Negative impact of malignant effusion on osimertinib treatment for non-small cell lung cancer harboring EGFR mutation.

3rd-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, have reasonable efficacy in non-small-cell lung cancers (NSCLC) with EGFR mutations. However, the efficacy of osimertinib in NSCLC patients with fluids, such as pleural, pericardial and abdominal effusions, is unclear. We evaluated the efficacy of osimertinib in this specific setting. NSCLC patients harboring EGFR T790 M mutations who experienced progressive disease after first EGFR-TKI treatment and started osimertinib treatment between April 2016 and August 2018 were retrospectively screened. In particular, we assessed the efficacy of osimertinib for NSCLC with EGFR T790 M mutations in patients who were diagnosed with EGFR T790 M mutation by malignant effusion. Among 90 patients with EGFR T790 M mutation who started osimertinib treatment after EGFR-TKI failure, 21 were diagnosed from malignant effusions excluding cerebrospinal fluid (F group) and 69 using other methods including tissue biopsies (NF group). Patient characteristics were well-balanced between the two groups. Overall response was 50%, and significantly worse in the F group (29%) than the NF group (57%; P = 0.025). Median progression-free survival with osimertinib treatment in the F group (7.1 months, 95% confidence interval [CI]: 2.3-14.0) was significantly shorter than that in the NF group (11.9 months, 95% CI: 9.5-16.0; P = 0.046)). Median drainage-free time was 10.9 months (95% CI: 1.4 months- not reached). The present study showed that the efficacy of osimertinib for NSCLC in which EGFR T790 M mutation is detected by malignant effusion may be less than in EGFR T790 M-mutated NSCLC detected by other methods.

Aquaporin-1 expression in fluoro-edenite-induced mesothelioma effusions: An approach by cell-block procedure.

OBJECTIVE: Aquaporin 1 (AQP-1) is a water channel protein found in cell membranes, whose expression has been considered an independent favourable prognostic factor in pleural malignant mesothelioma (MM). The aim of this study was to evaluate the expression of AQP-1 and its prognostic value in a series of pleural MM effusions, from a geographical area with high concentrations of fluoro-edenite (FE). METHODS: We selected 25 MM cases from Biancavilla (Italy), an area with high environmental concentrations of FE. Cytological samples, cell-blocks (CB), clinical and follow-up data were available for all cases. Immunohistochemistry for calretinin, CK5/6, WT1, CK7 and TTF1 was used on CB sections to confirm the cytological diagnosis of MM. Immunohistochemistry for AQP-1 was performed and high expression was defined when ≥50% of tumour cells showed linear and circumferential membranous staining. RESULTS: The cohort included 16 men and nine women (median age: 67.5 years; range: 49-88 years). The median survival was 14 months (range 1.5-60 months), with a significant value (P = 0.006). All cases have been histologically confirmed and classified as epithelioid (16 cases), biphasic (seven cases) and sarcomatoid (two cases). AQP-1 high expression has been observed in 16 cases. Comparing AQP-1 high expression to the survival of corresponding patients, a significant association with a slight increased overall survival of 12 months has been demonstrated. Nine patients with a AQP-1 score less than 50% showed a shorter median overall survival (7 months). CONCLUSIONS: AQP-1 high expression is detectable on cytological samples of FE-induced MM with a prognostic value.

A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer.

BACKGROUND: SRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study. PATIENTS AND METHODS: Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m(2) was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3 + 3 dose-escalation scheme. RESULTS: Fifteen patients enrolled (median age 54 years, range 35-74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70-120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease. CONCLUSION: In combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.

Host-derived interleukin-5 promotes adenocarcinoma-induced malignant pleural effusion.

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.

[A case of angiosarcoma of the scalp with severe fluid retention after administering docetaxel].

