based chemotherapy in small- to medium-sized dogs with multicentric lymphoma

Doxorubicin is an anthracycline antitumor antibiotic with dose-dependent and cumulative cardiotoxicity. However, the necessity for serial cardiac evaluation is unknown in dogs without risk factors for dilated cardiomyopathy (DCM). This study aimed to investigate serial changes in echocardiographic and electrocardiographic measures in small- and medium-sized dogs after four doxorubicin doses. We included 17 dogs, weighting < 20 kg, with multicentric lymphoma. All dogs received doxorubicin over 30 min every 4 weeks as part of a multi-drug chemotherapy protocol. The average doxorubicin dose was 3.8 times per dog. Clinical cardiotoxicity was not observed during the monitoring period. The incidence of developing arrhythmia was not significantly associated with the number of doxorubicin doses received (P = 0.600). The development of valvular regurgitations and mitral regurgitation in these dogs was not significantly associated with the number of doxorubicin doses (P = 0.363 and P = 0.779, respectively). The other echocardiographic results were not significantly different between each evaluation. In conclusion, our results showed no significant cardiotoxicity under echocardiogram and electrocardiogram in small- and medium-sized dogs without risk factors for DCM after four doses of doxorubicin in a 30-minute infusion method.

Nongestational ovarian choriocarcinoma with bilateral teratoma: A rare case report and literature review.

Trophoblastic neoplasms are often associated with pregnancy, and nongestational trophoblastic neoplasms are extremely rare. Nongestational ovarian choriocarcinoma (NGCO) is a highly aggressive germ cell-derived tumor frequently presenting with early hematogenous metastasis. Herein, we report a case of a 28-year-old unmarried woman with regular menstruation who experienced vaginal bleeding 1 week after her last menstrual cycle. Doppler ultrasound revealed bilateral adnexal masses and elevated serum human chorionic gonadotropin (hCG) levels. The patient was initially misdiagnosed as presenting an ectopic pregnancy. The final pathology confirmed an International Federation of Gynecology and Obstetrics stage IA NGCO with bilateral mature teratoma of the ovary. This is an extraordinary instance of ovarian choriocarcinoma which emerged without any prior gestation, and the patient's lack of a history of pregnancy made the diagnosis ignored. After initial surgery and 1 cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy, a laparoscopic fertility-preserving comprehensive staging surgery was performed. Two cycles of chemotherapy with BEP were administered as supplemental therapy postsurgery, and leuprorelin was administered to protect ovarian function. Menstruation resumed 4 months after chemotherapy completion, and tumor indicators were within the normal range. No signs of recurrence were observed at the 36-month follow-up. NGCO should be considered if a female patient exhibits irregular vaginal bleeding and masses in the adnexal area. The present case and our literature review also highlighted that fertility-sparing surgery and multidrug chemotherapy are effective methods for treating NGCO.

Abstract PO2-20-11: Safety and efficacy of KEYNOTE-522 in combination with anti-retroviral therapy in a patient with HIV and triple-negative breast cancer

