Cell-Free DNA as a Biomarker at Diagnosis and Follow-Up in 256 B and T-Cell Lymphomas.

BACKGROUND: Cell-free DNA (cfDNA) analysis has become a promising tool for the diagnosis, prognosis, and monitoring of lymphoma cases. Until now, research in this area has mainly focused on aggressive lymphomas, with scanty information from other lymphoma subtypes. METHODS: We selected 256 patients diagnosed with lymphomas, including a large variety of B-cell and T-cell non-Hodgkin and Hodgkin lymphomas, and quantified cfDNA from plasma at the time of diagnosis. We further selected 49 large B-cell lymphomas (LBCL) and analyzed cfDNA levels at diagnosis (pre-therapy) and after therapy. In addition, we performed NGS on cfDNA and tissue in this cohort of LBCL. RESULTS: Lymphoma patients showed a statistically significant higher cfDNA concentration than healthy controls (mean 53.0 ng/mL vs. 5.6 ng/mL, p < 0.001). The cfDNA concentration was correlated with lymphoma subtype, lactate dehydrogenase, the International Prognostic Index (IPI) score, Ann Arbor (AA), and B-symptoms. In 49 LBCL cases, the cfDNA concentration decreased after therapy in cases who achieved complete response (CR) and increased in non-responders. The median cfDNA at diagnosis of patients who achieved CR and later relapsed was higher (81.5 ng/mL) compared with levels of those who did not (38.6 ng/mL). A concordance of 84% was observed between NGS results in tumor and cfDNA samples. Higher VAF in cfDNA is correlated with advanced stage and bulky disease. CONCLUSIONS: cfDNA analysis can be easily performed in almost all lymphoma cases. The cfDNA concentration correlated with the characteristics of the aggressiveness of the lymphomas and, in LBCL, with the response achieved after therapy. These results support the utility of cfDNA analysis as a complementary tool in the management of lymphoma patients.

Patients´ and Therapists´ Reports of Psychotherapy Outcomes: Similarities and Differences.

BACKGROUND: Discrepancies between therapists' and patients' measures regarding therapeutic results indicate the need to analyze which symptoms and processes are being taken into consideration when reporting clinical change. This study analyzes the concordance between patient and therapist, at pre- and post-treatment, when reporting about anxiety, depression, Experiential Avoidance (EA), Cognitive Fusion (CF) and Activation (A). METHOD: Convergence was examined between information obtained by means of standardized measures and visual analogical scales (VAS) in 94 patients with anxiety and/or depression who participated in a controlled clinical study (TRANSACTIVA study). RESULTS: Statistically significant correlation ( p < .05) was found between all the measures of anxiety and depression, regardless of the source, timepoint, and measures procedure at 95% confidence. In the VAS, patient and therapist agreed ( p < .05) in their evaluation of specific symptoms. For EA, CF and A, the therapists' measures demonstrated stronger correlations than those of the patients, although, in each condition, all the patients' measures correlated with each other ( p < .05). CONCLUSIONS: Suitable agreement was found between therapist and patient when reporting clinical change. One-item VAS appeared to b suitable for identifying anxiety, depression and the transdiagnostic patterns of EA, CF and A.

Leukemic Involvement Is a Common Feature in Waldenström Macroglobulinemia at Diagnosis.

Waldenström Macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with bone marrow (BM) involvement and IgM monoclonal gammopathy. To date, no studies have focused specifically on peripheral blood (PB) involvement. In this study, 100 patients diagnosed with WM according to the World Health Organization (WHO) criteria were included based on the demonstration of MYD88mut in BM and the availability of PB multiparametric flow cytometry (MFC) analysis. Leukemic involvement by MFC was detected in 50/100 patients. A low percentage of mature small lymphocytes in PB smears was observed in only 15 cases. MYD88mut by AS-qPCR was detected in PB in 65/100 cases. In cases with leukemic expression by MFC, MYD88mut was detected in all cases, and IGH was rearranged in 44/49 cases. In 21/50 patients without PB involvement by MFC, molecular data were consistent with circulating disease (MYD88mut by AS-qPCR 3/50, IGH rearranged 6/50, both 12/50). Therefore, PB involvement by standard techniques was detected in 71/100 patients. MYD88mut was detected in PB by dPCR in 9/29 triple negative cases. Overall, 80% of the patients presented PB involvement by any technique. Our findings support the role of PB MFC in the evaluation of patients with IgM monoclonal gammopathy and provide reliable information on correlation with molecular features. The development of a feasible MFC assay may stand as an objective tool in the classification of mature B cell neoplasms presenting with IgM monoclonal gammopathy.