A 7 3-year-old man with angiosarcoma was treated with concurrent chemoradiotherapy, using docetaxel (25mg/m(2) weekly). While the size of the tumor reduced rapidly, fluid retention, considered as an adverse effect of docetaxel, appeared at the cumulative dose of 325mg/m(2). He required chest drainage for prolonged pleural effusion. Though fluid retention due to docetaxel is infrequently reported in Japan, it may lead to severe illness and require discontinuation of chemotherapy. When we administer docetaxel over a prolonged period, we should be aware of this adverse effect.

Human herpesvirus 8-unrelated primary effusion lymphoma-like lymphoma following tyrosine kinase inhibitor treatment for chronic myelogenous leukemia.

A 69-year-old man was diagnosed with chronic myelogenous leukemia (CML) and treated with dasatinib. After two years on dasatinib, the patient achieved complete molecular response, but dasatinib treatment was discontinued due to exacerbation of pleural effusion. Nilotinib and imatinib were started but stopped due to an increase in pleural effusion. Thoracentesis was performed and he was diagnosed with human herpesvirus 8-unrelated primary effusion lymphoma (PEL)-like lymphoma. Complex chromosomal abnormality, including BCL6 rearrangement, was found on chromosome analysis. To the best of our knowledge, this is the first report of PEL-like lymphoma following tyrosine kinase inhibitor treatment for CML.

Non-occupational malignant pleural mesothelioma due to asbestos and non-asbestos fibres.

BACKGROUND AND AIM: The occurrence of malignant pleural mesothelioma (MPM) has been reported among population groups with no documented professional exposure to asbestos fibres living in different geographic areas. This paper reviews existing data related to non occupational MPM including its occurrence in the province of Catania (Sicily, Italy). METHODS: An electronic search of literature related to non occupational MPM was performed including the year 2005. RESULTS: Non occupational MPM in subjects living in areas contaminated by a variety of asbestos and non asbestos fibres has been well documented through a number of epidemiologic studies including cases series, case-control studies, and a cohort study. In addition, the observation of familial clustering of MPM, suggests that genetic factors may play a role in the pathogenesis of this malignancy. The epidemiological evidence also suggests that MPM may occur as a result of the interaction between environmental carcinogens, genetic factors, and virus infection. CONCLUSION: It is likely that genetic predisposition and non-occupational exposure to low doses of asbestos and asbestos-like fibres may concur to the development of malignant mesothelioma. However, additional epidemiological and laboratory studies are needed to further understand the relationship between environmental exposure and individual susceptibility to this malignancy.

Pleurodesis in recurrent pleural effusions: a randomized comparison of a classical and a currently popular drug.

STUDY OBJECTIVES: Pleurodesis is generally regarded to give the best palliation in recurrent pleural effusion. Talc is now increasingly recommended but in our department quinacrine has been used successfully for many decades with good results and only minor side effects. It was therefore decided to make a prospective randomized clinical study comparing quinacrine (500 mg) with talc (5 g) with regard to efficacy and safety. METHODS: One hundred and ten eligible consecutive patients with recurrent and or malignant effusions, from 1 March 1996 till 31 March 1999 were randomized to chemical pleurodesis with either talc or quinacrine through a chest drainage tube after medical thoracoscopy. Patients were evaluated with chest radiographs at 2 weeks and 2, 4, and 6 months after pleurodesis. RESULTS: Chi-square test showed 84% power to distinguish between the groups and 10% to determine the primary endpoint. Primary success (fluid production < 50ml/24h within the first 6 days) was 96% of 56 patients with talc and 91% of 54 patients with quinacrine, a non-significant difference (P = 0.46). Quinacrine patients needed a repeated treatment in 31% (17 patients) and talc patients in 7% (4 patients) (P < 0.05). Side effects were minor with no significant difference between the substances. CONCLUSIONS: Both substances are effective. Talc treatment had less often to be repeated. This indicates that the recommendation of talc for pleurodesis is well founded. However, quinacrine is a good alternative.

Pleural effusion and pulmonary injury as an unusual complication to chemotherapy in non-small cell lung cancer patients.

