Wire-guided localization and surgical resection of non-palpable recurrent of thyroid carcinoma: A STROBE-compliant, retrospective cohort study.

BACKGROUND: Information on hook-wire guided (HWG) surgery for non-palpable thyroid carcinoma (TC), locoregional-recurrent disease (LRRD) is scarce. We analyze the results of HWG resection compared with the traditional procedure. METHODS: Cohort study performed between January 2016 and December 2020. Patients with TC and non-palpable LRRD were included. A "Standard cohort", patients with non-HWG resection and "HWG cohort", with HWG resection of LRRD were defined. Surgical morbidity, re-recurrent/progressive disease (RRD), and re-recurrence-free survival (RRFS) were defined. RESULTS: 43 and 23 patients were assigned to the Standard or HWG cohorts, respectively. Complications occurred in 28 % and 17.3 % of cases, in control or HWG cohorts, respectively. HWG cohort, size of primary TC, 131I dose >150 mCi, and thyroglobulin level >1 ng/ml at detection of LRRD were associated with RRD. HWG cohort, thyroglobulin level at LRRD, 131I treatment, and dose were associated with RRFS. CONCLUSIONS: HWG surgery of non-palpable TC LRRD had improved results regarding surgical morbidity, RRD, and RRFS.

The relapsed acute lymphoblastic leukemia network (ReALLNet): a multidisciplinary project from the spanish society of pediatric hematology and oncology (SEHOP).

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with survival rates exceeding 85%. However, 15% of patients will relapse; consequently, their survival rates decrease to below 50%. Therefore, several research and innovation studies are focusing on pediatric relapsed or refractory ALL (R/R ALL). Driven by this context and following the European strategic plan to implement precision medicine equitably, the Relapsed ALL Network (ReALLNet) was launched under the umbrella of SEHOP in 2021, aiming to connect bedside patient care with expert groups in R/R ALL in an interdisciplinary and multicentric network. To achieve this objective, a board consisting of experts in diagnosis, management, preclinical research, and clinical trials has been established. The requirements of treatment centers have been evaluated, and the available oncogenomic and functional study resources have been assessed and organized. A shipping platform has been developed to process samples requiring study derivation, and an integrated diagnostic committee has been established to report results. These biological data, as well as patient outcomes, are collected in a national registry. Additionally, samples from all patients are stored in a biobank. This comprehensive repository of data and samples is expected to foster an environment where preclinical researchers and data scientists can seek to meet the complex needs of this challenging population. This proof of concept aims to demonstrate that a network-based organization, such as that embodied by ReALLNet, provides the ideal niche for the equitable and efficient implementation of "what's next" in the management of children with R/R ALL.

Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B-ALL. Although hyperdiploidy represents an important prognostic factor in childhood B-ALL, the specific chromosome gains with prognostic value in HHD-B-ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD-B-ALL remains very limited. We applied automated sequential-iFISH coupled with single-cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n = 62) and matched relapse (REL, n = 10) samples from HHD-B-ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD-B-ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD-B-ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)-negative childhood HHD-B-ALL patients: relapse-free survival beyond 5 years: 22.1% versus 87.9%, P < 0.0001 and 33.3% versus 80%, P < 0.0001, respectively. Moreover, longitudinal analysis of matched DX-REL HHD-B-ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub-stratification of pediatric MRD-negative HHD-B-ALL patients.

LKB-1 Expression and High-Risk Histopathology are Independent Prognostic Factors for Patients with Oral Cavity Carcinoma.

BACKGROUND: The expression of liver kinase B1 (LKB-1) has been associated with prognosis in squamous cell carcinoma of the oral cavity (SCCOC). This study aimed to define the prognostic role of LKB-1 expression for patients with SCCOC and the suitability of its integration into a multivariate prognostic model. METHODS: A retrospective cohort study of patients with SCCOC was conducted in a cancer center. Expression of LKB-1 was evaluated by immunohistochemistry, and multivariate analysis defined prognostic factors associated with recurrence, recurrence-free survival (RFS), and overall survival (OS). The logistic regression model was used to construct a predictive computer software program. RESULTS: Of the 201 patients in this study, 104 (51.7%) experienced recurrence of their disease. Lower expression of LKB-1, high-risk histopathology, and advanced tumor-node-metastasis (TNM) stages were independent factors via multivariate analysis associated with the increased recurrence risk, poor RFS, and poor OS. If lack of LKB-1 expression is considered the reference category, the factors independently associated with recurrence were low (odds ratio [OR], 0.157; 95% confidence interval [CI], 0.044-0.557), intermediate (OR, 0.073; 95% CI, 0.017-0.319), and intense (OR, 0.047; 95% CI, 0.007-0.304) expression of LKB-1. This model permitted construction of a computer software program capable of prediction with receiver operating characteristic analysis (area under the curve, 0.925) and led to the definition of five prognostic groups with a biologic gradient. CONCLUSION: These results suggest that LKB-1 expression in patients with SCCOC is of robust prognostic value and complements the TNM staging system. The proposed model requires external validation in prospective observational studies.