Evaluation of 4 prognostic indices in follicular lymphoma treated in first line with immunochemotherapy.

Several clinical risk models have been proposed to predict the outcome of follicular lymphoma (FL). The development of next-generation sequencing technologies has allowed the integration of somatic gene mutations into clinical scores to build genotyped-based risk models, such as the m7-Follicular Lymphoma International Prognostic Index (FLIPI). We explored 4 clinical or clinicogenetic-risk models in patients with symptomatic FL who received frontline immunochemotherapy. Of 191 patients with FL grades 1 to 3a, 109 were successfully genotyped. The treatment consisted of rituximab (R) plus cyclophosphamide, vincristine, and prednisone (R-CVP)/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (72.5%) or R-bendamustine (R-B) (27.5%). The proportion of cases classified as high risk for FLIPI, FLIPI-2, PRIMA-prognostic index, or m7-FLIPI were 39.3%, 14%, 30.3%, and 22%, respectively. No case with low-intermediate FLIPI was upgraded in the m7-FLIPI, but 18 of the 42 high-risk patients with FLIPI were downgraded to low-risk m7-FLIPI. The sensitivity and specificity for the prediction of POD24 were highest for FLIPI. The discrimination between progression-free survival (PFS) and overall survival (OS) was the best for FLIPI (c-index: 0.644 and 0.727, respectively). When analyzed only in patients treated with R-B, m7-FLIPI showed a higher discrimination between PFS and OS. Thus, the FLIPI remains the clinical risk score with higher discrimination in patients with advanced FL treated with immunochemotherapy; however, the performance of the m7-FLIPI should be further investigated in patients treated with R-B.

Is Activation the Active Ingredient of Transdiagnostic Therapies? A Randomized Clinical Trial of Behavioral Activation, Acceptance and Commitment Therapy, and Transdiagnostic Cognitive-Behavioral Therapy for Emotional Disorders.

Studying the usefulness of contextual and cognitive transdiagnostic therapies calls for an analysis of both their differential efficacy and their specificity when acting on the transdiagnostic conditions on which they focus. This controlled trial compares the post-treatment and 3- and 6-month follow-up effects of Behavioral Activation (BA), Acceptance and Commitment Therapy (ACT) and Cognitive-Behavioral Transdiagnostic Therapy (TD-CBT) on emotional symptomatology, and analyses the role played by Experiential Avoidance, Cognitive Fusion, Activation and Emotion Regulation in the clinical change. One hundred twenty-eight patients who fulfilled diagnostic criteria for anxiety and/or depression (intention-to-treat sample) were randomly assigned to three experimental group-treatment conditions (BA, n = 34; ACT, n = 27; TD-CBT n = 33) and one control group (WL, n = 34). Ninety-nine (77.34%) completed the treatment (per-protocol sample). In the post-treatment, all therapies reduced anxiety and depression symptomatology. In the follow-ups, the reduction in emotional symptomatology was greater in the condition which produced greater and more prolonged effects on Activation. Activation appears to be the principal condition in modifying all the transdiagnostic patterns and BA was the most efficacious and specific treatment. The trial was registered at ClinicalTrials.gov NCT04117464. Raw data are available online http://dx.doi.org/10.17632/krj3w2hfsj.1.

Outcomes and molecular profile of oligomonocytic CMML support its consideration as the first stage in the CMML continuum.