Abstract Introduction: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2), accounting for about 15% of all BC. TNBC is more aggressive than other BC with a higher risk of recurrence and mortality. The current standard of care for high-risk, early-stage TNBC based on the KEYNOTE-522 trial is neoadjuvant multidrug chemotherapy (paclitaxel and carboplatin [TCb] weekly x 12 weeks and doxorubicin and cyclophosphamide [AC] Q3 weeks) with pembrolizumab (P). The trial demonstrated patients who received chemotherapy plus P had a higher pathological complete response and event-free survival compared to patients who received chemotherapy plus placebo. However, the trial excluded patients with any autoimmune disease requiring treatment within 2 years, a diagnosis of immunodeficiency or steroids within 7 days before the first treatment, or a known history of human immunodeficiency virus (HIV). While limited data exist on immune checkpoint inhibitors (ICI) in patients with immunodeficiencies, subsequent data demonstrate that patients with HIV have similar efficacy and immune-related adverse events (irAE) compared to patients without HIV, and 2017 consensus recommendations encouraged broader eligibility in clinical trials to include patients with HIV. We present one of the first reported clinical cases of a patient with HIV diagnosed with stage IIB TNBC, treated per KEYNOTE-522 and anti-retroviral therapy (ART). Clinical Case: A 55-year-old female with a medical history significant for HIV, self-detected a mass in her left breast. Diagnostic imaging demonstrated a suspicious 4.0 cm mass in the left breast without adenopathy. An ultrasound-guided biopsy of the mass revealed grade 3 invasive ductal carcinoma with ER 0%, PR &amp;lt; 1%, and HER-2 1+. The clinical stage was cT2N0M0, prognostic stage IIB. Genetic testing was positive for germline BRCA2 pathogenic variant. HIV PCR &amp;lt; 20 copies/mL and CD4 count 1.298 K/uL prior to neoadjuvant chemotherapy. The patient was adherent to HIV ART with bictegravir, emtricitabine, and tenofovir alafenamide. The patient received KEYNOTE-522, including 11 cycles of TCb-P, followed by four cycles of AC-P. Following neoadjuvant treatment, the patient underwent a left segmental mastectomy and sentinel lymph node biopsy and achieved a pathological complete response. She completed left whole breast radiation (RT) with 3DCRT plus 3DCRT tumor bed boost to a total dose of 48.06 cGy and one-year of adjuvant P. Treatment-related adverse events included grade 4 febrile neutropenia after cycle one AC without growth factor, requiring a 5-day hospitalization; and grade 3 peripheral neuropathy, resulting in discontinuation of week 12 of TCb. The patient also developed paronychia, and a pulmonary embolism after week 11 of TCb. She had no irAE. Radiation-related adverse events included grade 1 left breast dermatitis and fatigue and mild left breast soreness. Discussion: Among the subset of patients diagnosed with TNBC, the percentage of patients with HIV or immunodeficiency receiving active BC treatment is low. Safety and efficacy data for novel cancer therapeutics including ICI are limited since historically patients with HIV and other immunodeficiency states were excluded from trials. Anti-PD-1 ICI has become a key part of the standard of care for the treatment of breast cancer. Patients with HIV experience rare infectious complications and have a life expectancy near the general population with ART. We support the inclusion of patients with HIV in future clinical trials for TNBC and/or ICI and recommend treatment of patients with HIV and TNBC per standard of care in multi-disciplinary collaboration with HIV clinicians. Citation Format: Stephanie Haddad, Stephanie Graff, Matthew Hadfield, Yihong Wang, Charu Taneja, Kara Leonard, Martha Sanchez, Robert Ward, Ana Lourenco, Mary Anne Fenton. Safety and efficacy of KEYNOTE-522 in combination with anti-retroviral therapy in a patient with HIV and triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-11.

Abstract 3349: Identification of new potential vulnerabilities for differentiation-based therapeutic strategies against osteosarcoma

