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PURPOSE - Malignant effusions challenge diagnostic accuracy due to cytomorphologic overlaps between various malignant primaries. Workup of this material to establish a correct diagnosis is time consuming and limited by the sparsity of material. In order to circumvent these drawbacks, the use of MALDI imaging MS (IMS) as a diagnostic platform has been explored.
EXPERIMENTAL DESIGN - Cytology cell blocks from malignant effusions (serous ovarian carcinoma and several non-ovarian carcinomas including gastric adenocarcinoma) containing at least 30% neoplastic cells are selected for generation of cytology microarrays (CMA). CMA sections are transferred to conductive glass slides, subjected to on-tissue tryptic digestion, and matrix application for MALDI-IMS analysis.
RESULTS - Supervised classification analysis identifies serous ovarian carcinomas as the source of malignant effusions with a sensitivity of 85.7% when compared to samples from all other included primary sites. When compared to gastric adenocarcinoma, serous ovarian carcinoma samples can be delineated with a sensitivity of 97.3%.
CONCLUSION AND CLINICAL RELEVANCE - These preliminary results highlight that MALDI-IMS allows subtyping of malignant effusions to identify the precise origin of neoplastic cells. While achieving similar results compared to classical approaches such as immunocytology, more material is conserved that will be available for further tests.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKKα-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1β. Indeed, IKKα is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-κB signaling. IL-1β fuels addiction of mutant KRAS to IKKα resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1β-mediated NF-κB induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKKα, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKKα-mediated responsiveness of tumor cells to host IL-1β, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.
BACKGROUND - Malignant pleural effusion is a common complication of advanced malignancies. Indwelling tunneled pleural catheter (IPC) placement provides effective palliation but can be associated with complications, including infection. In particular, hematologic malignancy and the associated immunosuppressive treatment regimens may increase infectious complications. This study aimed to review outcomes in patients with hematologic malignancy undergoing IPC placement.
METHODS - A retrospective multicenter study of IPCs placed in patients with hematologic malignancy from January 2009 to December 2013 was performed. Inclusion criteria were recurrent, symptomatic pleural effusion and an underlying diagnosis of hematologic malignancy. Records were reviewed for patient demographics, operative reports, and pathology, cytology, and microbiology reports.
RESULTS - Ninety-one patients (mean ± SD age, 65.4 ± 15.4 years) were identified from eight institutions. The mean × SD in situ dwell time of all catheters was 89.9 ± 127.1 days (total, 8,160 catheter-days). Seven infectious complications were identified, all of the pleural space. All patients were admitted to the hospital for treatment, with four requiring additional pleural procedures. Two patients died of septic shock related to pleural infection.
CONCLUSIONS - We present, to our knowledge, the largest study examining clinical outcomes related to IPC placement in patients with hematologic malignancy. An overall 7.7% infection risk and 2.2% mortality were identified, similar to previously reported studies, despite the significant immunosuppression and pancytopenia often present in this population. IPC placement appears to remain a reasonable clinical option for patients with recurrent pleural effusions related to hematologic malignancy.
The burden of pleural diseases continues to rise and affects an increasingly complex and aging patient population. As such, thoracentesis is one of the most common procedures performed by respiratory physicians, as pleural fluid analysis can establish the diagnosis of pleural effusions in approximately 75% of the cases. When a diagnosis is not reached, options include image-guided biopsies, only possible when focal pleural lesions can be identified by computed tomography or ultrasound; closed pleural biopsies, associated with a relatively low diagnostic yield; and surgical pleural biopsies, which typically require general anesthesia and a hospital stay. Medical thoracoscopy addresses some of the limitations of these techniques, allows a comprehensive pleural examination and targeted pleural biopsies, and offers the possibility of treatment of recurrence in the same setting. As such, medical thoracoscopy is ideally positioned as a valuable tool in the diagnosis of unexplained exudative pleural effusions.