Chromosome banding analysis and genomic microarrays are both useful but not equivalent methods for genomic complexity risk stratification in chronic lymphocytic leukemia patients.

Genome complexity has been associated with poor outcome in patients with chronic lymphocytic leukemia (CLL). Previous cooperative studies established five abnormalities as the cut-off that best predicts an adverse evolution by chromosome banding analysis (CBA) and genomic microarrays (GM). However, data comparing risk stratification by both methods are scarce. Herein, we assessed a cohort of 340 untreated CLL patients highly enriched in cases with complex karyotype (CK) (46.5%) with parallel CBA and GM studies. Abnormalities found by both techniques were compared. Prognostic stratification in three risk groups based on genomic complexity (0-2, 3- 4 and ≥5 abnormalities) was also analyzed. No significant differences in the percentage of patients in each group were detected, but only a moderate agreement was observed between methods when focusing on individual cases (κ=0.507; P<0.001). Discordant classification was obtained in 100 patients (29.4%), including 3% classified in opposite risk groups. Most discrepancies were technique-dependent and no greater correlation in the number of abnormalities was achieved when different filtering strategies were applied for GM. Nonetheless, both methods showed a similar concordance index for prediction of time to first treatment (TTFT) (CBA: 0.67 vs. GM: 0.65) and overall survival (CBA: 0.55 vs. GM: 0.57). High complexity maintained its significance in the multivariate analysis for TTFT including TP53 and IGHV status when defined by CBA (hazard ratio [HR] 3.23; P<0.001) and GM (HR 2.74; P<0.001). Our findings suggest that both methods are useful but not equivalent for risk stratification of CLL patients. Validation studies are needed to establish the prognostic value of genome complexity based on GM data in future prospective studies.

Prognostic impact of micromegakaryocytes in primary myelodysplastic syndromes.

Micromegakaryocytes (microMKs) are considered a myelodysplastic feature of myeloid neoplasms in adults, with an adverse prognosis connotation. However, this notion in MDS has not been well proved. In our cohort of 287 MDS, patients with microMKs showed lower overall survival (OS) (HR, 2.12; 95% CI, 1.47-3.06; p = 0.000036) and higher risk of acute myeloid leukemia (AML) evolution (HR, 4.8; 95% CI, 2.9-11.01; p = 0.00021). Results were validated with an independent cohort. In multivariate analysis, the presence of microMKs maintained its independent association with OS (HR, 1.54, 95% CI, 1.13-2.1, p = 0.0059) and AML transformation (HR, 2.28, 95% CI, 1.2-4.4, p = 0.014). Moreover, by adding 1 point to the IPSS-R score in patients with microMKs, we improved the IPSS-R accuracy. Interestingly, adding that 1-point, 29% of intermediate IPSS-R risk group patients were upgraded to the high-risk group. In summary, we confirmed that the presence of microMKs implies worse outcomes in MDS and suggested a modification improving IPSS-R.

Is acute lymphoblastic leukemia with mature B-cell phenotype and KMT2A rearrangements a new entity? A systematic review and meta-analysis.

The association between mature B-cell phenotype and KMT2A rearrangements in acute lymphoblastic leukemia is a very rare finding. It identifies a group of patients with similar clinical and biological characteristics that clearly differs from the entity B-cell lymphoblastic leukemia/lymphoma with t(v;11q23)/KMT2A-rearranged, which typically presents an immature pro B-cell phenotype. We describe the clinical-biological characteristics and disease outcome of three pediatric ALL patients with these features treated at our institution, and review 28 cases described in the literature. Most cases occur in children under 2 years-old, presenting a mature B-cell phenotype that uniformly expresses cytoplasmic and surface IgM with lambda light chain restriction, with heterogeneous co-expression of immaturity antigens. Patients do not have MYC rearrangements and all show KMT2A abnormalities, with 76% presenting t(9;11)(p21;q23)/MLLT3-KMT2A. These patients have an unfavorable clinical outcome and a 48% relapse rate. In-depth knowledge of this disease entity is needed to improve outcome.

