Characterizing the Bone Marrow Environment in Advanced-Stage Myelofibrosis during Ruxolitinib Treatment Using PET/CT and MRI: A Pilot Study.

Current diagnostic criteria for myelofibrosis are largely based on bone marrow (BM) biopsy results. However, these have several limitations, including sampling errors. Explorative studies have indicated that imaging might form an alternative for the evaluation of disease activity, but the heterogeneity in BM abnormalities complicates the choice for the optimal technique. In our prospective diagnostic pilot study, we aimed to visualize all BM abnormalities in myelofibrosis before and during ruxolitinib treatment using both PET/CT and MRI. A random sample of patients was scheduled for examinations at baseline and after 6 and 18 months of treatment, including clinical and laboratory examinations, BM biopsies, MRI (T1-weighted, Dixon, dynamic contrast-enhanced (DCE)) and PET/CT ([15O]water, [18F]NaF)). At baseline, all patients showed low BM fat content (indicated by T1-weighted MRI and Dixon), increased BM blood flow (as measured by [15O]water PET/CT), and increased osteoblastic activity (reflected by increased skeletal [18F]NaF uptake). One patient died after the baseline evaluation. In the others, BM fat content increased to various degrees during treatment. Normalization of BM blood flow (as reflected by [15O]water PET/CT and DCE-MRI) occurred in one patient, who also showed the fastest clinical response. Vertebral [18F]NaF uptake remained stable in all patients. In evaluable cases, histopathological parameters were not accurately reflected by imaging results. A case of sampling error was suspected. We conclude that imaging results can provide information on functional processes and disease distribution throughout the BM. Differences in early treatment responses were especially reflected by T1-weighted MRI. Limitations in the gold standard hampered the evaluation of diagnostic accuracy.

The Impact of Thoracic Ultrasound on Clinical Management of Critically Ill Patients (UltraMan): An International Prospective Observational Study.

OBJECTIVES: To investigate the impact of thoracic ultrasound (TUS) examinations on clinical management in adult ICU patients. DESIGN: A prospective international observational study. SETTING: Four centers in The Netherlands and Italy. PATIENTS: Adult ICU patients (> 18 yr) that received a clinically indicated lung ultrasound examination. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinicians performing TUS completed a pre- and post-examination case report form. Patient characteristics, TUS, and resulting clinical effects were recorded. First, change of management, defined as a TUS-induced change in clinical impression leading to a change in treatment plan, was reported. Second, execution of intended management changes within 8 hours was verified. Third, change in fluid balance after 8 hours was calculated. A total of 725 TUS performed by 111 operators across 534 patients (mean age 63 ± 15.0, 70% male) were included. Almost half of TUS caused a change in clinical impression, which resulted in change of management in 39% of cases. The remainder of TUS confirmed the clinical impression, while a minority (4%) did not contribute. Eighty-nine percent of management changes indicated by TUS were executed within 8 hours. TUS examinations that led to a change in fluid management also led to distinct and appropriate changes in patient's fluid balance. CONCLUSIONS: In this international observational study in adult ICU patients, use of TUS had a major impact on clinical management. These results provide grounds for future randomized controlled trials to determine if TUS-induced changes in decision-making also lead to improved health outcomes.

Physical Activity is Associated with Health Related Quality of Life in Lymphoma Survivors Regardless of Body Mass Index; Results from the Profiles Registry.

BACKGROUND: Being obese and having a sedentary lifestyle is associated with impaired health-related quality of life (HRQoL) among cancer survivors. The aim of the present study is to investigate the combined influence of body mass index (BMI) and physical activity on HRQoL in lymphoma survivors. METHODS: Lymphoma survivors diagnosed between 1999 and 2012 were invited to complete questionnaires about body height and weight, physical activity and HRQoL using the EORTC QLQ-C30. Multivariable analyses were conducted to evaluate the association of BMI and physical activity on HRQoL. RESULTS: 1.339 lymphoma survivors responded (response rate of 72%) of whom 43% had a healthy weight, 41% were overweight and 14% were obese. They spent on average 10 h, on moderate to vigorous physical activity (MVPA) per week. Multivariable linear regression analysis shows that relatively high active survivors reported higher HRQoL scores and less fatigue compared to relatively low active lymphoma survivors, regardless of BMI. CONCLUSION: MVPA was associated with higher HRQoL in lymphoma survivors regardless of BMI. Further studies, are needed to investigate effects of healthy lifestyle changes to improve HRQoL in lymphoma survivors. Research in understanding association of lifestyle factors may guide future support for lymphoma cancer survivors.