We report the appearance of pleural effusion, or pulmonary failure after chemotherapy, followed by tumor reduction, in a small number of patients. Five hundred and fifty-four patients with lung cancer have undergone chemotherapy at our Institute during the last ten years. Three patients with non-small cell lung cancer (NSCLC), with locally advanced disease, exhibited an unusual consequence following cytotoxic drug treatment. Two patients with NSCLC had pleural effusion which improved within 2-3 weeks, together with tumor reduction, which allowed the continuation of treatment. One patient had pulmonary failure with pleural effusion and recovered within two weeks. Two of the three patients had positive cytology for cancer cells in the fluid. All three patients achieved partial remission with no repetition of the complication. The patients' recovery, response to treatment and the tumor reduction suggest that this complication was not due to disease progression.

Severe flare-up in a prostate cancer patient treated with luteinizing hormone-releasing hormone analogue depot.

A 65-year-old man with advanced prostate cancer was treated with a luteinizing hormone-releasing hormone (LH-RH) analogue. Four days after the initial injection of 3.6 mg of goserelin acetate, severe dyspnea developed due to worsening pleuritis carcinomatosa, which was considered as a flare-up. Chest drainage was required to save his life. Therefore, we emphasize the importance of treatment to prevent tumor flare during LH-RH analogue therapy.

[Weekly docetaxel therapy is useful for gastric carcinoma as a second-line chemotherapy].

In the present study, we demonstrate the results of weekly administered docetaxel treatments as a second-line chemotherapy after TS-1 treatment in 4 gastric cancer patients. Twenty-five mg/m2 of docetaxel was administered once a week for 3 weeks followed by a 1-week rest period as one cycle. The treatment was continued for 2 to 16 weeks. In case 1, a 60% reduction of the primary tumor was observed for 20 weeks. In cases 2 and 3, the decrease of tumor marker was observed. In one case, progression of the tumor was observed and the treatment was not performed. As for adverse effects, no hematological toxicity was observed; however, in one case, grade 2 hair loss, pleural effusion and grade 2 nail changes were observed. These results indicate that the weekly docetaxel therapy is useful for gastric carcinoma patients, as it reduces the hematologic toxicities and improves the quality of life of the patients in the outpatient setting.

[Preface-importance of supportive therapies against adverse drug reactions in cancer treatment].

Importance of this special articles on the prevention and management of various adverse drug reactions was described. Among various adverse reactions, cardiac, lung and neuro-toxicities in cancer chemotherapy and the means to prevent or manage such adverse reactions were mainly reviewed. In addition, this special issue include special supportive therapies in cancer treatment at home, importance of QOL in cancer therapy and future prospect on the management of adverse drug reactions.

Intrapleural or intraperitoneal lobaplatin for treatment of patients with malignant pleural effusion or ascites.

AIMS: To explore efficacy and side effects of intrapleural or intraperitoneal lobaplatin for treating patients with malignant pleural or peritoneal effusions. METHODS: Patients in Jiangsu Cancer Hospital and Research Institute with cytologically confirmed solid tumors complicated with malignant pleural effusion or ascites were enrolled into this study. Lobaplatin (20-30 mg/m2) was intrapleurally or intraperitoneally infused for patients with malignant pleural effusion or ascites. RESULTS: From 2012 to 2013, intrapleural or intraperitonea lobaplatin was administered for patients with colorectal or uterus cancer who were previous treated for malignant pleural effusion or ascites. Partial response was achieved for them. Main side effects were nausea/vomiting, and bone marrow suppression. No treatment related deaths occurred. CONCLUSION: Intrapleural or intraperitoneal infusion of lobaplatin is a safe treatment for patients with malignant pleural effusion or ascites, and the treatment efficacy is encouraging.

Blockage of vascular endothelial growth factor (VEGF) reduces experimental pleurodesis.

