New Prognostic Frontiers for Lung Neuroendocrine Tumors

Purpose Well-differentiated lung neuroendocrine tumors (Lu-NET) are classified as typical (TC) and atypical (AC) carcinoids, based on mitotic counts and necrosis. However, prognostic factors, other than tumor node metastasis (TNM) stage and the histopathological diagnosis, are still lacking. The current study is aimed to identify potential prognostic factors to better stratify lung NET, thus, improving patients’ treatment strategy and follow-up. Methods A multicentric retrospective study, including 300 Lung NET, all surgically removed, from Italian and Spanish Institutions. Results Median age 61 years (13-86), 37.7% were males, 25.0% were AC, 42.0% were located in the lung left parenchyma, 80.3% presented a TNM stage I-II. Mitotic count was ≥2 per 10 high power field (HPF) in 24.7%, necrosis in 13.0%. Median overall survival (OS) was 46.1 months (0.6-323), median progression free survival (PFS) was 36.0 months (0.3-323). Female sex correlated with a more indolent disease (T1; N0; lower Ki67; lower mitotic count and the absence of necrosis). Left-sided primary tumors were associated with higher mitotic count and necrosis. At Cox multivariate regression model, age, left-sided tumors and nodal (N) positive status resulted independent negative prognostic factors for OS and PFS. Conclusions This study confirms the prognostic relevance of TNM stage and diagnosis to stratify LuNET. However, the current analysis suggests a wider spectrum of clinical and pathological prognostic factors, including age and primary tumor’s location. These parameters could help clinicians to personalize the management of Lu-NET.

Time for an individualized approach to first-line management of follicular lymphoma

Follicular lymphoma is a heterogeneous B-cell lymphoma both in presentation and at progression. For most patients it is a chronic, relapsing indolent disease with overall survival expectations now potentially beyond 20 years. However, in a significant minority (~20%) who experience early progression or histological transformation after treatment, the disease no longer has an indolent behavior. This review looks at the development of prognostic indices, staging and therapies for follicular lymphoma, identifying where the data can, and cannot, guide the multidisciplinary team to determine an individualized approach to first-line therapy. A nuanced patient- and disease-specific approach is necessary to maximize disease response and survival while minimizing therapeutic toxicity.

Risk Stratification and Treatment in Smoldering Multiple Myeloma

Smoldering multiple myeloma is a heterogeneous asymptomatic precursor to multiple myeloma. Since its identification in 1980, risk stratification models have been developed using two main stratification methods: clinical measurement-based and genetics-based. Clinical measurement models can be subdivided in three types: baseline measurements (performed at diagnosis), evolving measurements (performed over time during follow-up appointments), and imaging (for example, magnetic resonance imaging). Genetic approaches include gene expression profiling, DNA/RNA sequencing, and cytogenetics. It is important to accurately distinguish patients with indolent disease from those with aggressive disease, as clinical trials have shown that patients designated as “high-risk of progression” have improved outcomes when treated early. The risk stratification models, and clinical trials are discussed in this review.