Abstract Osteosarcoma (OS), a mesenchymal bone tumor affecting mainly children and adolescents is characterized by a particularly aggressive behavior, with 20% of patients showing lung metastasis already at diagnosis. Current OS treatment strategies rely on multi-drug chemotherapy, and the prognosis for metastatic cases remains grim, underscoring the pressing need for novel therapeutic approaches. OS is considered a differentiation-related disorder, stemming from the inability of mesenchymal stem cells or osteoblastic progenitors to progress towards terminal differentiation. In our study we explored the impact of targeting ZEB1, a transcription factor known to play a pivotal role in maintaining mesenchymal and stemness characteristics in cancer, on OS cells. We employed CRISPR-Cas9 and shRNA interference techniques to inhibit ZEB1 expression in mouse immune competent OS models. In vitro, ZEB1 deficiency significantly diminished the stemness potential of OS cells, as assessed by spheroid formation assays, while promoting osteogenic differentiation. In vivo, ZEB1 deletion in OS cells led to a significant reduction in primary tumor growth. Tumors originating from ZEB1 KO cells exhibited a more differentiated morphology and higher extracellular matrix deposition compared to controls. Intriguingly, the absence of ZEB1 in tumor cells also influenced the immune infiltrate, with ZEB1-deficient tumors showing significantly fewer pro-tumoral CD206+ M2-like macrophages. This observation is in line with the significant down-modulation of CCL2 expression we detected in ZEB1 KO cells. When injected intravenously, ZEB1-deficient cells produced fewer and smaller lung metastases than control cells. Transcriptional changes induced by ZEB1 deletion were investigated by gene expression profile (GEP) and identified 849 down-regulated and 1093 up-regulated genes in ZEB1 knockout (KO) clones versus ZEB1-competent controls. Gene set enrichment analysis showed a down-modulation of pathways related to cellular proliferation and survival, such as MTORC1 signaling, MYC targets, GM2 checkpoint, E2F targets and oxidative phosphorylation in the absence of ZEB1. Single gene analysis identified among the most up-regulated genes in ZEB1-deficient cells Sfrp1, a negative regulator of the WNT/b-CAT pathway, which in turn regulates MYC, whose pathway is indeed repressed in ZEB1 KO cells. We hypothesize that a high expression of SFRP1 could vicariate the effects of ZEB1 inhibition on OS cell stemness, differentiation state, and in vivo aggressiveness, and therefore could act as a tumor suppressor, which could be potentially exploited for therapeutic strategies. Citation Format: Caterina Cascini, Daniele Lecis, Valeria Cancila, Katia Scotlandi, Claudio Tripodo, Mario P. Colombo, Claudia Chiodoni. Identification of new potential vulnerabilities for differentiation-based therapeutic strategies against osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3349.

Abstract 5471: Ribosome heterogeneity and RNA polI inhibition in osteosarcoma heterogeneity

Abstract Osteosarcoma is the most common primary bone tumour in adolescents and young adults, with an incidence rate of 3.8 per million. These tumors affect the long bones of the body such as femur. Current standard therapy includes tumour resection associated with multi-drug chemotherapy. The 5-year survival rate can reach 65% but is significantly reduced to 30% when pulmonary metastases are detected at the time of diagnosis. As this rate has not improved in the last 50 years, it is necessary to identify new therapeutic strategies. Inhibition of ribosomal biogenesis is one of the strategies developed in many cancer studies. This can be obtained by inhibition of RNA pol I, and in particular by BMH-21. The objective of this study was to analyze the complexity and heterogeneity of osteosarcomas through the ribosomal spectrum. The effect of BMH-1 on survival was also studied in osteosarcoma cell lines. The data obtained showed that there was no difference in ribosome protein composition in the “core” ribosome in different osteosarcoma cell lines. In addition, BMH-21 decreased cell viability in all osteosarcoma and chemoresistant cell lines. However, any activation of the apoptotic pathway by caspases was detected, nor any impact on the formation of new colonies after treatment with BMH-21. These results suggest a rather cytostatic mechanism. Moreover, a G0/G1 arrest in cell cycle was shown for U2OS cells. Finally, BMH-21 does not appear to have any impact on migration in HOS and U2OS cells. The different molecular mechanisms involved in the regulation of proliferation need to be further investigated. Citation Format: Marc Baud'huin, Elvina Colleville, Rose Anne Thepault, Emilien Orgebin, Francois Lamoureux, Benjamin Ory. Ribosome heterogeneity and RNA polI inhibition in osteosarcoma heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5471.

Chimeric Antigen Receptor (CAR)-T Cell Therapy for Non-Hodgkin's Lymphoma.

This review focuses on the use of chimeric antigen receptor (CAR)-T cell therapy to treat non-Hodgkin's lymphoma (NHL), a classification of heterogeneous malignant neoplasms of the lymphoid tissue. Despite various conventional and multidrug chemotherapies, the poor prognosis for NHL patients remains and has prompted the utilization of groundbreaking personalized therapies such as CAR-T cells. CAR-T cells are T cells engineered to express a CAR that enables T cells to specifically lyse tumor cells with extracellular expression of a tumor antigen of choice. A CAR is composed of an extracellular antibody fragment or target protein binding domain that is conjugated to activating intracellular signaling motifs common to T cells. In general, CAR-T cell therapies for NHL are designed to recognize cellular markers ubiquitously expressed on B cells such as CD19+, CD20+, and CD22+. Clinical trials using CAR-T cells such as ZUMA-7 and TRANSFORM demonstrated promising results compared to standard of care and ultimately led to FDA approval for the treatment of relapsed/refractory NHL. Despite the success of CAR-T therapy for NHL, challenges include adverse side effects as well as extrinsic and intrinsic mechanisms of tumor resistance that lead to suboptimal outcomes. Overall, CAR-T cell therapies have improved clinical outcomes in NHL patients and generated optimism around their future applications.

Evolving survival gains in patients with young-onset colorectal cancer and synchronous resectable liver metastases

We aimed to evaluate the practice and the associated outcomes of surgical treatment for young-onset colorectal cancer (YOCRC) patients presenting with synchronous liver metastases. The study cohort was divided into two groups according to surgery date: 131 patients in the early era (EE, 1998–2011) and 179 in the contemporary era (CE, 2012–2020). The CE had a higher rate of node-positive primary tumors, higher carcinoembryonic antigen level, and lower rate of RAS/BRAF mutations. The CE had higher rates of reverse or combined resection, multi-drug prehepatectomy chemotherapy, and two-stage hepatectomy. The median survival was 8.4 years in the CE and 4.3 years in the EE (p = 0.011). On multivariate analysis, hepatectomy in the CE was independently associated with improved overall survival (HR 0.48, p = 0.001). With a combination of perioperative systemic therapy, careful selection of treatment approach, and coordinated resections, durable cure can be achieved in YOCRC patients.

Clinical efficacy and safety of flumatinib versus dasatinib combined with multi-drug chemotherapy in adults with Philadelphia-positive acute lymphoblastic leukemia

Introduction: Flumatinib, a highly selective ABL kinase inhibitor, exhibits stronger inhibition of intracellular BCR-ABL tyrosine kinase activity, compared to Imatinib. However, there is limited research comparing the real-world efficacy and safety of flumatinib and dasatinib in patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Objective: Investigating the differences in therapeutic efficacy and safety between flumatinib and dasatinib in combination with multi-drug chemotherapy for the treatment of newly diagnosed Ph+ ALL. Method: In this study, we assessed 43 patients with newly diagnosed Ph+ ALL (20 in the flumatinib group, 23 in the dasatinib group). Results: There were no significant differences in gender, age, fusion gene type, initial blood routine, bone marrow blast cell ratio or chromosome karyotype between the two groups. Within 1 month, there were no significant differences in the complete response (CR), major molecular response (MMR) or minimal residual disease (MRD) negativity rate between the flumatinib and dasatinib groups. Similarly, within 3 months, there were no significant differences in CR or MMR rates between the two groups. However, the rates of complete molecular response (CMR) and MRD negativity within 3 months were significantly higher in the flumatinib group, compared to the dasatinib group (P < 0.05). Additionally, the flumatinib group exhibited fewer adverse reactions compared to the dasatinib group. Conclusion: These findings suggest that flumatinib is a safe and effective tyrosine kinase inhibitor (TKI) for achieving CMR and MRD negativity in patients with Ph+ ALL, as supported by this small series of patients.

