Risk Stratification Treatment Research Articles

Ibrutinib as part of risk-stratified treatment for posttransplant lymphoproliferative disorder: the phase 2 TIDaL trial

AbstractPosttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to R-CHOP immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as # ISRCTN32667607.

Risk stratification for synchronous/metachronous recurrence after endoscopic submucosal dissection for Barrett's esophageal adenocarcinoma using the length of Barrett's esophagus.

In Japan, the standard management of Barrett's esophageal adenocarcinoma after endoscopic submucosal dissection involves follow-up; however, multifocal synchronous/metachronous lesions are sometimes observed after endoscopic submucosal dissection. Risk stratification of multifocal cancer facilitates appropriate treatment, including eradication of Barrett's esophagus in high-risk cases; however, no effective risk stratification methods have been established. Thus, we identified the risk factors for multifocal cancer and explored risk-stratified treatment strategies for residual Barrett's esophagus. We retrospectively reviewed the data of 97 consecutive patients with superficial Barrett's esophageal adenocarcinomas who underwent curative resection with endoscopic submucosal dissection. Multifocal cancer was defined by the presence of synchronous/metachronous lesions during follow-up. We used Cox regression analysis to identify the risk factors for multifocal cancer and subsequently analyzed differences in cumulative incidences. The cumulative incidences of multifocal cancer at 1, 3, and 5years were 4.4%, 8.6%, and 10.7%, respectively. Significant risk factors for multifocal cancer were increased circumferential and maximal lengths of Barrett's esophagus. The cumulative incidences of multifocal cancer at 3years were lower for patients with circumferential length < 4cm and maximal length < 5cm (2.9% and 1.2%, respectively) than for patients with circumferential length ≥ 4cm and maximal length ≥ 5cm (51.5% and 49.1%, respectively). Risk stratification of multifocal cancer using length of Barrett's esophagus was effective. Further multicenter prospective studies are needed to substantiate our findings.

Abstract 6278: Effect of tumor size and BRAF mutational status in Middle Eastern differentiated thyroid cancer

Abstract Background: Risk stratified treatment strategies have become a focus in the treatment of Differentiated Thyroid Cancer (DTC). Tumor size at diagnosis has been widely used as a major mortality risk factor in risk stratification of DTC, but whether this is generally applicable, particularly in patient with different BRAF genetic backgrounds, is unclear. The current study was designed to analyze whether tumor size at diagnosis is a major prognostic factor in Middle Eastern DTC. Methods: We conducted a comparative study of the relationship between tumor size at diagnosis and event free survival with respect to BRAF status in 1709 consecutive patients treated surgically for Middle Eastern DTC. Patients were divided into four groups according to the size of tumor (≤4 cm vs. &amp;gt;4 cm) and BRAF mutation status: Group 1 (≤4 cm without BRAF mutation, n = 587), Group 2 (≤4 cm with BRAF mutation, n = 765), Group 3 (&amp;gt;4 cm without BRAF mutation, n = 198) and Group 4 (&amp;gt;4 cm with BRAF mutation, n = 159). Predictors of event-free survival (EFS) were compared using the Log-rank test and Cox proportional hazards models. Results: Following multivariate analysis, patients with tumors &amp;gt;4cm did worse than patients with tumors &amp;lt;4cm with respect to EFS (Group 3 vs Group1 HRadjusted=1.38, 95% CI=1.02-1.86, p = 0.0359; Group 4 vs Group 2 HRadjusted=1.61, 95% CI=1.20-2.16, p = 0.0017). However, patients did not differ according to EFS, regardless of the presence of BRAF mutation within each size category (Group 2 vs Group 1 HRadjusted=0.98 CI=.78-1.23, p=0.8415 ; Group 4 vs Group 3 HRadjusted=1.17, 95% CI=0.84-1.62, p=0.3523] Conclusion: Tumor size is an independent predictor of EFS in Middle Eastern DTC patients, regardless of BRAF mutational status. Citation Format: Rong Bu, Abdul K. Siraj, Sandeep K. Parvathareddy, Kaleem Iqbal, Saud Azam, Zeeshan Qadri, Maha Al-Rasheed, Wael Haqawi, Allianah D. Benito, Khawla S. Al-Kuraya. Effect of tumor size and BRAF mutational status in Middle Eastern differentiated thyroid cancer [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 6278.

Blood levels of glial fibrillary acidic protein for predicting clinical progression to Alzheimer’s disease in adults without dementia: a systematic review and meta-analysis protocol

BackgroundThere is urgent clinical need to identify reliable prognostic biomarkers that predict the progression of dementia symptoms in individuals with early-phase Alzheimer’s disease (AD) especially given the research on and predicted applications of amyloid-beta (Aβ)-directed immunotherapies to remove Aβ from the brain. Cross-sectional studies have reported higher levels of cerebrospinal fluid and blood glial fibrillary acidic protein (GFAP) in individuals with AD-associated dementia than in cognitively unimpaired individuals. Further, recent longitudinal studies have assessed the prognostic potential of baseline blood GFAP levels as a predictor of future cognitive decline in cognitively unimpaired individuals and in those with mild cognitive impairment (MCI) due to AD. In this systematic review and meta-analysis, we propose analyzing longitudinal studies on blood GFAP levels to predict future cognitive decline.MethodsThis study will include prospective and retrospective cohort studies that assessed blood GFAP levels as a prognostic factor and any prediction models that incorporated blood GFAP levels in cognitively unimpaired individuals or those with MCI. The primary outcome will be conversion to MCI or AD in cognitively unimpaired individuals or conversion to AD in individuals with MCI. Articles from PubMed and Embase will be extracted up to December 31, 2023, without language restrictions. An independent dual screening of abstracts and potentially eligible full-text reports will be conducted. Data will be dual-extracted using the CHeck list for critical appraisal, data extraction for systematic Reviews of prediction Modeling Studies (CHARMS)-prognostic factor, and CHARMS checklists, and we will dual-rate the risk of bias and applicability using the Quality In Prognosis Studies and Prediction Study Risk-of-Bias Assessment tools. We will qualitatively synthesize the study data, participants, index biomarkers, predictive model characteristics, and clinical outcomes. If appropriate, random-effects meta-analyses will be performed to obtain summary estimates. Finally, we will assess the body of evidence using the Grading of Recommendation, Assessment, Development, and Evaluation Approach.DiscussionThis systematic review and meta-analysis will comprehensively evaluate and synthesize existing evidence on blood GFAP levels for prognosticating presymptomatic individuals and those with MCI to help advance risk-stratified treatment strategies for early-phase AD.Trial registrationPROSPERO CRD42023481200.

Risk Stratified Treatment for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase 1/2 Non-Randomized Study of Trametinib and Azacitidine with or without Chemotherapy

Background: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating mutations in NF1, NRAS, KRAS, RRAS, RRAS2, SH2B3, PTPN11,or CBL. While hematopoietic stem cell transplantation (HSCT) can be curative, 5-year event-free survival of children with JMML after HSCT is only ~50%. Recently, several studies have identified mutational burden and DNA methylation as predictive of clinical outcomes in patients with JMML. In the T2020-004 phase 1/2 clinical trial, we will define lower-risk patients as those with one somatic alteration and low DNA methylation and high-risk patients as those with more than one somatic alteration or intermediate/high DNA methylation. Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 in the Ras/MAPK signaling pathway. Trametinib is FDA-approved for the treatment of adults with advanced melanoma with BRAF V600E or V600K mutations and in children with Ras-mutant solid tumors in combination with dabrafenib. Clinical investigation of trametinib monotherapy via the Children's Oncology Group ADVL1521 phase 2 trial (NCT03190915) showed efficacy in children with relapsed/refractory JMML. Phase 2 clinical trial evaluation of azacitidine in children with newly-diagnosed JMML was also efficacious and led to its FDA approval. In this trial, trametinib will be tested in combination with azacitidine in lower-risk patients and in combination with azacitidine and chemotherapy for high-risk patients. Study Design and Methods: This is a non-randomized, risk stratified, Phase 1/2 study for patients with newly-diagnosed JMML (NCT05849662) conducted via the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium with safety and efficacy phases for both lower-risk and high-risk cohorts. Lower-risk patients will receive trametinib once-daily for 28 days in combination with azacitidine administered daily for five days per cycle. Lower-risk patients can receive up to 12 cycles and will proceed to HSCT only if they experience progressive disease or relapse. High-risk patients will receive trametinib administered once-daily for 28 days in combination with azacitidine, fludarabine, and cytarabine (aza/FLA) administered daily for five days per cycle. High-risk patients will receive up to two cycles of therapy before proceeding to HSCT off protocol. Key Eligibility: Patients aged 1 month to 21 years who meet World Health Organization criteria for JMML will be eligible. Objectives: The primary safety objectives are to determine the safety of combining trametinib with azacitidine for lower-risk patients and combining trametinib with aza/FLA for high-risk patients. The secondary efficacy objectives are to determine the event-free survival for lower-risk patients in the absence of HSCT and the molecular response rates pre-HSCT for high-risk patients. Sample Size and Statistical Design: A rolling 6 trial design will be used during Phase 1 of the study to determine the recommended phase II dose (RP2D) of trametinib for lower-risk and high-risk patients in combination with their respective therapies. Starting trametinib dose is 0.032mg/kg daily if less than 6 years of age, or 0.025mg/kg daily if 6 years or older, with one dose level de-escalation if indicated. Phase II of the study involves lower-risk and high-risk cohort expansions at the RP2D of trametinib. Target accrual is 22 patients in the lower-risk arm and 42 patients in the high-risk arm. The study is open to accrual at all TACL consortium sites. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Novartis Pharmaceuticals Corporation provided the investigative drug in support of this trial. This study is supported by the National Institute of Health, National Cancer Institute (R37CA266550), the Pediatric Cancer Research Foundation, and the Cannonball Kids Cancer Foundation.

High Success Rates Utilizing Local Standard of Care Cytogenetic Testing for Risk Stratified Frontline Therapy for Newly Diagnosed Multiple Myeloma: Experience from the Ukmra RADAR Study

Background. Recent studies in genetically high risk (HR) multiple myeloma (MM) such as the UKMRA OPTIMUM study have reported high response rates with intensive induction and post-ASCT consolidation and maintenance strategies, providing the rationale for stratified therapy based on genetic risk. Whilst centralised testing in clinical trials offers ready uniformity and quality control, the use of local laboratories for testing within a clinical trial paves the way for genetic testing to be available for all patients, facilitating risk stratified therapy in routine care. We designed the UKMRA RADAR study to use local laboratories for cytogenetic (CGN) testing to assign treatment according to genetic risk. Methods. RADAR is an ongoing national, multi-center, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial for patients with newly diagnosed MM eligible for ASCT. Patients receive induction with RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Post ASCT, HR patients are randomised to receive isatuximab or not, alongside RBorD consolidation and R maintenance whilst standard risk (SR) patients receive MRD response guided regimens. A protocol amendment (2022) included isatuximab throughout the HR pathway, removing the post-ASCT randomisation. Risk assessment, failure rates and turnaround time are overseen by a genomics working group (GWG) including clinical and specialist cytogenetic representation. Genetic risk testing is undertaken in local genetic labs on CD138 selected bone marrow (BM) plasma cells. HR is assigned based on the presence of at least two of: t(4;14), t(14;16), t(14:20), del(17p), del(1p) and gain(1q). Clone size cut-offs are 10% for IgH translocations and 20% for copy number changes. CGN results from local laboratories are centrally reviewed to assign risk in real-time. Indeterminate cases are discussed by the GWG. Repeat testing is mandated if the initial sample fails to yield a definitive risk result for risk. Subjects with no definitive result despite 2 samples are treated as SR. Results. As of 19 th June 2023, the trial has recruited 472 patients from 72 sites across the UK. Median age is 61 years, 59.3% male, 79.9% white, 11.7% other ethnicity and 8.5% missing ethnicity data. 25 local laboratories were used for CGN testing. Of those with CGN results 354/453 patients (78.1%) were assigned standard risk, 84 (18.5%) high risk and 15 (3.3%) risk category undefined. Risk stratification is ongoing for 19 patients. Of the high risk lesions gain(1q) was most prevalent (35%), followed by t(4;14)(10.6%), del(17p)(8.7%), del(1p32)(8.7%), t(14;16)(3.8%) and t(14;20)(0.8%). In 376/453 patients (83.0%), risk was assigned from a first BM sample. 77 (17.0%) patients required a second sample; the success rate of repeat samples is 71.4%, 22 (4.9%) patients were unable to be risk-stratified despite 2 samples. Figure 1 shows the success rate of first and repeat tests. The overall median turnaround time (from D1 cycle 1 until site notified of result) was 11 days (IQR 0 to 21). Sites were sent risk status prior to cycle 1 in 99 (21.9%) patients , 285 (62.9%) prior to cycle 2 and 341 (75.3%) cycle 3. Note this is calculated where treatment data is available. Conclusion. The RADAR study demonstrates that risk-stratified treatment approaches are feasible in the context of a national phase II/III clinical trial with the use of local laboratories for risk assignment. The vast majority of patients have been successfully allocated to a risk-adapted treatment pathway following a first FISH test (83.0%). Protocol v4 requires time-critical risk-stratification for addition of isatuximab to induction treatment from cycle 2 in high-risk patients, and this has proven to be achievable in almost 2/3 of patients with over ¾ by the end of cycle 2. The RADAR study also enables hospitals across the UK to access CGN testing via a network model of laboratories with standardization of testing and clinically relevant turnaround times. This model is applicable internationally in both public and privately funded healthcare systems and supports the infrastructure for accessible genetic risk stratification for all newly diagnosed MM patients. Ongoing studies within the RADAR trial are evaluating novel and clinically deliverable risk stratification protocols to inform risk stratified approaches in newly diagnosed MM.