Patients with oligomonocytic chronic myelomonocytic leukemia (OM-CMML) are currently classified according to the 2017 World Health Organization myelodysplastic syndromes classification. However, recent data support considering OM-CMML as a specific subtype of chronic myelomonocytic leukemia (CMML), given their similar clinical, genomic, and immunophenotypic profiles. The main purpose of our study was to provide survival outcome data of a well-annotated series of 42 patients with OM-CMML and to compare them to 162 patients with CMML, 120 with dysplastic type (D-CMML), and 42 with proliferative type (P-CMML). OM-CMML had significantly longer overall survival (OS) and acute myeloid leukemia-free survival than did patients with CMML, considered as a whole group, and when compared with D-CMML and P-CMML. Moreover, gene mutations associated with increased proliferation (ie, ASXL1 and RAS-pathway mutations) were identified as independent adverse prognostic factors for OS in our series. We found that at a median follow-up of 53.47 months, 29.3% of our patients with OM-CMML progressed to D-CMML, and at a median follow-up of 46.03 months, 28.6% of our D-CMML group progressed to P-CMML. These data support the existence of an evolutionary continuum of OM-CMML, D-CMML, and P-CMML. In this context, we observed that harboring more than 3 mutated genes, carrying ASXL1 mutations, and a peripheral blood monocyte percentage >20% significantly predicted a shorter time of progression of OM-CMML into overt CMML. These variables were also detected as independent adverse prognostic factors for OS in OM-CMML. These data support the consideration of OM-CMML as the first evolutionary stage within the proliferative continuum of CMML.

Psychological Inflexibility, Anxiety and Depression: The Moderating Role of Cognitive Fusion, Experiential Avoidance and Activation.

BACKGROUND: Evidence about how cognitive fusion (CF) and experiential avoidance (EA) interact with emotional distress underlines the importance of analyzing the interrelationships between the different processes of psychological inflexibility in order to improve ways of addressing emotional problems. This study analyzes the moderating effect of CF, EA and activation (A) in relation to four criteria of anxiety and depression. METHOD: A cross-sectional study of a clinical sample of adults was carried out by means of a questionnaire administered before (N = 172) and 6 months after (N = 114) participation in a clinical study. RESULTS: Regression analyses gave results which were consistent in the two evaluations. The EAxCF interaction modulated anxiety symptomatology, whereas A was not a significant predictor. Nevertheless, a reduction in A was the principal modulating condition in the symptomatology of depression; and although CF and EA did act as independent predictors, the EAxCF interaction was not significant. CONCLUSIONS: The presence and intensity of manifestations of emotional distress are explained and modulated by the progressive concurrence of CF, EA and reduction in A. The use of therapeutic approaches which increase activation could be a beneficial strategy with regard to decreasing cognitive fusion and experiential avoidance.

Molecular and cytogenetic characterization of myelodysplastic syndromes in cell-free DNA.

Molecular and cytogenetic studies are essential for diagnosis and prognosis in patients with myelodysplastic syndromes (MDSs). Cell-free DNA (cfDNA) analysis has been reported to be a reliable noninvasive approach for detecting molecular abnormalities in MDS; however, there is limited information about cytogenetic alterations and monitoring in cfDNA. We assessed the molecular and cytogenetic profile of a cohort of 70 patients with MDS by next-generation sequencing (NGS) of cfDNA and compared the results to sequencing of paired bone marrow (BM) DNA. Sequencing of BM DNA and cfDNA showed a comparable mutational profile (92.1% concordance), and variant allele frequencies (VAFs) strongly correlated between both sample types. Of note, SF3B1 mutations were detected with significantly higher VAFs in cfDNA than in BM DNA. NGS and microarrays were highly concordant in detecting chromosomal alterations although with lower sensitivity than karyotype and fluorescence in situ hybridization. Nevertheless, all cytogenetic aberrations detected by NGS in BM DNA were also detected in cfDNA. In addition, we monitored molecular and cytogenetic alterations and observed an excellent correlation between the VAFs of mutations in BM DNA and cfDNA across multiple matched time points. A decrease in the cfDNA VAFs was detected in patients responding to therapy, but not in nonresponding patients. Of note, cfDNA analysis also showed cytogenetic evolution in 2 nonresponsive cases. In summary, although further studies with larger cohorts are needed, our results support the analysis of cfDNA as a promising strategy for performing molecular characterization, detection of chromosomal aberrations and monitoring of patients with MDS.