Helpful Criteria When Implementing NGS Panels in Childhood Lymphoblastic Leukemia.

The development of Next-Generation Sequencing (NGS) has provided useful diagnostic, prognostic, and therapeutic strategies for individualized management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Consequently, NGS is rapidly being established in clinical practice. However, the technology's complexity, bioinformatics analysis, and the different available options difficult a broad consensus between different laboratories in its daily routine introduction. This collaborative study among Spanish centers was aimed to assess the feasibility, pros, and cons of our customized panel and other commercial alternatives of NGS-targeted approaches. The custom panel was tested in three different sequencing centers. We used the same samples to assess other commercial panels (OncomineTM Childhood Cancer Research Assay; Archer®FusionPlex® ALL, and Human Comprehensive Cancer Panel GeneRead Panel v2®). Overall, the panels showed a good performance in different centers and platforms, but each NGS approach presented some issues, as well as pros and cons. Moreover, a previous consensus on the analysis and reporting following international guidelines would be preferable to improve the concordance in results among centers. Our study shows the challenges posed by NGS methodology and the need to consider several aspects of the chosen NGS-targeted approach and reach a consensus before implementing it in daily practice.

Treatment of Unresectable Differentiated Thyroid Carcinoma With Upfront External Radiotherapy and Salvage Surgery: A STROBE-Compliant Retrospective Cohort Study.

INTRODUCTION: In patients with unresectable Differentiated thyroid cancer (DTC), the use of external beam radiation therapy (EBRT), leads mostly to palliation. Our aim is to define the role of upfront EBRT, followed or not by salvage surgery, on Progression-free survival (PFS) or Overall survival (OS) in patients with DTC. METHODS: This is a cohort study of patients with initially unresectable DTC who received EBRT. Cohort A received EBRT followed by rescue surgery and cohort B, EBRT only. The Kaplan-Meier method and Cox model were employed for survival analysis. RESULTS: Thirty-three patients were included; 69.6% females and 30.3% males. Mean age was 60.6 and mean tumor diameter was 10.4 cm; 17 and 16 patients were included in cohorts A and B, respectively. Belonging to cohort A (Hazard ratio [HR] 0.177, 95% CI 0.05-0.7) and use of intensity modulated radiotherapy (HR 0.177, 95% CI 0.03-1.08) were associated to better PFS, while high-risk histopathology (HR 6.6, 95% CI 0.9-50) and EBRT dose (HR 1.05, 95% CI 1.01-1.08) were independently associated with lower PFS. Patients from cohort A (HR 0.061, 95% CI 0.01-0.3) had improved OS, while high-risk histopathology (HR 5.7, 95% CI 1.1-28.6) and EBRT dose (HR 1.05, 95% CI 1.01-1.09) were independently associated to worse OS. CONCLUSION: EBRT, and when feasible, salvage surgery, should be an integral part of the therapeutic strategy in initially unresectable DTC.

Measurable Residual Disease Assessed by Flow-Cytometry Is a Stable Prognostic Factor for Pediatric T-Cell Acute Lymphoblastic Leukemia in Consecutive SEHOP Protocols Whereas the Impact of Oncogenetics Depends on Treatment.

Robust and applicable risk-stratifying genetic factors at diagnosis in pediatric T-cell acute lymphoblastic leukemia (T-ALL) are still lacking, and most protocols rely on measurable residual disease (MRD) assessment. In our study, we aimed to analyze the impact of NOTCH1, FBXW7, PTEN, and RAS mutations, the measurable residual disease (MRD) levels assessed by flow cytometry (FCM-MRD) and other reported risk factors in a Spanish cohort of pediatric T-ALL patients. We included 199 patients treated with SEHOP and PETHEMA consecutive protocols from 1998 to 2019. We observed a better outcome of patients included in the newest SEHOP-PETHEMA-2013 protocol compared to the previous SHOP-2005 cohort. FCM-MRD significantly predicted outcome in both protocols, but the impact at early and late time points differed between protocols. The impact of FCM-MRD at late time points was more evident in SEHOP-PETHEMA 2013, whereas in SHOP-2005 FCM-MRD was predictive of outcome at early time points. Genetics impact was different in SHOP-2005 and SEHOP-PETHEMA-2013 cohorts: NOTCH1 mutations impacted on overall survival only in the SEHOP-PETHEMA-2013 cohort, whereas homozygous deletions of CDKN2A/B had a significantly higher CIR in SHOP-2005 patients. We applied the clinical classification combining oncogenetics, WBC count and MRD levels at the end of induction as previously reported by the FRALLE group. Using this score, we identified different subgroups of patients with statistically different outcome in both Spanish cohorts. In SHOP-2005, the FRALLE classifier identified a subgroup of high-risk patients with poorer survival. In the newest protocol SEHOP-PETHEMA-2013, a very low-risk group of patients with excellent outcome and no relapses was detected, with borderline significance. Overall, FCM-MRD, WBC count and oncogenetics may refine the risk-stratification, helping to design tailored approaches for pediatric T-ALL patients.

Prognostic Impact of Direct 131I Therapy After Detection of Biochemical Recurrence in Intermediate or High-Risk Differentiated Thyroid Cancer: A Retrospective Cohort Study.

Background: Patients treated for intermediate- or high-risk differentiated thyroid carcinoma (DTC) and Thyroglobulin (TG) elevation during follow-up, require a diagnostic whole-body scan (DWBS) and if positive, 131I treatment. This approach can lead to a delay in treatment and increased costs. The purpose of this study is to compare the oncologic outcomes associated to administration of direct therapy with 131I at first biochemical recurrence. Methods: Retrospective cohort study of patients with intermediate- or high-risk DTC treated with total thyroidectomy, 131I ablation and who developed TG elevation during follow-up, between January 2007 and December 2015. Cohort A included patients who underwent a DWBS with 5 mCi of 131I, and if negative an MRI and/or 18FDG PET-CT prior to the therapeutic dosage, and cohort B included those who only received a therapeutic dosage of 131I, without a DWBS or extensive image studies. Main outcomes were second recurrence (SR) and disease-free survival (DFS). The diagnostic accuracy of DWBS was analyzed. Results: Cohorts A and B had 74 and 41 patients, each. By multivariate analysis, age, differentiation grade, TN classification, ablation dose, and performed DWBS (odds ratio 55.1; 95% CI 11.3-269) were associated with SR (p < 0.0001); age, male gender, ablation dose and performed DWBS (hazard ratio 7.79; 95% CI 3.67-16.5) were independent factors associated with DFS (p < 0.0001). DWBS diagnostic accuracy was 36.48%. Conclusion: 131I treatment in patients with DTC biochemical recurrence and no DWBS or extensive image studies is associated with a significantly lower frequency of SR and an increased DFS. The diagnostic accuracy of DWBS is low, and its clinical efficiency should be defined in prospective phase III studies.

Polymorphisms in MDM2 and TP53 Genes and Risk of Developing Therapy-Related Myeloid Neoplasms.

One of the most severe complications after successful cancer therapy is the development of therapy-related myeloid neoplasms (t-MN). Constitutional genetic variation is likely to impact on t-MN risk. We aimed to evaluate if polymorphisms in the p53 pathway can be useful for predicting t-MN susceptibility. First, an association study revealed that the Pro variant of the TP53 Arg72Pro polymorphism and the G allele of the MDM2 SNP309 were associated with t-MN risk. The Arg variant of TP53 is more efficient at inducing apoptosis, whereas the Pro variant is a more potent inductor of cell cycle arrest and DNA repair. As regards MDM2 SNP309, the G allele is associated with attenuation of the p53 apoptotic response. Second, to evaluate the biological effect of the TP53 polymorphism, we established Jurkat isogenic cell lines expressing p53Arg or p53Pro. Jurkat p53Arg cells presented higher DNA damage and higher apoptotic potential than p53Pro cells, after treatment with chemotherapy agents. Only p53Pro cells presented t(15;17) translocation and del(5q). We suggest that failure to repair DNA lesions in p53Arg cells would lead them to apoptosis, whereas some p53Pro cells, prone to cell cycle arrest and DNA repair, could undergo misrepair, generating chromosomal abnormalities typical of t-MN.

Dichotomization of the new revised international prognostic scoring system for a better clinical stratification of patients with myelodysplastic syndromes.

