A Deeper Depth of Response After Salvage Therapy Improves Outcomes of Autologous Stem Cell Transplantation in Relapsed Lymphoma and the Feasibility of Non-controlled Rate Freezing of Peripheral Blood Stem Cells.

Background High-dose chemotherapy followed by autologous stem cell transplantation is considered a standard treatment approach for patients with relapsed Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma (NHL). The goal of autologous stem cell transplant in relapsed lymphoma is to achieve long-term disease control, i.e., cure, in contrast to disorders like multiple myeloma, where it only prolongs the duration of remission, progression-free survival, and improves the quality of life. Published outcomes of high-dose therapy and ASCT and the impact of different factors affecting survival in low- to middle-income countries are very limited. Our study analyzed all the autologous stem cell transplants performed in our center over a six-year period to ascertain engraftment, responses, outcomes, and variables that may have impacted transplant outcomes. Methods We conducted a retrospective study including 76 patients from January 2015 to December 2020. Data were retrieved from electronic medical records at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Results Out of a total of 82 autologous transplant patients, 76 were eligible for the study, out of which 50 (66%) had HL and 26 (34%) had NHL. The median age was 29 years (range 18-53) and 29 years (range 20-45) for HL and NHL, respectively. The male-to-female ratio was 5:2 and 4:1 for HL and NHL, respectively. The majority had advanced-stage disease, 85% in HL and 75% in NHL. The minimum cell dose infused was 2.5 million CD34+ cells/kg. Median days to platelets and ANC engraftment were 14 and 11 days, respectively. The 30-day transplant-related mortality was 8.9% and 7.4% in HL and NHL, respectively. The 100-day mortality was 15.2% and 11% in HL and NHL, respectively. The two-year disease-free survival (DFS) and overall survival (OS) were 83% and 83%, respectively, in HL patients. The two-year DFS and OS were 78% and 85%, respectively, in NHL patients. Conclusion High-dose therapy and autologous stem cell transplantation in low- to middle-income countries are limited to relatively younger patients, potentially curative conditions such as lymphoma, and predominantly after achieving a complete response to salvage therapy due to limited resources. Due to these factors, our study shows excellent response rates and survival outcomes compared to internationally published data. Engraftment was also excellent and comparable to published data despite the non-controlled rate freezing of peripheral blood stem cells.

Real-World Challenges of Managing Diffuse Large B-Cell Lymphoma in a Developing Country.

PURPOSE: To highlight challenges and cancer care disparities in patients of diffuse large B-cell lymphoma management in resource-constrained settings. MATERIALS AND METHODS: This multicenter retrospective study included 738 patients from 12 public and private sector hematology-oncology centers across Pakistan. Patients were divided into limited-resource and enhanced-resource settings as per national diffuse large B-cell lymphoma (DLBCL) guidelines. RESULTS: The median age at diagnosis was 47 years (range, 14-89). Male:female ratio was 2.5:1. Majority of the patients (69.3%) were treated in limited-resource settings. Computed tomography was used as a staging modality in 442 (60%) patients. Limited-stage DLBCL was present in 13.5% of patients, while 86.3% had advanced-stage disease at diagnosis. First-line regimens included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in 56% and cyclophosphamide, doxorubicin, vincristine, prednisone in 34% of patients, while 10% of patients received palliative regimens upfront. Of evaluable data, complete remission was documented in 299 (74.4%) patients, 39 (9.8%) had partial response and 63 (13.5%) had progressive disease. Disease-free survival (DFS) and overall survival (OS) status were not available for 345 (46.8%) patients at the time of data collection. Overall study cohort had a median follow-up of 2.2 years with a median OS of 3.6 years (95% CI, 3.1 to 4.1), median DFS of 3.1 years (95% CI, 2.6 to 3.6), and a 5-year OS of 40% and DFS of 36%. CONCLUSION: Patients from low- and middle-income countries present at an earlier age and have more advanced disease. Patients were frequently lost to follow-up, and record keeping was inadequate more so in patients treated in limited-resource settings. There is a need to establish a national lymphoma registry, improve record keeping, and standardize treatments to ensure improvement in treatment outcomes.

Management of Acute Lymphoblastic Leukemia During Pregnancy: A Case Report and Review of the Literature.

Acute lymphoblastic leukemia (ALL) during pregnancy necessitates treatment with high-dose chemotherapy, which can threaten the lives of both the mother and fetus. The aim of the treatment not only focuses on selecting and administering optimal chemotherapy with appropriate doses to the mother but also reflects the crucial understanding of the fetal gestational age at the time of administration of chemotherapy to minimize fetal exposure. We describe the case of a 19-year-old patient diagnosed with ALL at 29 weeks gestation. She received treatment in the third trimester with the Berlin-Frankfurt-Munster (BFM) 2000 induction chemotherapy protocol consisting of a combination of daunorubicin, vincristine, pegaspargase, prednisolone, and intrathecal (IT) methotrexate and gave birth to a healthy baby girl via vaginal delivery four weeks after initiating the induction of chemotherapy.

The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: Proposals for the N and the M Components for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.

INTRODUCTION: Stage classification is an important underpinning of management in patients with cancer and rests on a combination of three components-T for tumor extent, N for nodal involvement, and M for distant metastases. This article details the revision of the N and the M components of thymic epithelial tumors for the ninth edition of the TNM classification of malignant tumors proposed by the Thymic Domain of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee. METHODS: The N and M components of the eighth edition staging system were verified by a large international collaborative data source through a data-driven analysis. A total of 9147 cases were included for analysis, including 7662 thymomas, 1345 thymic carcinomas, and 140 neuroendocrine thymic tumors. RESULTS: Lymph node involvement rates were 1.5% in thymomas and 17.6% and 27.7% in thymic carcinomas and neuroendocrine thymic tumors, respectively. Rates of lymph node metastasis were increasingly higher in tumors with higher T stage and higher-grade histologic type. Survival analysis validated the differences in the N and M categories proposed in the eighth edition staging system. Good discrimination in overall survival was detected among pathologic (p)N and pM categories in patients with thymoma and thymic carcinoma. CONCLUSIONS: No changes are proposed from the eighth edition for the N and M components. The proposed stage classification will provide a useful tool for management of the disease among the global thymic community.

Postoperative Radiation Therapy for Thymic Carcinoma: An Analysis of the International Thymic Malignancy Interest Group/European Society of Thoracic Surgeons Database.

INTRODUCTION: R0 resection and radiation therapy have been associated with improved overall survival (OS) in patients with thymic carcinoma (TC). Here, we analyzed which subgroups of patients derive the greatest benefit from postoperative radiation therapy (PORT). METHODS: Clinical, pathologic, treatment, and survival information of 462 patients with TC from the International Thymic Malignancy Interest Group/European Society of Thoracic Surgeons database were analyzed. Variables included age, sex, continent of treatment, paraneoplastic syndrome, carcinoma subtype, tumor size, pathologic Masaoka stage, resection status, and use of chemotherapy. OS was the primary end point using the Kaplan-Meier method. Time to recurrence (TTR) was the secondary end point using a competing risk analysis. A 3-month landmark analysis was performed. RESULTS: PORT was associated with a significant OS benefit (5-y OS 68% versus 53%, p = 0.002). In patients with R0 resection, PORT was associated with increased OS for advanced (stages III-IV, p = 0.04), but not early (stages I-II, p = 0.14) stage TC. In patients with an R1/2 resection of advanced-stage TC, PORT was associated with significantly longer OS (5-y OS 53% versus 38%; p < 0.001). Subset analyses did not reveal clear associations of PORT with TTR. On multivariable analysis, lower pathologic stage, PORT, and R0 resection status were associated with an OS benefit, whereas only higher age and lower pathologic stage had an association with longer TTR. CONCLUSIONS: In the largest individual patient data set on patients with TC reported to date, PORT was associated with a meaningful OS benefit in patients with advanced-stage TC after an R0 or R1/2 resection.

Developing an Allogeneic Hematopoietic Progenitor Cell Transplant Service in a Resource-Limited Country: Challenges and Outcomes.

Introduction Allogeneic stem cell transplant has curative potential for many hematological disorders. Building an allogeneic hematopoietic progenitor cell transplant (HPCT) unit requires huge investment, infrastructure, equipment, medical supplies, and training of health care professionals. The key objective of this study is to share our experience of developing an allogeneic HPCT service at our tertiary care cancer hospital in a low-middle-income country. In addition, this study presents the outcomes of the first 30 allogeneic HPCTs done at our center. Methods This retrospective observational study included adult patients 18 years old or older with hematological malignancies who underwent allogeneic HPCT between July 2019 and April 2023 at Shaukat Khanum Memorial Cancer Hospital and Research Centre. Result Of the 30 patients, 24 underwent matched sibling donor (MSD) transplants in which a myeloablative-conditioning regimen (MAC) was used in 19, and a reduced conditioning regimen (RIC) was used in one. Of the six haploidentical-related donor transplants, four received MAC, and two received RIC. The median recipient age at HPCT was 23 and 21 years for MSD and Haplo-related donor transplants, respectively. The median follow-up duration was 12 months (Range: 10 days - 33 months). The overall survival rate at one year was 71.3% among all allogeneic stem cell transplant patients, whereas the disease-free survival rate at one year was 63.7%. In the acute lymphoblastic leukemia group, the disease-free survival rate at one year post allograft was 51.5%, while in the acute myeloid leukemia group, it was 78.7%. Conclusion This study demonstrates the successful development of an allogeneic bone marrow transplant unit at our hospital despite significant financial constraints. This has allowed us to provide a potentially curative and life-saving treatment to a substantial number of cancer patients. The bone marrow transplant outcomes of this study are comparable to those reported by international bone marrow transplant registries.

The International Association for the Study of Lung Cancer Thymic Epithelial Tumor Staging Project: A Re-Assessment of the International Thymic Malignancy Interest Group/International Association for the Study of Lung Cancer Lymph Node Map for Thymic Epithelial Tumors for the Forthcoming Ninth Edition of the TNM Classification of Malignant Tumors.

INTRODUCTION: A lymph node map is the pillar on which accurate assignment and documentation of nodal classification stands. The International Thymic Malignancy Interest Group created the first map for thymic epithelial malignancies in conjunction with the eighth edition of the TNM classification, representing the first official TNM classification of thymic epithelial malignancies. The map was based on clinical experience and published studies, but it was largely empirical because of limited available data. Dissemination of the map and implementation of a standard thymic stage classification across the world in 2017 have provided more consistent and granular data. METHODS: More than twice as many cases of node involvement are available for analysis in the current database compared with that of the eighth edition database, allowing validation of many aspects of the eighth edition map. This article details the process and considerations for refinement of the thymic map for the ninth TNM used by the Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer. The committee evaluated a large international collaborative data set, published anatomical and clinical studies pertaining to lymph node spread from thymic epithelial tumors, in conjunction with the analysis underlying refinements of the TNM components for the ninth edition TNM classification. RESULTS: The node map boundaries of the N1 and N2 categories remain unchanged. Visual clarifications have been added to the nomenclature of nodal stations within these regions. CONCLUSIONS: On the basis of the recommendation to keep the N component unchanged for the ninth edition TNM classification, the lymph node map remains unchanged as well; however, clarifications have been added to facilitate clinical use.

The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: Proposal for a Stage Classification for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.

INTRODUCTION: A TNM-based system for all types of thymic epithelial tumors was introduced in the eighth edition of the TNM classification of thoracic malignancies. The Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, composed of multispecialty international experts, was charged to develop proposals for the ninth edition. This article outlines the proposed definitions for the T, the N, and the M components and their combination into stage groups. METHODS: A large central database of 11,347 patients with thymic epithelial tumors was assembled thanks to the contribution of the major thymic organizations worldwide and analyses were carried out for the T, the N, and the M components and the stage groups. Overall survival was the outcome measure for patients with completely and incompletely resected tumors, and recurrence for those with complete resection. When the number of patients was sufficient, analyses were performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors. RESULTS: Tumor size is included in the T1 category as T1a (≤5cm) and T1b (>5 cm); the mediastinal pleura is dropped as a T descriptor; invasion of the lung or phrenic nerve is reclassified as T2 (instead of T3). No changes are proposed for the N and the M components from the eighth edition. The stage groups remain the same. CONCLUSIONS: The proposed changes for the ninth edition of the TNM classification set the stage for further progress in the future for these rare tumors.

The International Association for the Study of Lung Cancer Thymic Epithelial Tumors Staging Project: An Overview of the Central Database Informing Revision of the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.

INTRODUCTION: In 2014, a TNM-based system for thymic epithelial tumors was proposed. The TNM stage classification system was published as a result of a joint project from the International Association for the Study of Lung Cancer and the International Thymic Malignancy Interest Group for the eighth edition of the American Joint Commission on Cancer and the Union for International Cancer Control stage classification system. The Thymic Domain of the Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer received the mandate to make proposals for the ninth edition of the TNM stage classification. METHODS: A central thymic database was collected by the Cancer Research And Biostatistics with the contribution of the major thymic associations in the world. RESULTS: A total of 11,347 patients were collected. Submitting organizations were the following: Japanese Association for Research in the Thymus, European Society of Thoracic Surgeons, Chinese Alliance for Research in Thymoma, Korean Association for Research in the Thymus, International Thymic Malignancy Interest Group, and Réseau tumeurs THYMiques et Cancer. Additional contributions came from centers in the United States, United Kingdom, Turkey, Australia, Spain, and Italy. A total of 9147 cases were eligible for analysis. Eligible cases for analysis came from Asia and Australia (5628 cases, 61.5%), Europe (3113 cases, 34.0%), and North America (406 cases, 4.4%). CONCLUSIONS: This report provides an overview of the database that has informed the proposals for the updated T, N, and M components and the stage groups for the ninth TNM of malignant tumors.

The International Association for the Study of Lung Cancer Thymic Epithelial Tumor Staging Project: Proposal for the T Component for the Forthcoming (Ninth) Edition of the TNM Classification of Malignant Tumors.

INTRODUCTION: A TNM-based stage classification system of thymic epithelial tumors was adopted for the eighth edition of the stage classification of malignant tumors. The Thymic Domain of the Staging and Prognostics Factor Committee of the International Association for the Study of Lung Cancer developed a new database with the purpose to make proposals for the ninth edition stage classification system. This article outlines the proposed definitions for the T categories for the ninth edition TNM stage classification of thymic malignancies. METHODS: A worldwide collective database of 11,347 patients with thymic epithelial tumors was assembled. Analysis was performed on 9147 patients with available survival data. Overall survival, freedom-from-recurrence, and cumulative incidence of recurrence were used as outcome measures. Analysis was performed separately for thymomas, thymic carcinomas, and neuroendocrine thymic tumors. RESULTS: Proposals for the T categories include the following: T1 category is divided into T1a (≤5 cm) and T1b (>5 cm), irrespective of mediastinal pleura invasion; T2 includes direct invasion of the pericardium, lung, or phrenic nerve; T3 denotes direct invasion of the brachiocephalic vein, superior vena cava, chest wall, or extrapericardial pulmonary arteries and veins; and T4 category remains the same as in the eighth edition classification, involving direct invasion of the aorta and arch vessels, intrapericardial pulmonary arteries and veins, myocardium, trachea, or esophagus. CONCLUSIONS: The proposed T categories for the ninth edition of the TNM classification provide good discrimination in outcome for the T component of the TNM-based stage system of thymic epithelial tumors.

Antihypertensive effect of patulitrin and other constituents from Tagetes patula L. (French marigold) in acute L-NAME induced hypertensive rats.

The work is aimed to evaluate the blood pressure reducing effect of constituents from methanol extract and associated constituents of Tagetes patula flowers in normotensive and L-NAME induced hypertensive rats. The HPLC analysis of methanol extract of Tagetes patula flowers (JFM) resulted in the quantitative identification and percent comparison of four phenolic constituents, protocatechuic acid (PA), methyl protocatechuate (MPA), patulitrin (TRIN) and patuletin (PAT). All the extracts, fractions and compounds examined showed significant blood pressure lowering activity. Patulitrin (TRIN) which has emerged as the major constituent (15.33%) of T. patula flowers showed significant 30% and 68% fall in blood pressure in normotensive and L-NAME induced hypertensive rats respectively. The patuletin (PAT), which is an aglycone of TRIN displayed high percentage (84%) of antihypertensive activity. Further, comprehensive and advanced studies on these constituents may result in preparation of an effective blood pressure lowering medicine with active precious rare flavonoids, patuletin and patulitrin.

Effect of donor smoking and substance use on post-lung transplant outcomes.

OBJECTIVE: The study objective was to determine effects of donor smoking and substance use on primary graft dysfunction, allograft function, and survival after lung transplant. METHODS: From January 2007 to February 2020, 1366 lung transplants from 1291 donors were performed in 1352 recipients at Cleveland Clinic. Donor smoking and substance use history were extracted from the Uniform Donor Risk Assessment Interview and medical records. End points were post-transplant primary graft dysfunction, longitudinal forced expiratory volume in 1 second (% of predicted), and survival. RESULTS: Among lung transplant recipients, 670 (49%) received an organ from a donor smoker, 163 (25%) received an organ from a donor with a 20 pack-year or more history (median pack-years 8), and 702 received an organ from a donor with substance use (51%). There was no association of donor smoking, pack-years, or substance use with primary graft dysfunction (P > .2). Post-transplant forced expiratory volume in 1 second was 74% at 1 year in donor nonsmoker recipients and 70% in donor smoker recipients (P = .0002), confined to double-lung transplant, where forced expiratory volume in 1 second was 77% in donor nonsmoker recipients and 73% in donor smoker recipients. Donor substance use was not associated with allograft function. Donor smoking was associated with 54% non-risk-adjusted 5-year survival versus 59% (P = .09) and greater pack-years with slightly worse risk-adjusted long-term survival (P = .01). Donor substance use was not associated with any outcome (P ≥ 8). CONCLUSIONS: Among well-selected organs, lungs from smokers were associated with non-clinically important worse allograft outcomes without an inflection point for donor smoking pack-years. Substance use was not associated with worse allograft function. Given the paucity of organs, donor smoking or substance use alone should not preclude assessment for lung donation or transplant.

How Much Delay Matters? How Time to Treatment Impacts Overall Survival in Early Stage Lung Cancer.

OBJECTIVES: The aim of this study was to identify drivers of time from diagnosis to treatment (TTT) of surgically resected early stage non-small cell lung cancer (NSCLC) and determine the effect of TTT on post-resection survival. SUMMARY BACKGROUND DATA: Large database studies that lack relevant comorbidity data have identified longer TTT asa driver of worse overall survival. METHODS: From January 1, 2014 to April 1, 2018, 599 patients underwent lung resection for clinical stage I and II NSCLC. Random forest classification, regression, and survival were used to estimate likelihood of TTT = 0 (tissue diagnosis obtained at surgery), >0 (diagnosis obtained pre-resection), and effect of TTT on all-cause mortality. RESULTS: Patients with TTT > 0 (n = 413) had median TTT of 42 days (25-75 th percentile: 27-59 days). Patients with TTT = 0 (n = 186) had smaller tumors and higher percent predicted forced expiratory volume in 1 second (FEV 1 %). Patients with history of stroke, oncology consultation, invasive mediastinal staging, low and high extremes of FEV 1 % had longer TTT. Higher clinical stage, lack of preoperative stress test, anemia, older age, lower FEV1% and diffusion lung capacity, larger tumor size, and longer TTT were the most important predictors of all-cause mortality. One- and 5-year overall survival decreased when TTT was >50 days. CONCLUSIONS: Preoperative physiologic workup and multidisciplinary evaluation were the predominant drivers of longer TTT. Patients with TTT = 0have more favorable presentation and should be considered in TTT analyses for early stage lung cancer populations. The time needed to clinically stage and optimize patients for resection is not deleterious to overall survival until resection is performed after 50 days from diagnosis.

Novel Use of the Penumbra CAT 12 Lightning Aspiration System for the Treatment of a Complex Thrombus.

Debulking procedures using aspiration devices have been previously described in the literature to treat vegetations or thrombi on intracardiac structures such as the tricuspid valve. Transcatheter therapy has also been shown to be an effective alternative to surgical treatment for managing high risk or non-surgical patients. Furthermore, aspiration procedures can help identify the unique etiologies of intracardiac masses which can greatly impact differing treatment modalities. Utilization of aspiration devices combined with blood-loss limiting technologies have led to an increased interest in using aspiration systems to address a wider array of clinical situations that can occur. Herein we describe our experience in using the Penumbra CAT 12 Lightning Aspiration System in addressing and treating a mobile mass attached to the lead of an implantable cardiac device.

Adjuvant Therapy After Neoadjuvant Therapy for Esophageal Cancer: Who Needs It?

OBJECTIVE: We hypothesized that, on average, patients do not benefit from additional adjuvant therapy after neoadjuvant therapy for locally advanced esophageal cancer, although subsets of patients might. Therefore, we sought to identify profiles of patients predicted to receive the most survival benefit or greatest detriment from adding adjuvant therapy. BACKGROUND: Although neoadjuvant therapy has become the treatment of choice for locally advanced esophageal cancer, the value of adding adjuvant therapy is unknown. METHODS: From 1970 to 2014, 22,123 patients were treated for esophageal cancer at 33 centers on 6 continents (Worldwide Esophageal Cancer Collaboration), of whom 7731 with adenocarcinoma or squamous cell carcinoma received neoadjuvant therapy; 1348 received additional adjuvant therapy. Random forests for survival and virtual-twin analyses were performed for all-cause mortality. RESULTS: Patients received a small survival benefit from adjuvant therapy (3.2±10 months over the subsequent 10 years for adenocarcinoma, 1.8±11 for squamous cell carcinoma). Consistent benefit occurred in ypT3-4 patients without nodal involvement and those with ypN2-3 disease. The small subset of patients receiving most benefit had high nodal burden, ypT4, and positive margins. Patients with ypT1-2N0 cancers had either no benefit or a detriment in survival. CONCLUSIONS: Adjuvant therapy after neoadjuvant therapy has value primarily for patients with more advanced esophageal cancer. Because the benefit is often small, patients considering adjuvant therapy should be counseled on benefits versus morbidity. In addition, given that the overall benefit was meaningful in a small number of patients, emerging modalities such as immunotherapy may hold more promise in the adjuvant setting.

Bleomycin-Induced Fulminant Hyperpyrexia: A Report of Two Cases and Review of Literature.

Bleomycin is a commonly used cytotoxic agent that has proven its efficacy over the years. Though a common part of many protocols targeting lymphomas and germ cell tumors, it does have some serious adverse effects. Bleomycin is notorious for pulmonary toxicity and very rarely may cause fulminant hyperpyrexia. We describe two cases of classical Hodgkin's lymphoma (cHL) developing acute fulminant hyperpyrexia after administration of the first dose of bleomycin as part of chemotherapy protocol. This is a rare adverse reaction that closely mimics anaphylaxis and has an unpredictable and possibly fatal course. Health care professionals involved in the administration of chemotherapy need to be very vigilant in monitoring for symptoms of this reaction.