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BACKGROUND - Malignant pleural effusions are common complications of advanced malignancies and are associated with significant morbidity and reduced survival. Tunnelled indwelling pleural catheters (TIPCs) are implantable devices used for palliation of symptomatic malignant pleural effusions. Although complication rates are overall low, their use in the setting of concurrent chemotherapy has not been carefully reviewed. We report our experience with infectious complications directly attributable to TIPCs (pleural or local soft tissue infections) in those patients receiving concurrent chemotherapy.
METHODS - We conducted a retrospective analysis of patients who underwent TIPC placement for malignant pleural effusion in a 6-year period from November 2005 to March 2011. We reviewed the incidence of infection in these patients receiving catheter placement and attempted to determine whether chemotherapy was associated with an increased infectious risk.
RESULTS - A total of 262 TIPC procedures, performed in 243 patients, were included in the study. Out of 262, 173 (66%) TIPC were in the chemotherapy group and 89 TIPC were in the nonchemotherapy group. Infections developed in 16 of the 262 TIPC placements (6.1%). The rate of complications in the chemotherapy group was 9 of the 173 TIPCs (5.2%) compared with 7 of the 89 TIPCs (7.9%) in the other group, a difference that was not statistically different (P=0.4).
CONCLUSIONS - The overall risk of infection in TIPC is low. Patients undergoing chemotherapy while the TIPC is in place do not seem to have an increased risk of infection, and therefore chemotherapy should not necessarily be viewed as a contraindication to TIPC insertion.
BACKGROUND - Malignant pleural effusion (MPE) is encountered at an advanced stage of disease progression and often heralds a poor prognosis. The most reliable predictive factor of survival in such patients is the primary tumor. Thoracoscopy is often performed for accurate diagnosis and/or thoracoscopic talc insufflation as a therapeutic modality. It remains unknown whether pleural tumor burden, as visualized on thoracoscopy, has potential prognostic value. The objective of this study was to determine the prognostic accuracy of pleural tumor extent and localization (parietal, visceral, or diaphragmatic involvement), as assessed during medical thoracoscopy.
METHODS - Medical records of all patients who underwent thoracoscopy for suspicion of MPE between 2001 and 2008 at a tertiary care referral hospital were reviewed. Patients were included if pleural metastatic invasion was confirmed on tissue biopsy and survival status ascertained.
RESULTS - Four hundred twenty-one patients underwent diagnostic or therapeutic medical thoracoscopy at our referral center. Among them, 122 had confirmed metastatic pleural spread, but survival data were lacking in 15. Primary tumor consisted of non-mall cell lung cancer in 56, breast cancer in 23, melanoma in eight, and other malignancies in 20. Median survival of the entire population was 9.4 months. On univariate analysis, the following variables were significantly associated with reduced median overall survival: pleural metastatic melanoma, age less than 60 years, bloody MPE, extensive pleural adhesions, and widespread visceral pleural nodules (p < 0.05). On multivariate analysis, only melanoma as a primary tumor, pleural fluid appearance and extent of pleural adhesions remained independent and significant predictors of survival.
CONCLUSION - No significant association was found between the extent or localization of pleural tumor burden and overall survival.
RATIONALE - IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE.
OBJECTIVES - To determine the role of IL-5 in MPE formation.
METHODS - The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5(+/+)) and IL-5-deficient (il5⁻(/)⁻) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray.
MEASUREMENTS AND MAIN RESULTS - Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5(+/+) mice, il5⁻(/)⁻ mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5(+/+) and il5⁻(/)⁻ mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5(+/+) mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo.
CONCLUSIONS - Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.
BACKGROUND - We have previously shown that nuclear factor (NF)-kappaB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-kappaB activation and not proliferation specifically inhibits MPE formation by LLC cells.
RESULTS - Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-kappaB activation and NF-kappaB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-kappaB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation.
CONCLUSIONS - These studies indicate that proteasome inhibition tailored to block NF-kappaB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE.