Prognostic impact of nutritional and inflammation-based risk scores in follicular lymphoma in the era of anti-CD20 targeted treatment strategies.

BACKGROUND: The composition of the tumor microenvironment (TME) is conditioned by immunity and the inflammatory response. Nutritional and inflammation-based risk scores have emerged as relevant predictors of survival outcome across a variety of hematological malignancies. METHODS: In this retrospective multicenter trial, we ascertained the prognostic impact of established nutritional and inflammation-based risk scores [Glasgow Prognostic Score (GPS), C-reactive-protein/albumin ratio (CAR), neutrophil-lymphocyte ratio (NLR), prognostic nutritional index (PNI), and prognostic index (PI)] in 209 eligible patients with histologically confirmed CD20+ follicular lymphoma (FL) of WHO grade 1 (37.3%), 1-2 (16.3%), 2 (26.8%) or 3A (19.8%) admitted to the participating centers between January 2000 and December 2019. Characteristics significantly associated with overall or progression-free survival (OS, PFS) upon univariate analysis were subsequently included in a Cox proportional hazard model. RESULTS: In the study cohort, the median age was 63 (range 22-90 years). The median follow-up period covered 99 months. The GPS and the CAR were identified to predict survival in FL patients. The GPS was the only independent predictor of OS (p < 0.0001; HR 2.773; 95% CI 1.630-4.719) and PFS (p = 0.001; HR 1.995; 95% CI 1.352-2.944) upon multivariate analysis. Additionally, there was frequent occurrence of progression of disease within 24 months (POD24) in FL patients with a calculated GPS of 2. CONCLUSION: The current results indicate that the GPS predicts especially OS in FL patients. Moreover, GPS was found to display disease-specific effects in regard to FL progression. These findings and potential combinations with additional established prognosticators should be further validated within prospective clinical trials.

Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype-phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype-phenotype correlations encouraging further analyses.

Population-based patterns of care in the first-line treatment of patients with advanced esophagogastric adenocarcinoma in Germany.

BACKGROUND: Randomized studies proved the efficacy of new drugs for the systemic treatment of advanced gastric cancer in the past 5 years. However, little is known about the use of firstline chemotherapy in clinical practice in patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (AEG) and the stomach. We investigated temporal trends in therapy and factors influencing treatment decisions for these patients during a 4-year period. PATIENTS AND METHODS: 1058 patients (median age 67 years) with advanced AEG or gastric cancers undergoing treatment decisions were documented with the Therapiemonitor® in 2006-2009. Therapiemonitor collects population-based data regarding treatment decisions and strategies. Time trends of drug use and intensity in the first-line treatment were analyzed in the entire patient group and according to age (cut-off 65 years) and Karnofsky performance status (KPS; cut-off 80%). RESULTS: Over time, the use of oxaliplatin and docetaxel as well as capecitabine increased while cisplatin and irinotecan use slightly declined. The use of chemotherapy triplets rose from 10.1% in 2006 to 47.0% in 2009. Treatment patterns significantly varied by age and KPS: Older patients were significantly less likely to receive chemotherapy triplets, cisplatin and docetaxel but tended to more often receive oxaliplatin. Likewise, triplets, cisplatin and docetaxel were less frequently used in patients with KPS < 80%, while capecitabine and irinotecan were significantly more often used in this patient group. CONCLUSIONS: A clear tendency towards the use of more intensive chemotherapy regimens in patients with AEG and gastric cancer was observed over time. Older or less fit patients were treated preferably with monotherapy or chemotherapy doublets during 2006-2009. Oxaliplatin and docetaxel use has substantially risen.

The Glasgow Prognostic Score at Diagnosis Is a Predictor of Clinical Outcome in Patients with Multiple Myeloma Undergoing Autologous Haematopoietic Stem Cell Transplantation.

Background: Immunity and inflammatory response affect the tumour microenvironment and the progression of malignancies. Metabolic and inflammatory parameters and ratios of the peripheral blood correlate with outcome in cancer patients. There exist several established and validated inflammation-based scores of prognostic significances including the Glasgow Prognostic Score (GPS). Methods: In this retrospective, multicentre study, we investigated the prognostic capabilities of baseline GPS in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation as a complementary resource for risk stratification. For GPS calculation, a C-reactive-protein (CRP) value of >10 mg/dL counts as one point and an albumin value of <35 g/L connotes another point, resulting in three different subgroups (group I: 0 points; group II: 1 point; and group III: 2 points). Patients with MM admitted to the participating institutions between January 2010 and July 2018 were screened, and established prognostic scores and ratios were assessed. Characteristics significantly associated with overall survival (OS) or progression-free survival (PFS), upon univariate analysis, were included in a Cox proportional hazards model. Results: Following initial assessment, we identified 224 fully evaluable patients who underwent autologous haematopoietic stem cell transplantation for multiple myeloma. A centralised review of pathology and cytogenetic reports was conducted, and a central hematopathology assessment was performed in 175 of 224 cases (78.1%). Proceeding to high-dose chemotherapy and subsequent autologous stem cell transplantation was the main inclusion criterion for all transplant-eligible patients in the study. The median age at diagnosis was 59 years (range: 35-76 years) with a median follow-up of 76 months. Multivariate analysis revealed neutrophil-platelet score (NPS) (HR = 0.528, 95% CI = 0.284-0.984) and B symptoms at primary diagnosis (HR = 1.838, 95% CI = 1.232-2.740) to be independent predictors of PFS while high-risk cytogenetic changes (HR = 2.358, 95% CI = 1.413-3.934, p = 0.001) could be identified as an independent predictor of OS, and GPS to be the only independent predictor of both OS and PFS (OS: HR = 2.127, 95% CI = 1.431-3.162, p < 0.0001 and PFS: HR = 1.405; 95% CI = 1.058-1.867, p = 0.019). Conclusions: Our data show that baseline GPS correlates with rates of relapse and refractory disease in MM patients undergoing autologous transplantation. In a multivariate analysis, these effects were proven to hold prognostic capabilities beyond and independent from established prognosticators. These results require further validation in a prospective setting.

Trofosfamide in the treatment of elderly or frail patients with diffuse large B-cell lymphoma.

PURPOSE: The introduction of immunochemotherapy has led to a significant improvement in treatment results and prognosis of diffuse large B-cell non-Hodgkins lymphoma (DLBCL) both at initial diagnosis and in relapse. Trofosfamide, an oxazaphosphorine derivative, has been utilized as alternative treatment option for patients with lymphoproliferative diseases unsuitable for conventional chemotherapy agents and protocols because of age, comorbidity, or poor performance score. While data on the activity and safety of single-agent trofosfamide have been published, the potential value of this agent in immunochemotherapy in combination with anti-CD20 antibodies such as rituximab has not been investigated to our knowledge. METHODS: Safety and therapeutic effectiveness of trofosfamide given orally at a dose of 50 mg twice daily alone, or in combination with standard-dose rituximab, was investigated in a cohort of elderly and/or highly comorbid patients with histologically confirmed primary or secondary DLBCL. RESULTS: Treatment with trofosfamide in this combination setting was generally well tolerated with no treatment-related deaths and manageable side effects, most of which were WHO class I-II; the most clinically relevant toxicity was cytopenia. 19 of 21 examined patients responded to therapy with 11 of 21 (52.4%) achieving a complete remission (CR). Median overall and progression-free survival (OS and PFS) in the CR-group was 14 and 9 months, respectively. In the subgroup with trofosfamide-based first-line therapy, 7 of 10 (70%) achieved CR and median PFS was not reached. CONCLUSIONS: Immunochemotherapy with rituximab and trofosfamide (RT) is safe and effective in elderly and poor-performance patients with DLBCL. Response rates are comparable to most commonly used primary and salvage treatment protocols. The potential value of TR regimen in both first-line and relapsed/refractory DLCBL merits further investigation and is probably underestimated.

NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer.

We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with KRAS wild-type (KRASWT) tumors (4 of 17). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASWT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC.Significance: Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as NRG1 fusions as disease-driving events in KRASwt tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. Cancer Discov; 8(9); 1087-95. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.

Five-year, disease-free survival after repeat palliative multimodality therapy in a patient with recurrent metastatic bladder cancer.

In appropriately selected cases, palliative therapeutic strategies can be adapted to those special features of cancer biographies that indicate an atypical course of disease. Elucidating these features, and adapting multimodal treatment strategies to them, can lead to significantly superior effects when compared to the routine application of conventional treatment algorithms. A case of regionally metastatic bladder cancer is presented that documents the value of repeat debulking-surgery and repeat radiotherapy leading to unexpected short-term and long-term treatment results.

[Anaemia in the elderly]. / Anämie im Alter.