Screening for Prognostic microRNAs Associated with Treatment Failure in Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) treatment with R-CHOP regimen produces 5-year progression-free survival and overall survival of around 60-70%. Our objective was to discover prognostic biomarkers allowing early detection of the remaining 30-40% with poor long-term outcome. For this purpose, we applied a novel strategy: from a cohort of DLBCL patients, treated with standard therapy, a discovery group of 12 patients with poor prognosis (advanced stage III-IV, R-IPI > 2) was formed, consisting of six chemoresistant (refractory/early relapse < 12 months) and six chemosensitive (complete remission > 3 years) subjects. By using microarray assays, the most differentially expressed miRNAs were defined as an initial set of prognostic miRNA candidates. Their expression was then analyzed in a validation cohort of 68 patients and the three miRNAs with the most significant impact on event-free and overall survival were selected. In the DLBCL cell line U-2932 the transfection with miR-1244 and miR-193b-5p, but not miR-1231, blocked the effect of CHOP on cell viability. A subsequent gene set enrichment analysis in patients revealed the implication of the first two miRNAs in cell cycle control and chemoresistance-related pathways, whereas the last one was involved in immunological processes. In conclusion, this novel strategy identified three promising prognostic markers for DLBCL patients at high risk of failure with standard therapy.

Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity.

Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 patients with FL for HBV infection status, clinical features, and gene mutational profile. Anti-HBc was detectable in 16 patients (13.2%), although all had undetectable HBV DNA. Anti-HBcore+ (anti-HBc+) cases presented with older age at diagnosis than anti-HBc- cases (68.1 vs 57.2 years; P = .007) and higher ß2-microglobulin (56.3% vs 28.9%; P = .04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year progression-free survival (PFS; 12.9% vs 58.3%; P < .0001) and overall survival (OS; 22.0% vs 86.2%; P < .0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, 2 key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile.

Psychological Inflexibility, Anxiety and Depression: The Moderating Role of Cognitive Fusion, Experiential Avoidance and Activation / Inflexibilidad Psicológica, Ansiedad y Depresión: el Papel Moderador de la Fusión Cognitiva, la Evitación Experiencial y la Activación

Background: Evidence about how cognitive fusion (CF) and experientialavoidance (EA) interact with emotional distress underlines the importanceof analyzing the interrelationships between the different processesof psychological inflexibility in order to improve ways of address ingemotional problems. This study analyzes the moderating effect of CF, EAand activation (A) in relation to four criteria of anxiety and depression.Method: A cross-sectional study of a clinical sample of adults was carriedout by means of a questionnaire administered before (N = 172) and 6months after (N = 114) participation in a clinical study. Results: Regressionanalyses gave results which were consistent in the two evaluations. TheEAxCF interaction modulated anxiety symptomatology, whereas A wasnot a significant predictor. Nevertheless, a reduction in A was the principalmodulating condition in the symptomatology of depression; and althoughCF and EA did act as independent predictors, the EAxCF interaction wasnot significant. Conclusions: The presence and intensity of manifestationsof emotional distress are explained and modulated by the progressiveconcurrence of CF, EA and reduction in A. The use of therapeuticapproaches which increase activation could be a beneficial strategy withregard to decreasing cognitive fusion and experiential avoidance.

Antecedentes: las evidencias sobre la interacción entre la fusión cognitiva(FC) y la evitación experiencial (EE) con el distrés emocional señalan laimportancia de analizar las interrelaciones entre los diferentes procesos deinflexibilidad psicológica. Este estudio analiza el efecto moderador de laCF, EA y la activación (A) en relación con cuatro criterios de ansiedady depresión. Método: se evaluó transversalmente mediante cuestionariouna muestra clínica de adultos antes (N = 172) y 6 meses después (N =114) de participar en un estudio clínico. Resultados: análisis de regresión mostraron resultados consistentes entre medidas. La interacción EA ×CF moduló la sintomatología de ansiedad, pero la A no resultó predictor significativo. Sin embargo, la reducción de A fue la principal condición moduladora de la sintomatología depresiva; y aunque la CF y EA síactuaron como predictores independientes, la interacción EA × CF noresultó significativa. Conclusiones: se sugiere que la presencia e intensidad de las manifestaciones de malestar emocional se explica y modulada por laprogresiva concurrencia de CF, EA y pérdida de A. Podría ser beneficioso intervenir en la dirección de incrementar la activación como una estrategia adecuada para disminuir la fusión cognitiva y la evitación de experiencias.