Unraveling the impact of upfront chemotherapy and proton beam therapy on treatment outcome and follow-up in central nervous system germ cell tumors: a single center experience.

Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

Induction therapy choices and responses in a third world country: A single center study from Pakistan

BackgroundLeukaemia accounts for approximately 2.5% of all new cancer incidence and 3.1% of cancer-related mortality with a significant number of the total presenting as Acute Lymphocytic Leukemia. Acute Lymphocytic Leukemia (ALL) poses a healthcare burden in the majority of the countries of the world but is more so a case in resource-limited countries where access to comprehensive healthcare is often limited and scarcely available. This article tries to highlight the challenges in ALL treatments in one such region by presenting the facts regarding treatments employed and patient outcomes seen. MethodThis was a retrospective single-institution study in a tertiary care setup examining Ph neg ALL patient data from Jan 2019 to Dec 2020. It was stratified according to various parameters ranging from presentation to mode of diagnosis as well as treatment strategies and responses achieved after induction including mortality. Conventional chemotherapy regimens for ALL treatment were used with corticosteroids, vincristine, anthracyclines, asparaginase, cytosar, and MTX being the backbone of ALL induction. Cytogenetics were not possible due to resource constraints. ResultsData showed 85 patients being managed during the mentioned time period. 65 percent were males and 68 percent were between the age 15 to 30 years. Approximately 80 percent had no co-morbid condition including diabetes, hypertension, ischemic heart disease or Hep B/C positivity. Around 60 percent were diagnosed on immunophenotyping by flowcytometry and 62 percent used HyperCVAD as the induction protocol. Patients who achieved CR were 62 percent after single induction and most were assessed after count recovery on (3-4 weeks) or after 6 weeks with the percentages being 32 and 41 respectively. Duration of admission was for 1-3 weeks for almost 70 percent of the patients and those alive at the end of induction were around 90 percent. ConclusionIn conclusion, the treatment of Acute Lymphocytic Leukemia in resource-limited countries remains a formidable task,sometimes requiring innovative and sustainable approaches. Due to limited resources, a resource stratified rather than risk-stratified treatment approach is often utilized to tailor therapy. This approach ensures that relatively better resourced patients receive more intensive treatment others are spared unnecessary toxicity. While the challenges in resource-limited settings are significant, the treatment strategies and chemotherapy protocols, if modified as per need and implemented effectively, hold promise in improving outcomes for patients with Ph negative Acute Lymphocytic Leukemia in regions which have limited resources at their disposal.

Prognostic model using 18F-FDG PET radiomics predicts progression-free survival in relapsed/refractory Hodgkin lymphoma

AbstractInvestigating prognostic factors in patients with relapsed or primary refractory classical Hodgkin lymphoma (R/R cHL) is essential to optimize risk-adapted treatment strategies. We built a prognostic model using baseline quantitative 18F-fluorodeoxyglucose positron emission tomography (PET) radiomics features and clinical characteristics to predict the progression-free survival (PFS) among patients with R/R cHL treated with salvage chemotherapy followed by autologous stem cell transplantation. Metabolic tumor volume and several novel radiomics dissemination features, representing interlesional differences in distance, volume, and standard uptake value, were extracted from the baseline PET. Machine learning using backward selection and logistic regression were applied to develop and train the model on a total of 113 patients from 2 clinical trials. The model was validated on an independent external cohort of 69 patients. In addition, we validated 4 different PET segmentation methods to calculate radiomics features. We identified a subset of patients at high risk for progression with significant inferior 3-year PFS outcomes of 38.1% vs 88.4% for patients in the low-risk group in the training cohort (P < .001) and 38.5% vs 75.0% in the validation cohort (P = .015), respectively. The overall survival was also significantly better in the low-risk group (P = .022 and P < .001). We provide a formula to calculate a risk score for individual patients based on the model. In conclusion, we developed a prognostic model for PFS combining radiomics and clinical features in a large cohort of patients with R/R cHL. This model calculates a PET-based risk profile and can be applied to develop risk-stratified treatment strategies for patients with R/R cHL. These trials were registered at www.clinicaltrials.gov as #NCT02280993, #NCT00255723, and #NCT01508312.

Paediatric B lymphoblastic leukaemia with hyperdiploidy and a false-positive KMT2A fluorescence in situ hybridization result

The dramatic improvement in the event-free survival of paediatric B-lymphoblastic leukaemia (B-ALL) has led to risk-stratified treatment. Through a combination of clinical features, cytogenetic abnormalities and assessment of treatment response, patients are stratified to receive different intensities of therapy. The presence of high hyperdiploidy (>50 chromosomes) is considered a favourable genetic feature. Conversely, KMT2A fusion genes in B-ALL are associated with a poor prognosis, resulting in intensification of treatment. We present a seven-year-old female with B-ALL, a high hyperdiploid karyotype (56 chromosomes) and KMT2A rearrangement detected on FISH, but with no productive fusion identified. Single nucleotide polymorphism (SNP) array suggested the KMT2A rearrangement was due to chromosome 11 chromothripsis. Subsequent targeted RNA fusion panel and whole transcriptomic sequencing (mRNA-seq) did not detect an expressed KMT2A fusion. Differential expression analyses of the mRNA-seq data led to clustering of this case with other hyperdiploid cases, consistent with the hyperdiploid cytogenetic results. Given the additional intensity and potential toxicity of high-risk treatment, unusual findings by chromosome analysis, FISH and/or chromosomal microarray should prompt consideration of testing for a KMT2A fusion by another method to avoid misclassification.

Multiparametric MRI-Based Radiomics Signature with Machine Learning for Preoperative Prediction of Prognosis Stratification in Pediatric Medulloblastoma

Despite advances in risk-stratified treatment strategies for children with medulloblastoma (MB), the prognosis for MB with short-term recurrence is extremely poor, and there is still a lack of evaluation of short-term recurrence risk or short-term survival. This study aimed to construct and validate a radiomics model for predicting the outcome of MB based on preoperative multiparametric magnetic resonance images (MRIs) and to provide an objective for clinical decision-making. The clinical and imaging data of 64 patients with MB admitted to Shenzhen Children's Hospital from December 2012 to December 2021 and confirmed by pathology were retrospectively collected. According to the 18-month progression-free survival, the cases were classified into a good prognosis group and a poor prognosis group, and all cases were divided into training group (70%) and validation group (30%) randomly. Radiomics features were extracted from MRI of each child. The consistency test, t-test, and the least absolute shrinkage and selection operator were used for feature selection. The support vector machine (SVM) and receiver operator characteristic were used to evaluate the distinguishing ability of the selected features to the prognostic groups. RAD score was calculated based on the selected features. The clinical characteristics and RAD score were included in the multivariate logistic regression, and prediction models were constructed by screening out independent influences. The radiomics nomogram was constructed, and its clinical significance was evaluated. A total of 1930 radiomic features were extracted from the images of each patient, and 11 features were included in the construction of radiomics score after selected. The area under the curve (AUC) values of the SVM model in the training and validation groups were 0.946 and 0.797, respectively. The radiomics nomogram was constructed based on the training cohort, and the AUC values in the training group and the validation group were 0.926 and 0.835, respectively. The results of clinical decision curve analysis showed that a good net benefit could be obtained from the nomogram. The radiomics nomogram established based on MRI can be used as a noninvasive predictive tool to evaluate the prognosis of children with MB, which is expected to help neurosurgeons better conduct preoperative planning and patient follow-up management.