Successful Multidrug Chemotherapy for Rhabdomyosarcoma in a Seven-Year-Old Girl: A Case Report

The most frequent soft tissue cancer in children is rhabdomyosarcoma (RMS). A diagnosis typically occurs between the ages of 5 and 6 in women. We report a seven-year-old girl was referred to Hospitals with complaints of a protruding left eye. The swelling was presented in July 2021, which was small earlier but has increased and become more prominent. An examination of the left eyelid showed a 2.5 x 2.5 x 1.5 cm solid mass with edema, erythema, and secretion in the superior and inferior affected eyelid. A Head CT scan revealed a left superolateral lacrimal duct tumour with a normal intracerebral structure. The histopathology examination found dacryoadenitis with an RMS tumour. This patient was treated using the RMS multidrug chemotherapy protocol (vincristine, actinomycin, and cyclophosphamide) for three sessions, which decreased tumour progressivity five months later. Early and appropriate treatment of this patient with chemotherapy regimens according to the protocol for RMS has a good prognosis.

A network meta-analysis of efficacy and safety for first-line and maintenance therapies in patients with unresectable colorectal liver metastases.

Background: Evidence comparing the efficacy of different treatments for patients with unresectable colorectal liver metastases (CRLM) receiving first-line or maintenance therapy is sparse. We aimed to assess the efficacy and safety of these treatments, with a distinct focus on evaluating first-line and maintenance treatments separately. Methods: We conducted Bayesian network meta-analyses, sourcing English-language randomized controlled trials (RCTs) published through July 2023 from databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and key conference proceedings. Phase Ⅱ or Ⅲ trials that assessed two or more therapeutic regimens were included. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), adverse events graded as 3 or above (SAE), and R0 liver resection rate. Hazards Ratios (HRs) and 95% confidence intervals (CI) were used as effect size for OS and PFS, Odds Ratios (ORs) and 95% CI were used for ORR, SAEs and R0 resection rate. Subgroup and sensitive analyses were conducted to analysis the model uncertainty (PROSPERO: CRD42023420498). Results: 56 RCTs were included (50 for first-line treatment, six for maintenance therapies), with a total of 21,323 patients. Regarding first-line, for OS, the top three mechanisms were: local treatment + single-drug chemotherapy (SingleCT), Targeted therapy (TAR)+SingleCT, and TAR + multi-drug chemotherapy (MultiCT). Resection or ablation (R/A)+SingleCT, S1, and Cetuximab + intensified fluorouracil-based combination chemotherapy (ICTFU) were identified as the best treatments. For PFS, the top three mechanisms were: Immune therapy + TAR + MultiCT, multi-targeted therapy (MultiTAR), TAR + SingleCT. The top three treatments were: Atezolizumab + Bevacizumab + fluorouracil-based combination chemotherapy (CTFU), TAS-102+bevacizumab, Bevacizumab + ICTFU. Cetuximab + CTFU was the best choice for RAS/RAF wild-type patients. Regarding maintenance treatment, Bevacizumab + SingleCT and Adavosertib were the best options for OS and PFS, respectively. For safety, MultiCT was the safest, followed by local treatment + MultiCT, TAR + MultiCT caused the most SAEs. Bevacizumab plus chemotherapy was found to be the safest among all targeted combination therapies. Conclusion: In first-line, local treatment or targeted therapsy plus chemotherapy are the best mechanisms. R/A + SingleCT or CTFU performed the best for OS, Atezolizumab + Bevacizumab + ICTFU was the best option regarding PFS. For RAS/RAF wild-type patients, Cetuximab + CTFU was the optimal option. Monotherapy may be preferred choice for maintenance treatment. Combination therapy resulted in more SAEs when compared to standard chemotherapy.

Surgical and Perioperative Treatments for Esophagogastric Junction Cancer.

Esophagogastric junction cancer (EGJC) is a rare malignant disease that occurs in the gastroesophageal transition zone. In recent years, its incidence has been rapidly increasing not only in Western countries but also in East Asia, and it has been attracting the attention of both clinicians and researchers. EGJC has a worse prognosis than gastric cancer (GC) and is characterized by complex lymphatic drainage pathways in the mediastinal and abdominal regions. EGJC was previously treated in the same way as GC or esophageal cancer, but, in recent years, it has been treated as an independent malignant disease, and treatment focusing only on EGJC has been developed. A recent multicenter prospective study revealed the frequency of lymph node metastasis by station and established the optimal extent of lymph node dissection. In perioperative treatment, the combination of multi-drug chemotherapy, radiation therapy, molecular targeted therapy, and immunotherapy is expected to improve the prognosis. In this review, we summarize previous clinical trials and their important evidence on surgical and perioperative treatments for EGJC.

Metastatic Desmoplastic Small Round Cell Tumor - A Case Report and Review of the Literature

Desmoplastic small round cell tumour is a rare malignancy most often seen in the abdomen or pelvis of young men. Unfortunately, this disease is usually metastatic at diagnosis and has dismal outcomes. Since 1991, when it was first described as a distinct clinical entity by Gerald WL and Rosai J some 200 cases were reported. All cases are characterized by the chromosomal translocation t (11;22) (p13; q12), which results in a formation of EWSR1-WT1 fusion gene. The diagnosis of IDSRCT is often made with core-needle tissue biopsy specimens of laparoscopy or laparotomy. Immunohistochemical analyses have shown the co-expression of epithelial, neuronal, myogenic, and mesenchymal differentiation markers. Multimodal therapy is usually indicated with chemotherapy, surgery &amp; radiotherapy. We report a rare and unusual case of an extensive abdominopelvic desmoplastic small round cell tumour with liver &amp; lung metastases, in an adolescent male patient from Bangladesh who presented with abdominal mass, pain &amp; hepatomegaly. With various difficulties in diagnosis, we ultimately reached at diagnosis by open biopsy and immunohistochemistry as desmoplastic small round cell tutor. Now patient is on multidrug chemotherapy (modified p6) protocol.

PH-Responsive Polypropylene Sulfide Magnetic Nanocarrier-Mediated Chemo-Hyperthermia Kills Breast Cancer Stem Cells by Long-Term Reversal of Multidrug Resistance and Chemotherapy Resensitization.

Cancer stem cells (CSCs) present a formidable challenge in cancer treatment due to their inherent resistance to chemotherapy, primarily driven by the overexpression of ABC transporters and multidrug resistance (MDR). Despite extensive research on pharmacological small-molecule inhibitors, effectively managing MDR and improving chemotherapeutic outcomes remain elusive. On the other hand, magnetic hyperthermia (MHT) holds great promise as a cancer therapeutic, but there is limited research on its potential to reverse MDR in breast CSCs and effectively eliminate CSCs through combined chemo-hyperthermia. To address these gaps, we developed tumor microenvironment-sensitive, drug-loaded poly(propylene sulfide) (PPS)-coated magnetic nanoparticles (PPS-MnFe). These nanoparticles were employed to investigate hyperthermia sensitivity and MDR reversion in breast CSCs, comparing their performance to that of small-molecule inhibitors. Additionally, we explored the efficacy of combined chemo-hyperthermia in killing CSCs. CSC-enriched breast cancer cells were subjected to low-dose MHT at 42 °C for 30 min and then treated with the chemical MDR inhibitor salinomycin (SAL). The effectiveness of each treatment in inhibiting MDR was assessed by measuring the efflux of the MDR substrate, rhodamine 123 (R123) dye. Notably, MHT induced a prolonged reversal of MDR activity compared with SAL treatment alone. After successfully inhibiting MDR, the breast CSCs were exposed to chemotherapy using paclitaxel to trigger synergistic cell death. The combination of MHT and chemotherapy demonstrated remarkable reductions in stemness properties, MDR reversal, and the effective eradication of breast CSCs in this innovative dual-modality approach.