In clinical practice, patients with myelodysplastic syndromes (MDS) are usually classified in low or high-risk groups to take therapeutic decisions, conservative for low-risk, whereas active for high-risk. Nevertheless, in the Revised International Prognostic Scoring System (IPSS-R) is not well stated which patients are low or high-risk. This study was aimed to ascertain in 364 MDS patients which IPSS-R threshold better dichotomized in low vs. high-risk. The best dichotomization was obtained with an IPSS-R cut-point of 3. Accordingly, 68% patients were classified as low-risk (median OS, 61.3 months) and 32% as high-risk MDS (median OS, 13.9 months) (p < .001). Interestingly, the intermediate IPSS-R risk patients presented an OS more related to the high IPSS-R than to the low IPSS-R risk group. In conclusion, an IPSS-R cut-point of 3 led to a meaningful stratification in low and high-risk that can be helpful for the clinical management of MDS patients.

Autoimmune disorders are common in myelodysplastic syndrome patients and confer an adverse impact on outcomes.

The coexistence of autoimmune disorders (AD) in patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) has been widely recognized, although with distinct results regarding their prevalence and impact on the outcomes of the underlying hematological process. This study was aimed to analyze the prevalence, clinical characteristics, and outcomes of MDS with AD in a series of 142 patients diagnosed with MDS and CMML. AD was ascertained by both the presence of clinical symptoms or compatible serological tests. In total, 48% patients were diagnosed as having AD, being hypothyroidism the most commonly reported clinical AD (8%) and antinuclear antibodies the most frequent serological parameter identified (23.2%). The presence of AD was associated with female gender, lower hemoglobin levels, and higher IPSS-R. Overall survival for patients with AD was inferior to those with no AD (69 vs. 88% at 30 months; HR 2.75, P = 0.008). Notably, clinical but not isolated immune serological parameters had an impact on the outcomes of patients with AD. Finally, in a multivariate analysis, the presence of AD (HR 2.26) along with disease risk categories (very low and low vs. intermediate, high, and very high IPSS-R; HR 4.62) retained their independent prognostic value (P < 0.001). In conclusion, AD are prevalent in MDS and CMML patients and have prognostic implications, especially in lower-risk MDS patients.

Characterizing patients with multiple chromosomal aberrations detected by FISH in chronic lymphocytic leukemia.

We analyzed the features of chronic lymphocytic leukemia (CLL) with multiple abnormalities (MA) detected by FISH. A local database including 2095 CLL cases was used and 323 with MA (15.4%) were selected. MA was defined by the presence of two or more alterations (deletions of 13q14 (13q-), 11q22 (11q-), 17p13 (17p-) or trisomy 12 (+12)). The combination of 13q- with 11q- and 13q- with 17p-, accounted for 58.2% of the series, in contrast to 11q- with 17p- (3.7%). Patients carrying MA since diagnosis presented a short time to first therapy(TTFT) (27 months) and overall survival (OS) (76 months). The combinations including 17p- had a shorter OS (58 months) than the ones without 17p- (not reached, p = .002). Patients with a complex-FISH were the ones with worse OS (34 months). MA imply poor prognosis when they emerge at diagnosis, probably due to the high incidence of bad prognosis markers, which may be a reflection of a more complex karyotype.

Clinical and biological significance of isolated Y chromosome loss in myelodysplastic syndromes and chronic myelomonocytic leukemia. A report from the Spanish MDS Group.

Isolate loss of chromosome Y (-Y) in myelodysplastic syndromes (MDS) is associated to a better outcome but it is also well described as an age-related phenomenon. In this study we aimed to analyze the prognostic impact of -Y in the context of the IPSS-R cytogenetic classification, evaluate the clinical significance of the percentage of metaphases with isolated -Y, and test whether finding -Y may predispose to over-diagnose MDS in patients with borderline morphological features. We evaluated 3581 male patients from the Spanish MDS Registry with a diagnosis of MDS or chronic myelomonocytic leukemia (CMML). -Y was identified in 177 patients (4.9%). Compared with the 2246 male patients with normal karyotype, -Y group showed a reduced risk of leukemic transformation that did not translate into a survival advantage. The overall survival and the risk of leukemic transformation were not influenced by the percentage of metaphases with -Y. The -Y group was not enriched in patients with minor morphologic traits of dysplasia, suggesting that the better outcome in the -Y group cannot be explained by enrichment in cases misdiagnosed as MDS. In conclusion, our results support the current recommendation of classifying patients with -Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated -Y would be of interest as it may provide a biological basis of protection against progression to acute leukemia.