Lung microbial and host genomic signatures as predictors of prognosis in early-stage adenocarcinoma.

BACKGROUND: Risk of early-stage lung adenocarcinoma (LUAD) recurrence after surgical resection is significant, and post-recurrence median survival is approximately two years. Currently there are no commercially available biomarkers that predict recurrence. Here, we investigated whether microbial and host genomic signatures in the lung can predict recurrence. METHODS: In 91 early-stage (Stage IA/IB) LUAD-patients with extensive follow-up, we used 16s rRNA gene sequencing and host RNA-sequencing to map the microbial and host transcriptomic landscape in tumor and adjacent unaffected lung samples. RESULTS: 23 out of 91 subjects had tumor recurrence over 5-year period. In tumor samples, LUAD recurrence was associated with enrichment with Dialister, Prevotella, while in unaffected lung, recurrence was associated with enrichment with Sphyngomonas and Alloiococcus. The strengths of the associations between microbial and host genomic signatures with LUAD recurrence were greater in adjacent unaffected lung samples than in the primary tumor. Among microbial-host features in the unaffected lung samples associated with recurrence, enrichment with Stenotrophomonas geniculata and Chryseobacterium were positively correlated with upregulation of IL-2, IL-3, IL-17, EGFR, HIF-1 signaling pathways among the host transcriptome. In tumor samples, enrichment with Veillonellaceae Dialister, Ruminococcacea, Haemophilus Influenza, and Neisseria were positively correlated with upregulation of IL-1, IL-6, IL17, IFN, and Tryptophan metabolism pathways. CONCLUSIONS: Overall, modeling suggested that a combined microbial/transcriptome approach using unaffected lung samples had the best biomarker performance (AUC=0.83). IMPACT: This study suggests that LUAD recurrence is associated with distinct pathophysiological mechanisms of microbial-host interactions in the unaffected lung rather than those present in the resected tumor.

Possible association between SP-C mutations and lung cancer: Two case reports and review of literature.

Surfactant protein C (SP-C) is one of four surfactant proteins produced by type II pneumocytes. Mutations in surfactant protein A are strongly associated with development of lung cancer. Mutations in the SP-C gene are rare and are associated with interstitial lung disease in the pediatric age group. We describe two patients with SP-C mutations who developed lung cancer. Both patients had concurrent interstitial lung disease, although the clinical phenotype was variable. In both cases, mutations were in translated region of the SP-C gene; one in the BRICHOS domain and the other in the transmembrane domain. Our paper suggests that patients with SP-C mutations can be at increased risk for the development of lung cancer, and it's reasonable to follow them routinely.

Diffuse alveolar hemorrhage in a healthy stem cell donor following administration of granulocyte colony - stimulating factor.

BACKGROUND: Granulocyte colony - stimulating factor (G-CSF) is frequently used in healthy adults prior to stem cell donation in order to mobilize stem cells to peripheral blood. Adverse events of G-CSF occur in about 30% and mainly include bone pain, fatigue, and headache. Pulmonary adverse events are rare. CASE PRESENTATION: Here, we describe a case of a healthy donor who developed diffuse alveolar hemorrhage after G-CSF administration. We suggest the underlying mechanism of this injury. CONCLUSION: Diffuse alveolar hemorrhage can occur following G-CSF administration. Treating physicians should be aware of this infrequent but often life-threatening pulmonary side effect of G-CSF.

Waterpipe smoking: a review of pulmonary and health effects.

Waterpipe smoking is an old form of tobacco smoking, originating in Persia and the Middle East. The popularity of the waterpipe is increasing worldwide, particularly among young adults, and there are widespread misconceptions regarding its negative health effects. The inhaled smoke of the waterpipe contain several toxic and hazardous materials including nicotine, tar, polyaromatic hydrocarbons and heavy metals, all of which are proven to be related to lung diseases and cancer. Regular waterpipe smoking is associated with respiratory symptoms, a decrease in pulmonary function and increased risk for lung disease such as COPD. Additional negative health effects include increased risk for arterial stiffness, ischaemic heart disease and several cancer types including lung cancer. This review summarises the negative health effects of waterpipe smoking, with emphasis on cardiorespiratory complications. Increased awareness and knowledge amongst healthcare professionals will hopefully help identify waterpipe smokers and promote patient education. Applying World Health Organization (WHO) regulations will provide a synergistic effect in reducing waterpipe use and associated disease.