Evaluation of routine CT scans in the follow-up of diffuse large B-cell lymphomas.

OBJECTIVE: Our aim was to retrospectively assess the role of routine CT scans within the first year of follow-up with a limited surveillance policy prior to Lugano recommendations in diffuse large B-cell lymphomas (DLBCL) achieving complete metabolic remission (CMR). We also evaluated the type of relapse detection and exposure to CT scans within the first five years. METHODS: Patients diagnosed with DLBCL who achieved CMR after first-line immunochemotherapy were included. Imaging studies and medical records were thoroughly reviewed. RESULTS: Among 101 DLBCL patients in the first CMR, a total of 19 relapses were identified in the study period (18.8% of DLBCL patients included). Nine patients relapsed within the first year (47.4% of all relapses) but only 3 of them were detected by the 202 surveillance CT scans performed during this first year of follow-up. CONCLUSIONS: Our real-world data provide clinically applicable results which are in agreement with the Lugano recommendations based on trial data, highlighting the lack of utility of routine CTs in DLBCL patients achieving CMR.

ctDNA to Guide Adjuvant Therapy in Localized Colorectal Cancer (CRC).

Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.

Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

BACKGROUND: In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, H. pylori negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive. METHODS: A total of 57 cases of H. pylori negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes. RESULTS: MALT1 translocation, most likely t(11;18)(q21;q21)/BIRC3-MALT1, was detected in 39% (22/57) cases, and IGH translocation was further seen in 12 MALT1-negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways (TNFAIP3 = 23%, CARD11 = 9%, MAP3K14 = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from MALT1, albeit not IGH translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy (p = 0.004). CONCLUSION: H. pylori negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways.

Plasmatic KRAS Kinetics for the Prediction of Treatment Response and Progression in Patients With KRAS-mutant Lung Adenocarcinoma / Estudio de la cinética del KRAS plasmático para predecir la respuesta al tratamiento y la progresión en pacientes con adenocarcinoma de pulmón con mutación de KRAS

Introduction: KRAS is the most common driver mutation in lung cancer. ctDNA-based assessment offers advantages over tumor as a minimally invasive method able to capture tumor heterogeneity. Monitoring KRAS mutational load in ctDNA may be useful in the management of the patients.Methods: Consecutive patients diagnosed with KRAS mutant lung adenocarcinoma in the tumor biopsy were included in this study. Plasma samples were obtained at different time points during the course of the disease. KRAS mutations in plasma were quantified using digital PCR and correlated with mutations in tumor and with radiological response and progression.Results: Two hundred and forty-five plasma samples from 56 patients were analyzed. The rate of detection of KRAS mutations in plasma in our previously characterized KRAS-mutant cases was 82% overall, reaching 96% in cases with more than 1 metastatic location. The dynamics of KRAS mutational load predicted response in 93% and progression in 63% of cases, 33 and 50 days respectively in advance of radiological evaluation. Progression-free survival for patients in whom ctDNA was not detectable in plasma after treatment initiation was significantly longer than for those in whom ctDNA remained detectable (7.7 versus 3.2 months; HR: 0.44, p=0.004).Conclusions: The detection of KRAS mutations in ctDNA showed a good correlation with that in tumor biopsy and, in most cases, predicted tumor response and progression to chemotherapy in advance of radiographic evaluation. The liquid biopsies for ctDNA-based molecular analyses are a reliable tool for KRAS testing in clinical practice. (AU)