BACKGROUND AND OBJECTIVE: Chemical pleurodesis controls recurrent malignant pleural effusion. The mechanism that determines pleural symphysis involves the action of vascular endothelial growth factor (VEGF). We assessed the influence of the anti-VEGF antibody (bevacizumab) on pleurodesis induced by talc or silver nitrate and analyzed the temporal development of pleural angiogenesis. METHODS: Sixty New Zealand rabbits received intrapleural injection (2mL) of talc (400mg/kg) or 0.5% silver nitrate. In each group, half of the animals received an intravenous injection of bevacizumab 30min before the sclerosing agent. Five animals from each group were euthanized 7, 14, or 28 days after the procedure. Adhesions and inflammation (scores: 0-4), thickness (µm), vascular density (vessels/field), and collagen fibers (µm(2)) were evaluated in the visceral pleura. RESULTS: Antibody anti-VEGF interferes in pleurodesis induced by talc or silver nitrate. Pleural inflammation was discreet with no difference between the groups, regardless the anti-VEGF treatment. Concerning the vascular density of the visceral pleura, a smaller number of neoformed vessels was noted in the animals that received bevacizumab. In the animals receiving silver nitrate, the decrement in adhesions and vascular density was associated with reduced thick and thin collagen fibers, resulting in less pleural thickness. CONCLUSION: The anti-VEGF antibody inhibits adhesions between pleural layers. Despite being an experimental study in animals with normal pleura, the results call attention to a likely lack of success in pleurodesis when VEGF blockers are used.

[Talc pleurodesis in malignant pleural effusions]. / Effektivität und zugrunde liegende Mechanismen der Talkumpleurodese bei malignem Pleuraerguss.

Pleural effusions associated with malignancy--either malignant or paramalignant diseases--were found in ca. 20% of these patients. Large pleural effusions cause mainly dyspnoea but also cough and chest pain. The presence and degree of dyspnoea depend on the size of the effusion and the patient's underlying pulmonary function. In acute cases and large effusions immediate chest drainage is indicated in symptomatic patients, followed by the treatment of the underlying disease, e. g. chemotherapy. The most effective therapy for controlling reiterated malignant pleural effusions is the thoracoscopic talc poudrage (2.5-10 g) which has been shown to have a success rate of > 90%. Talc induces a broad inflammatory reaction involving mesothelial cells of the pleura, coagulation parameters, fibroblast proliferation eventually leading to symphysis of the pleura. This procedure is reserved for patients who are in good general conditions, who are expected to have a reasonably long survival, and who failed chemical pleurodesis. A good predictor for longer survival time is a Karnofsky Performance Scale > or = 40 indicating a survival time > 30 days, which therefore should be considered prior to the procedure. The adult respiratory distress syndrome (ARDS) is the most important complication initially observed in the US in up to 9% of all cases. ARDS incidence was strongly related to high number (50%) of small talc particles < 15 microm. In summary, talc poudrage or slurry (talc particle size > 10 microm) in malignant pleura effusions is a safe and effective method to induce pleura symphysis. Complaints and complications such as chest pain, transient fever, and empyema are rare or very are which are almost exclusively related to the therapeutic procedure itself.

Low-dose rIL-2-induced remission of disseminated CD30+ anaplastic large-cell lymphoma through reinforcement of presumed T-cell-mediated tumor cell killing, complicated by unilateral drowning of lymphoma-infiltrated lung.

We report on the immuno-oncologic analysis and treatment of a remarkable case of disseminated CD30+ anaplastic non-Hodgkin's lymphoma. Its clinical course was characterized by repeated spontaneous regressions, which were probably due to a T-cell-mediated anti-lymphoma immune reaction, as tumor-infiltrating T lymphocytes were consistently observed in sections of lymphoma lesions and found to express high-affinity receptors for interleukin-2 (IL-2). This marker may be particularly suitable to predict a response to low-dose recombinant IL-2 (rIL-2), as confirmed in this case by prompt lymphoma regression after regional rIL-2 perfusion of a cutaneous lesion and by an impressive overall response to systemic rIL-2 treatment. Despite the very low dose of rIL-2, 600,000 IU/24 h as a continuous i.v. infusion, systemic treatment was complicated by generalized capillary leakage and life-threatening unilateral drowning of the lymphoma-infiltrated left lung.