Addition of high-dose methotrexate to standard treatment for patients with high-risk diffuse large B-cell lymphoma contributes to improved freedom from progression and survival but does not prevent central nervous system relapse.

Combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is regarded as standard care for diffuse large B-cell lymphoma (DLBCL) and upfront intensification of therapy is still controversial. The current study aimed to dertermine whether the addition of high-dose methotrexate (HDMTX) affects long-term outcomes and could also prevent central nervous system (CNS) relapse. Medical records of 480 patients with DLBCL treated between 1994 and 2013 at Rambam and Hadassah medical centers in Israel were reviewed; 130 (27%) had received HDMTX. Patients receiving HDMTX generally had higher International Prognostic Index (IPI) and CNS-IPI scores. HDMTX addition significantly improved progression free and overall survival (p = .001) and this advantage was maintained in multivariate analysis (HR for OS 0.3; 95% CI 0.19-0.47; p < .0001). Thirty-one (6.5%) patients had CNS relapse and in these cases high CNS-IPI, but not HDMTX treatment, was independently associated with CNS relapse (HR 1.2; 95% CI 1.2-11.5; p = .02). In conclusion, the addition of HDMTX to CHOP/RCHOP independently and significantly improved prognosis of patients with high-risk DLBCL, irrespective of their risk for CNS relapse.

Chronic Lymphocytic Leukemia and Myelofibrosis.

BACKGROUND: Chronic lymphocytic lymphoma (CLL) can be associated with several malignancies, but rarely with myelofibrosis. Only isolated case reports in the literature described the association between CLL and primary myelofibrosis (PMF) in the same patient. OBJECTIVES: We describe a case of CLL characterized by the development of PMF and a review of literature. METHODS: We describe an 86-year-old female diagnosed as having CLL and followed by the development of splenomegaly and progressively rising LDH levels 27 months later. A bone marrow biopsy was consistent with the diagnosis of PMF, with positive JAK-2 V617F mutation. We also review the clinical and molecular characteristics of patients with CLL and PMF. RESULTS: Patients with CLL and PMF are usually older. A lead diagnosis of CLL harbored by PMF is the most common clinical course, although concomitant diseases may occur in 31.7% of patients. JAK-2 V617F mutation can be found in 48.7% of patients. CONCLUSION: This case reported here constitutes an unusual situation of CLL characterized by the development of PMF. Etiologic and pathogenic associations-the role of t (1; 6) and JAK-2 V617F mutation-are discussed.

The prognostic value of bone marrow involvement at the molecular level in aggressive lymphoma.

We retrospectively studied the prognostic role of molecular (gene rearrangement, GRR) bone marrow (BM) involvement in diffuse large B-cell lymphoma (DLBCL, 424 patients) and in peripheral T-cell lymphoma (PTCL, 67 patients). When correlating BM GRR to histological findings at diagnosis, the GRR test was more sensitive (p = 0.036) but less specific (p < 0.0001) in PTCL than in DLBCL. For DLBCL (but not PTCL), a positive BM GRR correlated with advanced stage (p = 0.0001) and high IPI (p = 0.002), and worsened the progression free survival (PFS) (p = 0.05) and overall survival (OS) (p = 0.01), irrespective of rituximab treatment. Histologic negative/GRR positive cases had worse PFS/OS (p < 0.0001) than histologic/GRR double negative cases, however BM GRR was not an independent prognostic survival factor. End-of-treatment BM GRR did not predict survival. We conclude that BM GRR is unjustified as a prognostic tool for PTCL and should be reserved for a subset of DLBCL patients with negative histology of the BM.