Introducción: La mutación en KRAS es la mutación iniciadora más común en el cáncer de pulmón. La valoración basada en el ctDNA ofrece ventajas frente a la tumoral, al ser un método mínimamente invasivo capaz de capturar la heterogeneidad del tumor. La monitorización de la carga de KRAS mutado en el ctDNA puede ser útil en el manejo de los pacientes.Métodos: En este estudio se incluyó, mediante selección consecutiva, a pacientes diagnosticados con adenocarcinoma de pulmón con mutación en KRAS en la biopsia tumoral. Se obtuvieron muestras de plasma en diferentes momentos durante el curso de la enfermedad. Las mutaciones de KRAS en plasma se cuantificaron mediante PCR digital y se correlacionaron con las mutaciones en el tumor y con la respuesta radiológica y la progresión.Resultados: Se analizaron 245 muestras de plasma de 56 pacientes. La tasa de detección de mutaciones KRAS en plasma en aquellos casos previamente definidos con dicha mutación fue del 82% globalmente, porcentaje que alcanzó el 96% en aquellos casos con más de una ubicación metastásica. La dinámica de la carga de KRAS mutado predijo la respuesta en el 93% de los casos y la progresión en el 63%, a los 33 y 50 días, respectivamente, anteriores a la evaluación radiológica. La supervivencia libre de progresión para pacientes en los que el ctDNA no era detectable en plasma después del inicio del tratamiento fue significativamente más larga que para aquellos en los que el ctDNA permaneció detectable (7,7 frente a 3,2 meses; HR: 0,44; p = 0,004).Conclusiones: La detección de mutaciones KRAS en el ctDNA mostró una buena correlación con la de la biopsia tumoral y, en la mayoría de los casos, predijo la respuesta tumoral a la quimioterapia y la progresión antes de la evaluación radiológica. Las biopsias líquidas para análisis moleculares basados en ctDNA son una herramienta fiable para la valoración de KRAS en la práctica clínica. (AU)

Case Report: High Doses of Intravenous Immunoglobulins as a Successful Treatment for Late Onset Immune Agranulocytosis After Rituximab Plus Bendamustine.

Late onset neutropenia (LON) related to rituximab or rituximab plus chemotherapy is defined as an unexplained absolute neutrophil count of ≤1.5 × 109/L starting at least four weeks after the last rituximab administration. LON is infrequent and its pathophysiology remains unknown. There are no guidelines or consensus strategies for the optimal management of patients developing LON. The majority of the patients recover promptly with no specific treatment and only some cases need to be managed with granulocytic colony stimulating factor (G-CSF), usually with a rapid response. Here, we describe a 69-year-old patient with Waldenström's macroglobulinemia who presented a septic event in the context of severe LON after rituximab plus bendamustine. The diagnosed of agranulocytosis was established by bone marrow examination. Interestingly, anti-neutrophil antibodies bound to the patient's granulocytes were found suggesting an autoimmune mechanism. The patient did not respond to G-CSF but achieved a rapid response after high doses of intravenous immunoglobulins with full white blood cell recovery.

Plasmatic KRAS Kinetics for the Prediction of Treatment Response and Progression in Patients With KRAS-mutant Lung Adenocarcinoma.

INTRODUCTION: KRAS is the most common driver mutation in lung cancer. ctDNA-based assessment offers advantages over tumor as a minimally invasive method able to capture tumor heterogeneity. Monitoring KRAS mutational load in ctDNA may be useful in the management of the patients. METHODS: Consecutive patients diagnosed with KRAS mutant lung adenocarcinoma in the tumor biopsy were included in this study. Plasma samples were obtained at different time points during the course of the disease. KRAS mutations in plasma were quantified using digital PCR and correlated with mutations in tumor and with radiological response and progression. RESULTS: Two hundred and forty-five plasma samples from 56 patients were analyzed. The rate of detection of KRAS mutations in plasma in our previously characterized KRAS-mutant cases was 82% overall, reaching 96% in cases with more than 1 metastatic location. The dynamics of KRAS mutational load predicted response in 93% and progression in 63% of cases, 33 and 50 days respectively in advance of radiological evaluation. Progression-free survival for patients in whom ctDNA was not detectable in plasma after treatment initiation was significantly longer than for those in whom ctDNA remained detectable (7.7 versus 3.2 months; HR: 0.44, p=0.004). CONCLUSIONS: The detection of KRAS mutations in ctDNA showed a good correlation with that in tumor biopsy and, in most cases, predicted tumor response and progression to chemotherapy in advance of radiographic evaluation. The liquid biopsies for ctDNA-based molecular analyses are a reliable tool for KRAS testing in clinical practice.