In the elderly, even mild anaemia leads to significantly decreased quality of life and reduced survival rate. Therefore even mild anaemias should be worked up especially in the elderly. More than 75 % of all anaemias have a specific and treatable cause.Differential diagnosis of anaemia in the elderly is much more challenging compared to the differential diagnosis in younger patients: in older patients often more than one dysfunction is responsible for the anaemia simultaneously. Many routine laboratory parameters are changed by ageing and are therefore only of limited value for diagnosis of anaemia. Soluble transferinreceptor and hepcidin are two parameters feasible for differential diagnosis of the causes of anaemia in the elderly.The most common cause of iron deficiency anaemia in the elderly is gastrointestinal bleeding. Many causes for gastrointestinal bleeding -like angiodysplasia of the colon - can readily be treated with endoscopic therapy. For this reason, colonoscopy is part of the standard workup for elderly patients with iron-deficient anaemia (IDA) if no contraindications exist.Therapy of anaemia is based on the specific cause or the causes. In IDA, the first step other than causal treatment is to replace iron orally. If this is not tolerated because of side effects or does not lead to a sufficient rise in the haemoglobin level, intravenous iron replacement therapy is indicated. Folic acid deficiency is generally treated orally, whereas vitamin B12 deficiency is generally treated by the parenteral - preferably subcutaneous - route. In anaemia due to chronic renal failure and anaemia due to myelodysplastic syndromes, the underlying cause must be treated, furthermore erythropoiesis-stimulating agents can be indicated.

Endovascular recanalization of a port catheter-associated superior vena cava syndrome.

PURPOSE: Superior vena cava (SVC) syndrome owing to benign etiology is rare and endovascular techniques have been advocated as the treatment of choice. We report a case of endovascular revascularization of a port catheter-associated complete occlusion of the SVC with reversed flow in the azygos vein. METHODS: In this setting using a sheath in combination with its dilatator to pass the occlusion of the SVC after neither a diagnostic catheter nor a PTA balloon would pass the lesion may be a valid option. A dual venous approach was established using the right common femoral vein and an indwelling port catheter in the right cephalic vein to dilate and stent the lesion. Finally, a port may be implanted after the revascularization had been successful. RESULTS: Passage through the port catheter-associated occlusion of the SVC was only possible by use of the sheath in combination with its dilatator. A dual venous access by the femoral approach and the indwelling central catheter is helpful in treating a SVC occlusion. CONCLUSIONS: Long-term central venous catheters may cause SVC syndrome, especially with a catheter tip located too far cranially. An endovascular revascularization of a complete occlusion of the SVC represents the therapy of choice.

The role of high-dose chemotherapy in the treatment of non-small cell lung cancer.

The literature on high-dose chemotherapy in non-small cell lung cancer (NSCLC) with autologous bone marrow or peripheral blood stem cell transplantation does not - as of yet - provide evidence of relevant benefits. At the same time, the significant risks of treatment-related morbidity and mortality associated with dose-intensified chemotherapy in this vulnerable patient population are increasingly recognized. Whether the advent of new cytotoxic agents such as the Taxans or newer Topoisomerase inhibitors will help to improve the hitherto unsatisfying results of high-dose chemotherapy in NSCLC, remains to be determined. The few ongoing studies in the area strive to examine such newer drug-combinations in a multimodality treatment concept combining neo-adjuvant chemotherapy or chemoradiation with surgery and adjuvant thoracic radiation therapy.

Long-term disease-free survival in patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND AND OBJECTIVES: Patients with angioimmunoblastic T-cell lymphoma (AIL) have a poor prognosis with conventional treatment. DESIGN AND METHODS: We initiated an EBMT-based survey studying the impact of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation in patients with AIL. Data on 29 patients, who were transplanted between 1992 and 1998 in 16 transplant centers, were collected on standardized documentation forms. RESULTS: The median age at transplantation was 53 years. HDCT was given as part of 1st-line therapy (N=14; 48%) or 2nd/3rd-line therapy (N=15; 52%). Regimens for the mobilization of peripheral blood stem cells (PBSC) included VIPE (N=7; 26%), DexaBEAM (N=6; 22%), CHOP-like regimens (N=6; 22%), other regimens (N=5; 19%) or alternatively growth factor alone (N=3; 11%). The median yield of PBSC was 3.8x106 CD34+cells/kg. Two patients received autologous bone marrow. The HDCT consisted of BEAM-type regimens in 16 patients, ICE-type regimens in 7, and other regimens in 6 patients. There was one treatment-related death. The rate of complete remissions increased from 45% before HDCT to 76% after HDCT. As of January 2003, after a median observation time of living patients of 5 years (range 2.5 to 10 years), 14 patients have died (13 from progressive disease), and 15 patients are alive. The probability of 5-year overall and event-free survival was 44% (95% CI, 22% to 66%) and 37% (95% CI, 17% to 57%), respectively. Long-term disease-free survival was observed in patients transplanted during 1st-line treatment as well as in the context of 2nd/3rd-line therapy. INTERPRETATION AND CONCLUSIONS: There is evidence that AIL is susceptible to high-dose chemotherapy. HDCT and autologous stem cell transplantation should be considered in selected patients with AIL.

Poly (ADP-ribose) polymerase inhibitor efficacy in head and neck cancer.

OBJECTIVES: Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown single agent activity against tumors with deficiencies in the DNA repair mechanism homologous recombination including, but not limited to those harboring BRCA mutations. We hypothesized that, in the context of homologous recombination deficiency (HRD), PARPi could have an effect in head and neck cancer (HNC). MATERIALS AND METHODS: We evaluated TCGA data for evidence of HRD using a copy number data signature established for breast cancer. The comparative potency of three PARPi was evaluated using cell viability assays in a panel of HNC cell lines and response was compared to BRCA-deficient breast cancer cell lines. The change in foci formation of γH2AX and RAD51 was assessed with immunofluorescent staining after exposure to a PARPi. Baseline gene expression was analyzed using microarray data. RESULTS: We found a subgroup in the TCGA HNC cohort harboring genomic aberrations consistent with HRD in breast cancer. Rucaparib activity was superior to olaparib and veliparib and showed single agent activity in a subset of HNC cell lines that was comparable to BRCA-deficient breast cancer cell lines. Rucaparib-sensitive and rucaparib-resistant groups showed significant differences in γH2AX and RAD51 foci formation after rucaparib exposure. Expression of genes involved in chromosome structure was strongly associated with rucaparib resistance. CONCLUSION: We demonstrate that PARPi are effective in a subset of HNC cell lines and propose that HRD may be present in HNC in vivo suggesting that these compounds could play a role in the treatment of HNC.

Use of magnetic resonance imaging to detect neoplastic meningitis: limited use in leukemia and lymphoma but convincing results in solid tumors.

BACKGROUND: An early diagnosis of meningitis is important to improve patients' survival. Data about a direct comparison of cerebrospinal fluid cytology (CSF-cytology) and MRI are very limited. Therefore, the aim of this study was to compare these two diagnostic modalities in diagnosing meningitis in patients with hematopoietic and solid malignancies. METHODS: In 68 patients suspicious for neoplastic meningitis, cytology and MRI (1.5 T) was performed. The meningeal, pial or intraparenchymal hyperintense signal or contrast enhancement was correlated to the final CNS diagnosis and to cytology. RESULTS: 44 patients (64.7%) had neoplastic meningitis, 21 patients (30.9%) had non-neoplastic meningitis. The sensitivity to diagnose meningeal disease was 49.2% for MRI and 95.4% for cytology (p<0.001). In patients with neoplastic meningitis, sensitivity was 45.5% for MRI and 93.2% for cytology (p<0.001). In patients with infectious meningitis, sensitivity was 57.1% for MRI and 100% for cytology (p=0.0013). In patients with solid tumors, the sensitivity was 84.6% for both diagnostic methods. The sensitivity for MRI was low in patients with leukemia (20.0%) and lymphoma (37.5%). The positive predictive value (PPV) for MRI to differentiate infectious from neoplastic meningitis was high in patients with infectious meningitis (75.0%), in patients with lymphoma (83.3%), and in patients with solid tumors (72.7%). Ppv was low in patients with leukemia (33.3%). CONCLUSION: Diagnostic value of MRI for diagnosing meningitis is especially limited in patients with hematopoietic malignancies. MRI better detected leptomeningeal involvement caused by solid tumors than by leukemia or lymphoma. The ppv to specify neoplastic meningitis depends on tumor subtype.

Treatment of indolent lymphoma in Germany - results of a representative population-based survey.

BACKGROUND: In advanced-stage indolent lymphoma, therapeutic approaches may vary from watch and wait, antibody monotherapy, immunochemotherapy, or dose-intensified consolidation up to allogeneic strategies. In this nationwide survey, representative hematologic/oncologic centers monitored current treatment strategies in indolent lymphoma in general practice. METHODS: Four hundred ninety-five centers involved in the treatment of indolent lymphoma including university hospitals, community hospitals, and oncologists in practice were identified and contacted. Thirteen percent of centers provided information on 741 patients, which corresponds to 10% of the expected national prevalence. Detailed data on 576 unselected patients from 46 representative centers (2 university hospitals, 25 community hospitals, and 19 oncologists in practice) for whom a treatment decision took place in the fourth quarter of 2006 (start, change, or end of therapy) were included in this analysis. Data were verified by monitoring the pseudonymized patient documents. RESULTS: Median age was 67 years (range, 17 to 95 years) and 65% of patients were 60 years of age or older. Concomitant disease was frequent with cardiac disease (29%), hypertension (28%), diabetes (11%), and renal impairment (7%) being the most typical combinations. Histologies included 39% follicular lymphoma, 26% chronic lymphocytic leukemia (CLL), 10% marginal zone, 9% mantle cell lymphoma (MCL), and 16% other. Only 10% of the overall patient population were treated within these studies. The aim of initial therapy was curative in 35%, and physicians aimed at improved survival in 62% and palliation only in 54% of patients. Radiation (10%), antibody monotherapy (4%), chemotherapy (33%), and combined immunochemotherapy (31%) were the most frequent approaches. Applied chemotherapies included cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (46%), fludarabine combinations (F/FC/FCM: 15%), chlorambucil (14%), CVP/COP (9%) and bendamustin (4%). Maintenance was used in 12% and autologous/allogeneic stem cell consolidation were rarely applied (both in 3% of patients). At first relapse, combined approaches including immunochemotherapy (49%), maintenance therapy (16%), and autologous/allogeneic transplantation (14%/4%) were more frequently administered. As expected, different treatment strategies and response rates were observed in follicular lymphoma (FL), MCL, and CLL. Interestingly, supportive measures including antibiotics (34%), erythrocyte transfusions (32%), granulocyte colony-stimulating factor (22%), immunoglobulines (19%), antifungal drugs (13%), and erythropoetin (10%) were frequently applied even in first-line therapy. Overall response was 83% (FL: 97%, MCL: 95%, CLL: 74%) with a 39% complete response (FL 63%, MCL 54%, CLL 15%) rate. DISCUSSION: In this population-based survey, patients characteristics differed significantly from published study cohorts as did clinical strategies and therapeutic approaches. Thus, clinically more relevant studies in medically compromised patients are urgently warranted.

Primary B cell lymphoma of the sphenoid sinus: CT and MRI characteristics with correlation to perfusion and spectroscopic imaging features.

Primary non-Hodgkin lymphoma (NHL) of the paranasal sinuses is a rare neoplasm that cannot be easily diagnosed and differentiated as its clinical, histological, and imaging features are similar to those of other inflammatory and tumorous diseases in their early stages. We evaluated the morphological and functional imaging characteristics of primary NHL of the sphenoid sinus using CT and MR imaging. Morphological CT and MR imaging as well as perfusion CT imaging and proton MR spectroscopy (PRESS technique, TE = 135) was performed in three patients with the histological diagnosis of highly malignant primary B cell lymphoma of the sphenoid sinus. In all patients an inhomogeneous contrast agent enhancement as well as bony erosion of the sphenoid sinus was identified in CT and MR sections. In one patient an infiltration of the adjacent dura was present. The mean blood flow of the lymphomas was 135 ml/min per 100 g tissue, the mean blood volume was 8.06 ml/min, while the mean transit time and the mean permeability surface area product values were 5.11 s and 26.53 ml/min per 100 g, respectively. The mean choline to creatine ratio in the proton MR spectroscopy was 5.7. Cross-sectional imaging findings are not sufficient to establish the diagnosis of a primary NHL in the sphenoid sinus. Physiologic imaging offers valuable information that may be characteristic of the tumor. Future studies may lead to a safe differentiation of the lymphomas from other pathologic entities based on the combination of morphological and functional imaging.

[Vibrio vulnificus sepsis]. / Vibrio-vulnificus-Sepsis

A 59-year-old female patient with a history of malignant lymphoma presented with symptoms of septicaemia. The skin of the extremities showed bullous, necrotizing plaques. Blood culture revealed Vibrio vulnificus as the causative organism. The infection was most likely acquired while swimming in the unusually warm Baltic Sea through inadvertent swallowing of sea water. The disease is rare in Europe. It is discussed in view of its typical clinical and histological picture.