Role of Conventional Cytogenetics and FISH in the Laboratory Work Up of Plasma Cell Dyscrasias

AbstractPlasma cell dyscrasias are a heterogeneous group of neoplasms characterized by abnormal proliferation of plasma cells with or without over production of monoclonal immunoglobulins. Chromosomal abnormalities are acquired either early in the course of the disease or during disease progression. Plasma cell dyscrasias are categorized into multiple cytogenetic subtypes that form an integral component of risk-stratified treatment protocols. The primary genetic events are IgH gene translocations and non-random gains of chromosomes 3/5/7/9/11/15/19 and or 21. The secondary genetic events consist of chromosome 1 abnormalities (1p deletion and 1q gain or amplification), deletion 17p/TP53, deletion 13q, and MYC gene rearrangements. Plasma cells being at the end of differentiation spectrum of B cells, have low proliferative potential precluding the use of karyotyping in identification of chromosomal abnormalities. Analysis of enriched plasma cells using interphase fluorescent in situ hybridization (FISH) is the technique of choice for identifying these abnormalities. It is essential to enrich plasma cells before the FISH analysis, and numerous plasma cell enrichment techniques have been described. In the paper, we review the cytogenetic approach to identify clinically significant genetic aberrations including the effective use of FISH panels and plasma cell enrichment techniques.

The End Is in Sight: Current Strategies for the Elimination of HIV Vertical Transmission.

The goal of this review is to highlight and interpret recent trends and developments in the diagnosis, treatment, and prevention of HIV vertical transmission from a clinical perspective. Universal third-trimester retesting and partner testing may better identify incident HIV among pregnant patients and result in early initiation of antiretroviral therapy to prevent vertical transmission. The proven safety and efficacy of integrase inhibitors such as dolutegravir may be particularly useful in suppressing viremia in pregnant persons who present late for ART treatment. Pre-exposure prophylaxis (PrEP) during pregnancy may play a role in preventing HIV acquisition; however, its role in preventing vertical transmission is difficult to elucidate. Substantial progress has been made in recent years to eliminate HIV perinatal transmission. Future research hinges upon a multipronged approach to improving HIV detection, risk-stratified treatment strategies, and prevention of primary HIV infection among pregnant persons.

Divergent clinical presentations and outcomes among children and adolescents with Kaposi sarcoma in Malawi and Tanzania.

The Kaposi sarcoma (KS) T0 versus T1 staging classification does not address the unique clinical features of paediatric KS in human gammaherpesvirus 8 (HHV-8) endemic regions of Africa. This study seeks to define patterns of childhood KS using a paediatric-specific approach. The Lilongwe paediatric KS staging classification categorizes disease based on clinical phenotype: stage 1=mild/moderate KS limited to cutaneous/oral involvement, stage 2=primarily lymphadenopathic disease, stage 3=woody edema KS, stage 4=visceral and/or severe/disseminated mucocutaneous disease. Characteristics and outcomes were evaluated from paediatric referral centres in Lilongwe, Malawi, and Mbeya, Tanzania. Among 171 patients, the median age was 9.3 years, 37% (n=63) were female, and 87% (n=149) had HIV. Breakdown by stage was as follows: 18% (n=31) stage 1, 33% (n=56) stage 2, 19% (n=33) stage 3, and 30% (n=51) stage 4. Age (younger stage 2 and older stage 3), severe CD4 count suppression (lower CD4 for stages 1 and 4), and presence of severe anaemia and thrombocytopenia (worse for stages 2 and 4) differed across stages. Estimated 2-year event-free survival/progression-free survival/overall survival by stage was as follows: stage 1, 81%/81%/87%; stage 2, 50%/50%/63%; stage 3, 24%/49%/81%; and stage 4, 29%/34%/54%. Sub-analysis of stage 2 lymphadenopathic KS demonstrated superior long-term 6-year event-free survival of 70% (95% confidence interval [CI] 49-83) for younger children (aged <7 years) versus 27% (95% CI 8-51) for older children. This paediatric-specific staging classification categorizes patients with distinct characteristics and patterns of treatment response. This platform may guide clinicians to provide risk-stratified treatment with the hope of improving survival among children with KS.

Treatment-related deaths and non-fatal severe toxicities during the intensive treatment phases of the icicle-all-14 risk-stratified treatment protocol for newly-diagnosed acute lymphoblastic leukaemia

Treatment-related deaths and non-fatal severe toxicities during the intensive treatment phases of the icicle-all-14 risk-stratified treatment protocol for newly-diagnosed acute lymphoblastic leukaemia

Prognostic indices for peripheral T-cell lymphoma - not otherwise specified and adult T-cell leukemia/lymphoma: From past to future.

Several prognostic indices have been reported for peripheral T-cell lymphoma (PTCL) and adult T-cell leukemia/lymphoma (ATL). The clinical features and prognosis of PTCL differ in a specified pathological diagnosis, whereas those of ATL are more diverse, even in the same clinical subtypes of acute, lymphoma, chronic, and smoldering. The establishment of a prognostic index is important not only for a risk-stratified treatment approach, but also for the preliminary evaluation of therapeutic findings by novel modalities, particularly in rare and aggressive diseases such as ATL. Five prognostic indices for PTCL-not otherwise specified and 6 prognostic indices for ATL are discussed herein. Recent advances in molecular analyses have facilitated prognostication using molecular profiles. In addition to the external validation of these prognostic indices, which are mostly established by clinical information, the development of novel indices by incorporating molecular profiles is warranted to improve the outcomes of patients through the selection of optimal treatments.

Post-intubation tracheal lacerations: Risk-stratification and treatment protocol according to morphological classification.

Post-intubation tracheal laceration (PITL) is a rare condition (0.005% of intubations). The treatment of choice has traditionally been surgical repair. Following our first report in 2010 of treatment protocol tailored to a risk-stratified morphological classification there is now clear evidence that conservative therapy represents the gold standard in the majority of patients. In this paper we aim to validate our risk-stratified treatment protocol through the largest ever reported series of patients. This retrospective analysis is based on a prospectively collected series (2003-2020) of 62 patients with PITL, staged and treated according to our revised morphological classification. Fifty-five patients with Level I (#8), II (#36) and IIIA (#11) PITL were successfully treated conservatively. Six patients with Level IIIB injury and 1 patient with Level IV underwent a surgical repair of the trachea. No mortality was reported. Bronchoscopy confirmed complete healing in all patients by day 30. Statistical analysis showed age only to be a risk factor for PITL severity. Our previously proposed risk-stratified morphological classification has been validated as the major tool for defining the type of treatment in PITL.

Feasibility and Improvement in Survival with a Risk-Adapted Treatment Regimen for Childhood Acute Lymphoblastic Leukemia in a Limited Resource Setting

Introduction: High-intensity therapeutic regimens results in ALL have not been reproduced in limited resource settings, due to the lack of appropriate support therapy, diagnostic methods, limited access to drugs, and high treatment related mortality. For low and middle-income countries, treatment of these patients represents a challenge. In Mexico acute leukemia represents 49% of all pediatric cancers, with a 5-year overall survival between 50 and 60%, a relapse rate of 26%, induction related mortality of 3-10%, and a mortality in remission of 14%. We report the results of an adjusted treatment regimen based on an adapted risk stratification for a limited-resource setting. Objective: To implement a risk stratified treatment protocol for a limited resource setting, with the aim of reducing induction related mortality, and improving EFS and OS. Materials and Methods: From January 2017 to March 2020, all patients diagnosed with ALL between 0 and 15 years of age in a single center in northeast México were captured in a prospectively maintained database. Depending on risk stratification, patients received an adjusted treatment protocol with variations on intensity and duration for the different phases. The main differences were the amount of anthracycline doses during induction (2 for low, 3 for intermediate/high patients), the requirement of at least 20 doses of L-asparaginase for intermediate/high risk patients, and the use of Capizzi-style methotrexate for intermediate risk and high-dose methotrexate only for high-risk patients (Table1). Demographic data was reported using distribution analysis, and the Kaplan-Meier method was used to analyze and predict OS and EFS. Results: There were 59 male and 41 female patients; the median age at diagnosis was 5.5 years. B-cell and T-cell lymphoblastic leukemia was the diagnosis in 94% and 6% patients, respectively, with a follow-up of 41 (0.33-65) months. Regarding risk stratification, 42%, 34%, and 24% children were classified as high, intermediate, and low-risk, respectively. After one week of corticosteroids 80% of patients had a good response, and 84% of patients achieved a negative measurable residual disease (MRD) after induction chemotherapy. Estimated EFS and OS at 5 years were 70% and 77.5% respectively. Of the 93 patients evaluable for response, MRD positivity (16%), induction related mortality (6%), and relapse (16%) rates were lower in this cohort when contrasted with previous protocols. EFS for low, intermediate, and high-risk groups was 73%, 85%, and 56% and OS 88%, 90% and 61% (Figure 1) Conclusions: The implementation of a risk-adjusted chemotherapy regimen adapted for our limited-resource center, improved treatment continuity and was associated with better OS, and EFS. Early relapse rates were also reduced, without increasing induction mortality associated with toxicity. Periodic and prospective outcome evaluation in a limited-resource setting is fundamental to adjust and standardize therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical and Molecular Features in Medulloblastomas Subtypes in Children in a Cohort in Taiwan.

Medulloblastoma (MB) was classified into four molecular subgroups: WNT, SHH, group 3, and group 4. In 2017, 12 subtypes within 4 subgroups and 8 subtypes within non-WNT/non-SHH subgroups according to the differences of clinical features and biology were announced. In this study, we aimed to identify the heterogeneity of molecular features for discovering subtype specific factors linked to diagnosis and prognosis. We retrieved 70 MBs in children to perform RNA sequencing and a DNA methylation array in Taiwan. Integrated with clinical annotations, we achieved classification of 12 subtypes of pediatric MBs in our cohort series with reference to the other reported series. We analyzed the correlation of cell type enrichment in SHH MBs and found that M2 macrophages were enriched in SHH β, which related to good outcomes of SHH MBs. The high infiltration of M2 macrophages may be an indicator of a favorable prognosis and therapeutic target for SHH MBs. Furthermore, C11orf95-RELA fusion was observed to be associated with recurrence and a poor prognosis. These results will contribute to the establishment of a molecular diagnosis linked to prognostic indicators of relevance and help to promote molecular-based risk stratified treatment for MBs in children.

Prognostic value of TARC and quantitative PET parameters in relapsed or refractory Hodgkin lymphoma patients treated with brentuximab vedotin and DHAP.

Risk-stratified treatment strategies have the potential to increase survival and lower toxicity in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) patients. This study investigated the prognostic value of serum (s)TARC, vitamin D and lactate dehydrogenase (LDH), TARC immunohistochemistry and quantitative PET parameters in 65 R/R cHL patients who were treated with brentuximab vedotin (BV) and DHAP followed by autologous stem-cell transplantation (ASCT) within the Transplant BRaVE study (NCT02280993). At a median follow-up of 40 months, the 3-year progression free survival (PFS) was 77% (95% CI: 67-88%) and the overall survival was 95% (90-100%). Significant adverse prognostic markers for progression were weak/negative TARC staining of Hodgkin Reed-Sternberg cells in the baseline biopsy, and a high standard uptake value (SUV)mean or SUVpeak on the baseline PET scan. After one cycle of BV-DHAP, sTARC levels were strongly associated with the risk of progression using a cutoff of 500 pg/ml. On the pre-ASCT PET scan, SUVpeak was highly prognostic for progression post-ASCT. Vitamin D, LDH and metabolic tumor volume had low prognostic value. In conclusion, we established the prognostic impact of sTARC, TARC staining, and quantitative PET parameters for R/R cHL, allowing the use of these parameters in prospective risk-stratified clinical trials. Trial registration: NCT02280993.