Two Distinct Clinical Courses and Outcomes in T-Cell Prolymphocytic Leukemia

Introduction: T-cell prolymphocytic leukemia (T-PLL) is a rare type of mature T-cell neoplasm with a poor prognosis. Up to 30% of patients initially present with indolent disease course that may be observed until progression to T-PLL with aggressive behavior. We aimed to compare the clinicopathologic characteristics and outcomes of patients with initially indolent versus aggressive disease. We hypothesized that patients with indolent disease have less cytogenetic abnormalities and a favorable overall survival (OS). Methods: We identified 65 patients diagnosed with T-PLL between 2004 and 2020 who were treated at Moffitt Cancer Center. Clinical presentation, laboratory parameters, and bone marrow biopsy at the time of diagnosis were retrospectively reviewed. Patients were categorized into two groups: indolent or aggressive disease type. Patients were considered indolent if they did not have symptoms requiring immediate treatment such as B symptoms or fatigue, symptomatic lymphadenopathy, symptomatic organomegaly, hyperlymphocytosis, organ dysfunction, or cytopenias requiring transfusions. Patients with 3 or more chromosomal abnormalities were considered to have complex cytogenetics. Clinicopathologic characteristics were compared using Chi-square test. OS and factors that are potential influencers of survival were compared using the Kaplan Meier curve as well as Cox Proportional Hazards regression. Results: Of the 65 patients with T-PLL, 32 (49%) presented with indolent disease and 33 (51%) presented with aggressive disease. The median age at diagnosis was 68 years (range 43-88 years). Patients with aggressive disease presented with a higher WBC compared to those with indolent disease, with median WBC 79.7 x 10 9/L and 22.9 x 10 9/L, respectively (p=<0.001). Patients with aggressive disease also presented with a higher absolute lymphocyte count (ALC), with median ALC 47.8 x 10 9/L and 15.4 x 10 9/L (p=<0.001) (Table 1). Extra-nodal, skin, and CNS involvement was not significantly different between disease types. Flow cytometry was similar between indolent and aggressive disease with the exception with the exception of CD56 and CD57 which were rare and only observed in aggressive disease. Patients with aggressive disease were more likely to have complex karyotype compared to patients with indolent disease (p=0.023). FISH results for inversion 14 and trisomy 8 were similar between disease types. Median time from diagnosis to initial treatment was 379 days for indolent and 44 days for those with aggressive disease. 36 (55%) patients were treated with Alemtuzumab as first line treatment. A total of 15 (23%) patients ultimately underwent allogeneic hematopoietic stem cell transplant (HSCT). The median OS for the entire cohort was 30 months. The median OS for indolent and aggressive disease was 44 and 24 months, respectively (p=0.015, Figure 1). The median OS for patients who underwent HSCT compared to those who did not was 99 and 24 months, respectively (p=0.002). Among patients with indolent disease, those who underwent HSCT had a significantly longer median OS of 153 compared to 34 months for those who did not (p=0.022). There was a trend toward improved OS in patients with aggressive disease who underwent HSCT compared to those that did not (35 vs 16 months; p=0.08). In addition, there was a trend toward improved OS with earlier treatment (<12 months) in the indolent group (383 versus 86 months, p= 0.155). On multivariate analysis (Table 2), factors that negatively affected overall survival were aggressive disease type (HR 3.0, p=0.018), presence of inversion 14 (HR 2.5, p=0.032), presence of B symptoms (HR 2.4, p=0.036), and absence of HSCT (HR 0.2, p=0.001). Conclusion: Patients with T-PLL who present with aggressive disease, inversion 14, B symptoms, and those who are unable to undergo bone marrow transplant have lower overall survival. Characteristics that predict a more aggressive disease phenotype at diagnosis are high WBC, high ALC, presence of B symptoms, and complex karyotype. Figure 1 Figure 1. Disclosures Saeed: Kite Pharma: Consultancy, Other: investigator; Other-TG therapeutics: Consultancy, Other: investigator; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Epizyme, Inc.: Consultancy; Bristol-Myers Squibb Company: Consultancy; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; Nektar Therapeutics: Consultancy, Other: research investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees.

Impact of p53 Disruption on Mantle Cell Lymphoma (MCL) Treatment out-Come, Multi-Centre Retrospective Study

Background: MCL is a rare type of non-Hodgkin lymphoma (NHL) with an aggressive clinical course. MCL is associated with poor prognosis and incurable disease in the majority of patients. However, a minority of patients will not require any treatment for many years. TP53 mutations continue to confer a dismal prognosis in MCL with a median survival of 1.3 years. However, targeted therapy and, more recently, promising CAR-T treatment have revolutionised the outcome. Methods: Patients were identified through our pathology database, and informed consent was obtained. The patient's demographic characteristics, clinical features, laboratory findings, MIPI score, initial / subsequent treatment and survival were analysed. p53 expression percentage and its concordance with the mutational status were evaluated in a subset of patients. Results: One hundred and one patients were included in this study, with a male predominance (80%), median age 67 years (Range 37-89 years) and majority with advanced disease. Fifty-one patients (50%) presented with extra-nodal disease. Most of the patients presented with Classical MCL ( 75%) histological sub-type, 20 patients (20%) with blastoid variant and 6 patients (6%) with indolent disease. Seventy-four patients (73%) had a high MIPI risk score, while intermediate and low scores were noted in 17 patients (17%) and 10 patients (10%), respectively. Chemo-immunotherapy (CIT) was the main initial treatment modality in our cohort (79 patients / 78%). Watch and wait approach was applied in 6 patients with the indolent disease, 4 patients (4%) were not fit for any form of therapy. Forty-four patients (44%) had Rituximab maintenance and autologous stem cell transplant (Auto-SCT ) consolidation was used in 12 patients (12%). Five patients (5%) had allogeneic SCT (Allo-SCT) post-remission. Initially, 29 patient samples were used to validate immunohistochemistry (IHC) p53 expression percentage and its correlation with TP53 mutational data from genomic sequencing (SS and NGS). p53 expression of > 30% had 100% concordance with TP53 mutational status. A total of 128 patient samples, including 27 samples with relapsed disease, were screened for TP53 alterations using IHC p53 expression as a surrogate marker. Twenty samples (16%) showed p53 overexpression (15/12% diagnostic & 5/19% relapsed samples). At the final data compilation (31/01/2021), 44 patients were still alive, and 57 patients had died. The OS and PFS for the whole cohort were 69 and 47 months, respectively. (Figure 1) The prognostic impact of age (<65 years), MIPI score & disease sub-type were confirmed in this cohort with a P-value of P.00046, P.0.036 and P.0.0192, respectively. In the treated cohort, p53 disruption revealed a dismal prognosis and poor treatment outcome, with a median OS and PFS in the p53 wild-type cohort of 95 months and 50 months. In contrast, in patients harbouring p53 disruption, the median OS & PFS were 38months (P.0323) and 25 months (P.0383 ), respectively. (Figure 2) Conclusion This study reflects real-life MCL experience and the potential use of p53 expression using IHC in routine practice in assessing MCL disease prognosis. It also confirms the dismal outcome of MCL patients with TP53 mutations. Participation in clinical trials based on genetic risk stratification is warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Long-term survival in thymic carcinoma with postoperative pleural dissemination