Reduced-Dose Chemotherapy Followed By Blinatumomab As Induction Therapy in Treatment of Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia - Interim Results from a Multicenter, Single-Arm, Phase 2 Study

Introduction: Although intensive pediatric chemotherapeutic regimens have shown good efficacy in the treatment of Philadelphia Chromosome-negative (Ph-negative) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults, the high incidence of chemotherapy-related toxicities limits their use. Blinatumomab, a CD3/CD19 bispecific T-cell antibody, has shown high efficacy in relapsed/refractory or minimal residual disease (MRD) positive BCP-ALL; however, the efficacy of single-agent blinatumomab does not meet the treatment needs of adult patients. Therefore, combining low-intensity chemotherapy with blinatumomab could be a better induction regimen for newly diagnosed adult patients with BCP-ALL. Methods: This multicenter, single-arm, phase 2 trial (NCT05557110) enrolled adult patients (aged 15-59 years) with newly diagnosed Ph-negative BCP-ALL. The induction regimen comprised reduced intensity chemotherapy (idarubicin 8 mg/m 2 on day 1, vindesine 4 mg on day 1, and dexamethasone 9 mg/m 2/day from day 1-7) followed by 2 weeks of blinatumomab (9 ug/day from day 8-14, 28 ug/day from day 15-21). The primary endpoint was to assess the overall response rate (ORR=complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]) of this induction regimen. Secondary endpoints were MRD negativity (&amp;lt;1x10 -4 by flow cytometry), event-free survival (EFS), overall survival (OS) and safety. Bone marrow evaluation and one intrathecal injection chemotherapy were performed on day 22±2. Patients not achieving ORR continued blinatumomab for another 2 weeks (28 ug/day from day 1-14), followed by bone marrow re-evaluation. Consolidation therapy was given after achieving ORR with recommended multidrug combination chemotherapy (including high-dose methotrexate or cytarabine combined with asparaginase) or alternating with blinatumomab (28 ug/day for 28 days). If allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not performed, consolidation therapy needs at least 4 courses before 2 years of maintenance therapy. Results: Interim results are presented here.By July 6, 2023 (data cut-off), 25 patients were enrolled with a median age of 42 years (range: 15-53); 68% were females. The Eastern Cooperative Oncology Group Performance Status score ranged from 0-1. Eight (32.0%) patients had poor cytogenetic risk factors, including 3 with P2RY8::CRLF2, 2 with hypodiploidy, 2 with KMT2A rearranged and 1 with alterations of IKZF1 (Table 1). The bone marrow evaluation done in 19 patients on day 8 prior to blinatumomab treatment showed that none of the patients had got ORR. All 21 (100%) patients evaluable for the primary endpoint attained CR/Cri - 19 at the end of 2 weeks of blinatumomab and the remaining 2 after another 2 weeks of blinatumomab (Table 2). The MRD negativity rate was 90.5% (19/21) after 2 weeks of blinatumomab which increased to 95.5% (20/21) after another 2 weeks of treatment with blinatumomab. In 21 patients evaluated for safety, blinatumomab-related cytokine release syndrome was reported in 10 (47.6%) patients (grade 1: n=6, grade 2: n=3 and grade 3: n=1). No incidence of neurotoxicity was reported. Febrile neutropenia was reported in 4 (19%) patients (all ≥grade 3). The non-hematological AEs reported were fever in 7 (33.3%) patients (any grade), increased ALT in 10 (47.6%) patients (any grade) and infections in 4 (19%) patients, including pneumonia in 2 and sepsis in 2 (all ≥grade 3). The median duration of neutrophil deficiency (&amp;lt;0.5×10 9/L) and platelet deficiency (&amp;lt;20×10 9/L) during induction therapy was 9 days (range: 0-20) and 1 day (range: 0-18), respectively. The median follow-up time was 4 months and no relapse or leukemia-related deaths were observed. The median EFS and OS were not yet reached. All enrolled patients are alive except one who died of infection after multidrug combination consolidation chemotherapy. The median cycles for consolidation were 2 (range: 1-5) with 3 patients undergoing allo-HSCT. Conclusion: Thesepreliminary results indicate that the reduced intensity chemotherapy followed by blinatumomab is an effective regimen in adults with newly diagnosed Ph-negative BCP-ALL, resulting in favorable response rates, deep remission, and low-grade treatment-related AEs. These promising findings may provide a rationale for integrating blinatumomab into future induction therapy recommendations.