The value of bone marrow, liver, and spleen imaging in diagnosis, prognostication, and follow-up monitoring of myeloproliferative neoplasms: a systematic review.

BACKGROUND: Diagnostic and treatment response criteria for the JAK2/CALR/MPL mutation-related myeloproliferative neoplasms (MPNs) are largely based on bone marrow (BM) biopsy results. However, these biopsies have several limitations, such as the risk of sampling error. Also, the prognostic impact of BM abnormalities is largely unclear. Although not currently used in clinical practice, imaging techniques might offer additional information. In this review, we investigated the value of BM, liver, and spleen imaging for diagnosis, prognostication, and response monitoring of the JAK2/CALR/MPL mutation-related MPNs (i.e. essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)). METHODS: A systematic literature search was performed via PubMed, Embase and the Cochrane Library up to 2020 March 26th. Of 5505 identified records, 55 publications met the eligibility criteria (i.e. containing original data on the imaging appearance of BM, spleen, or liver in adult ET, PV, or MF patients, published in a peer-reviewed journal, written in English). RESULTS: Many explorative studies described imaging features, sometimes with comparisons to clinical characteristics. Studies reporting measures of diagnostic accuracy included 1) splenic transient elastography to predict BM fibrosis grade in MF, 2) dynamic contrast-enhanced MRI to discern MF patients from ET patients and healthy controls, and 3) 18-fluorodeoxyglucose PET to detect residual disease after stem cell transplantation in MF. The diagnostic accuracies of radiography and 99mTc-colloid scintigraphy were derived from several other articles. Except for the study on 18-fluorodeoxyglucose PET, we established substantial concerns regarding risk of bias and applicability across these studies, using the QUADAS-2 tool. Three publications described a correlation between imaging results and prognosis, of which one quantified the effect. CONCLUSIONS: Based on current data, MRI (T1-weighted/STIR, Dixon) seems especially promising for the evaluation of BM fat content - and indirectly cellularity/fibrosis - in MF, and possibly for estimating BM cellularity in ET/PV. 18-fluorodeoxyglucose and 18-fluorothymidine PET/CT might be useful for evaluating BM fibrosis, with good reported accuracy of the former for the diagnosis of residual disease. Further research on these and other techniques is warranted to determine their exact value. Future researchers should improve methodology and focus on evaluation of diagnostic accuracy and prognostic implications of results.

Covid-19 Pneumonia and Ventilation-induced Lung Injury: A Case Report.

We present the case of a 67-year-old male patient, who was admitted to the intensive care unit for hypoxemic respiratory failure due to severe COVID-19 pneumonitis, requiring mechanical ventilation. Despite close monitoring using transpulmonary pressure measurements and interventions to pursue lung-protective ventilation, the patient developed extensive barotrauma including a right-sided pneumothorax, subcutaneous emphysema and pneumomediastinum while on pressure support ventilation. We hypothesize that the high respiratory drive that COVID-19 patients seem to exhibit, combined with diffuse alveolar injury and increased alveolar pressure, resulted in gross barotrauma. CONCLUSION: The respiratory characteristics that COVID-19 patients seem to exhibit might expose those on mechanical ventilation to an increased risk of developing ventilation-induced lung injury. This case emphasizes that caution should be taken in the respiratory treatment of patients with COVID-19 pneumonitis.

Ruxolitinib in Myelofibrosis and Baseline Thrombocytopenia in Real Life: Results in Dutch Patients and Review of the Literature.

BACKGROUND: Ruxolitinib is an approved treatment for myelofibrosis patients, but data regarding patients with baseline thrombocytopenia are limited. The EXPAND study recently suggested tolerability of ruxolitinib, with a maximum starting dose of 10 mg 2 times a day (BID). However, the small sample size and vigorous follow-up in this trial hamper direct translation of these results to routine practice. PATIENTS AND METHODS: We report retrospective data on Dutch ruxolitinib-treated myelofibrosis patients, focusing on those with baseline thrombocytopenia. Additionally, we reviewed current literature regarding ruxolitinib treatment in this subgroup. RESULTS: In our cohort, 12 of 119 patients had a baseline platelet count of < 100 × 109/L. Spleen responses at a mean treatment duration of 25 weeks were documented in 1 of 6 and 15 of 47 patients with and without baseline thrombocytopenia, respectively. Despite a high rate of grade 3 or higher thrombocytopenia in thrombocytopenic versus nonthrombocytopenic patients (42% vs. 15%), no grade 3 or higher hemorrhage was reported. Median doses in thrombocytopenic patients were 15 and 10 mg BID at the start and after 12 weeks of treatment, respectively. Additionally, 238 thrombocytopenic patients were identified in the available literature, of whom 59 were treated in routine practice. Incidences of severe thrombocytopenia reported separately for patients with baseline thrombocytopenia were 30% to 59% (grade 3 or higher) and 4% to 60% (grade 4). Severe bleeding, pooled across our data and evaluable studies, occurred in 2.4%. CONCLUSION: Ruxolitinib treatment appears to be safe for patients with platelet counts of 50 to 100 × 109/L in real-life practice. We did not find any reason to discourage a starting dose of 10 mg BID in this subgroup.

Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs.

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n=89) and without (n=329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count <100×109/L (moderate 51-100×109/L; severe ≤50×109/L), was associated with anemia (76% vs. 45%, p<0.001), leukopenia (29% vs. 11%, p<0.001), and need for red blood cell transfusion (35% vs. 19%, p=0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p<0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p=0.04), leukopenia (40% vs. 20%, p=0.04), and transfusion requirements (51% vs. 20%, p=0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.

Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.

Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease.

PURPOSE: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. PATIENTS AND METHODS: Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). RESULTS: The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). CONCLUSION: The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

Dissecting the gray zone between follicular lymphoma and marginal zone lymphoma using morphological and genetic features.

Nodal marginal zone lymphoma is a poorly defined entity in the World Health Organization classification, based largely on criteria of exclusion and the diagnosis often remains subjective. Follicular lymphoma lacking t(14;18) has similar characteristics which results in a major potential diagnostic overlap which this study aims to dissect. Four subgroups of lymphoma samples (n=56) were analyzed with high-resolution array comparative genome hybridization: nodal marginal zone lymphoma, t(14;18)-negative follicular lymphoma, localized t(14:18)-positive follicular lymphoma and disseminated t(14;18)-positive follicular lymphoma. Gains on chromosomes 7, 8 and 12 were observed in all subgroups. The mean number of aberrations was higher in disseminated t(14;18)-positive follicular lymphoma than in localized t(14:18)-positive follicular lymphoma (P<0.01) and the majority of alterations in localized t(14:18)-positive follicular lymphoma were also found in disseminated t(14;18)-positive follicular lymphoma. Nodal marginal zone lymphoma was marked by 3q gains with amplifications of four genes. A different overall pattern of aberrations was seen in t(14;18)-negative follicular lymphoma compared to t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma is characterized by specific (focal) gains on chromosome 3, as observed in nodal marginal zone lymphoma. Our results support the notion that localized t(14:18)-positive follicular lymphoma represents an early phase of disseminated t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma bears aberrations that are more like those in nodal marginal zone lymphoma, suggesting a relation between these groups.

Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs.

PURPOSE: Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. PATIENTS AND METHODS: The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. RESULTS: MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P<.001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r=0.59; P<.001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P<.001 and absolute r≥0.50 except social functioning r=0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbach's α=.83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. CONCLUSION: The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.