Background We report a patient with thymic squamous cell carcinoma who underwent multiple rounds of surgical resection and definitive radiotherapy for both primary tumor and postoperative recurrence. However, the patient remains well and healthy 18 years after initial diagnosis. Since long-term survival after postoperative recurrence of thymic carcinoma is extremely rare, we also present her immunohistochemical staining results, which suggested indolent disease. Case presentation A 42-year-old woman with thymic squamous cell carcinoma underwent en bloc resection of the tumor and thymus gland. Pleural dissemination was noted in the right thoracic cavity 3, 10, and 16 years postoperatively. Where possible, the nodules were resected surgically: during the postoperative 3rd and 16th years. Definitive radiotherapy was administered for all nodules that could not be excised during the postoperative 3rd and 10th years. Disease-free survival is 25 months. Conclusions Local control of pleural dissemination may be beneficial in the treatment of postoperative recurrence of thymic carcinoma in limited cases of indolent disease.

Prediction of survival in patients with advanced, refractory colorectal cancer in treatment with trifluridine/tipiracil: real-world vs clinical trial data

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer (mCRC). A post hoc exploratory analysis of the RECOURSE randomized clinical trial (RCT) established two categories, a good prognosis corresponding to subjects having a low tumor burden and indolent disease. Other models in refractory mCRC are the FAS-CORRECT and Colon Life nomogram. The main objective was to externally validate the prognostic factors of the RECOURSE and FAS-CORRECT trials, and the Colon Life nomogram in a multicenter, real-world series of mCRC treated in 3rd and successive lines with trifluridine/tipiracil. The secondary aim was to develop an OS predictive model, TAS-RECOSMO. Between 2016 and 2019, 244 patients were recruited. Median OS was 8.15 vs 8.12 months for the poor (85% of the subjects) and good (15%) prognosis groups from the RESOURCE trial, respectively, log-rank p = 0.9. The most common grade 3–4 toxicities were neutropenia (17%), asthenia (6%), and anemia (5%). The AFT lognormal model TAS-RECOSMO included six variables: ECOG-PS, KRAS/NRAS/BRAF mutation status, time between diagnosis of metastasis and beginning of trifluridine/tipiracil, NLR, CEA, and alkaline phosphatase. The model’s bootstrapped bias-corrected c-index was 0.682 (95% CI, 0.636–0.722). The factors from the Colon Life model, FAS-CORRECT, and RECOURSE displayed a c-index of 0.690, 0.630, and 0.507, respectively. TAS-RECOSMO, FAS-CORRECT, and the Colon Life nomogram appear to predict OS in patients with refractory mCCR who begin trifluridine/tipiracil treatment in the real world. The prognostic groups of the RECOURCE RCT were unable to capture the situation of real-world subjects treated with trifluridine/tipiracil in this series.

Higher EU-TIRADS-Score Correlated with BRAF V600E Positivity in the Early Stage of Papillary Thyroid Carcinoma

The data demonstrating a correlation between sonographic markers of malignancy of thyroid cancer (TC) and its genetic status are scarce. This study aimed to assess whether the addition of genetic analysis at the preoperative step of TC patients’ stratification could aid their clinical management. The material consisted of formalin-fixed paraffin-embedded tumor fragments of 49 patients who underwent thyroidectomy during the early stages of papillary TC (PTC). Tumor DNA and RNA were subjected to next-generation sequencing (NGS) on Ion Proton using the Oncomine™ Comprehensive Assay panel. We observed a significant correlation between BRAF V600E and a higher EU-TIRADS score (p-value = 0.02) with a correlation between hypoechogenicity and taller-than-wide tumor shape in analysed patients. There were no other significant associations between the identified genetic variants and other clinicopathological features. For TC patient’s stratification, a strong suspicion of BRAF V600E negativity in preoperative management of TC patients could limit the over-treatment of asymptomatic, very low-risk, indolent disease and leave room for active surveillance.