Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties.

The proteasome inhibitor bortezomib (BTZ) is the first-line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin-33 (IL-33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti-MM effect of IL-33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL-33 expression levels were downregulated in MM, and that BTZ-treated MM patients with high IL-33 levels had better prognosis than those with low IL-33 levels. Moreover, the patients with high IL-33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL-33 can enhance the anti-MM immunity. IL-33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF-κB-p65, thereby decreasing the transcription of target stemness-related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N-acetylcysteine. In conclusion, our results indicated that IL-33 enhanced the sensitivity of MM to BTZ through ROS-mediated inhibition of nuclear factor kappa-B (NF-κB) signal and stemness properties.

Short-term efficacy and safety of neoadjuvant pyrotinib plus taxanes for early HER2-positive breast cancer: a single-arm exploratory phase II trial.

Background: The effectiveness and safety of pyrotinib have been substantiated in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (BC). However, the role of pyrotinib as a single HER2 blockade in neoadjuvant setting among BC patients has not been studied. The objective of this study was to evaluate the efficacy and tolerability of pyrotinib plus taxanes as a novel neoadjuvant regimen in patients with HER2-positive early or locally advanced BC. Methods: In this single-arm exploratory phase II trial, patients with treatment-naïve HER2-positive BC (stage IIA-IIIC) received pyrotinib 400 mg once daily and taxanes [docetaxel 75 mg/m2 or nanoparticle albumin-bound (nab)-paclitaxel 260 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly] for a total of four 21-day cycles before surgery. Efficacy assessment was based on pathological and clinical measurements. The primary endpoint of this study was the total pathological complete response (tpCR) rate. The secondary endpoints included breast pCR (bpCR) rate, investigator-assessed objective response rate (ORR) and adverse events (AEs) profiles. Results: From 1 September 2021 to 30 December 2022, a total of 31 patients were enrolled. One patient was withdrawn due to unbearable skin rash after the second cycle of neoadjuvant therapy. The majority of the intention-to-treat (ITT) population was premenopausal (54.8%), had large tumors (90.3%) and metastatic nodes (58.1%) at diagnosis and hormone-receptor positive tumors (64.5%). Most participants used nab-paclitaxel (74.2%) and received mastectomy (67.7%) after neoadjuvant treatment. The tpCR and bpCR rates were 48.4% [95% confidence interval (CI): 30.8-66%] and 51.6% (95% CI: 34-69.2%), respectively. Grade ≥3 treatment-related AEs were observed in 16.1% (5/31) of the ITT population, including diarrhea (n=2, 6.5%), hand and foot numbness (n=1, 3.2%), loss of appetite (n=1, 3.2%), and skin rash (n=1, 3.2%). AE related dose reduction or pyrotinib interruption was not required. Conclusions: In female patients with HER2-positive non-metastatic BC, neoadjuvant pyrotinib monotherapy plus taxanes appears to show promising clinical benefit and controllable AEs [Chinese Clinical Trial Registry (ChiCTR2100050870)]. The long-term efficacy and safety of this regime warrant further verification.

The burgeoning importance of PIWI-interacting RNAs in cancer progression.

PIWI-interacting RNAs (piRNAs) are a class of small noncoding RNA molecules that specifically bind to piwi protein family members to exert regulatory functions in germ cells. Recent studies have found that piRNAs, as tissue-specific molecules, both play oncogenic and tumor suppressive roles in cancer progression, including cancer cell proliferation, metastasis, chemoresistance and stemness. Additionally, the atypical manifestation of piRNAs and PIWI proteins in various malignancies presents a promising strategy for the identification of novel biomarkers and therapeutic targets in the diagnosis and management of tumors. Nonetheless, the precise functions of piRNAs in cancer progression and their underlying mechanisms have yet to be fully comprehended. This review aims to examine current research on the biogenesis and functions of piRNA and its burgeoning importance in cancer progression, thereby offering novel perspectives on the potential utilization of piRNAs and piwi proteins in the management and treatment of advanced cancer.

Effect of Fiber-Rich Diet and Rope Skipping on Memory, Executive Function, and Gut Microbiota in Young Adults: A Randomized Controlled Trial.

SCOPE: To investigate the effects of fiber-rich diets (FDs), rope skipping (RS), and the combination of these two interventions (fiber-rich diet with rope skipping [FD-RS]) on memory, executive function in young adults, and to explore their relationship with gut microbiota. MATERIALS AND RESULTS: The study is a 12-week parallel-design randomized controlled trial in which 120 undergraduates (19 ± 1 years) are randomized to FD (fiber ≥ 20 g day-1 ), RS (3 × 2000 times per week), FD-RS or control group (n = 30 per group). Memory and executive function are assessed by scales, and stool samples are collected at baseline and after the intervention. FD group and FD-RS group show fewer prospective and retrospective subjective memory impairments than the control group, but there is no significant difference between FD-RS and the intervention alone (FD or RS). No obvious change in executive function is observed throughout the trial. In terms of the gut microbiota, the α-diversity does not increase, but the microbial community evenness improves after the RS and FD intervention. Additionally, the relative abundance of phylum Firmicutes and genera Faecalibacterium, Eubacterium_coprostanoligenes_group in the RS group and NK4A214_group in the FD group significantly increase. In the RS group, a correlation is found between the increase in microbial evenness and the improvement in retrospective memory. CONCLUSION: The FD and FD-RS have beneficial effects on memory in young adults. Meanwhile, FD and RS can improve the microbial evenness and increase several beneficial genera of phylum Firmicutes.

Elevated first-trimester hepcidin level is associated with reduced risk of iron deficiency anemia in late pregnancy: a prospective cohort study.

Background: Iron deficiency (ID) and iron deficiency anemia (IDA) during pregnancy are highly prevalent worldwide. Hepcidin is considered an important biomarker of iron status. Currently, few longitudinal cohort studies have assessed the potential causal relationship between hepcidin and ID/IDA. Therefore, we aimed to investigate the association of first-trimester maternal serum hepcidin with third-trimester ID/IDA risk in a prospective cohort. Methods: Total of 353 non-ID/IDA pregnant women at 11-13 weeks' gestation were enrolled in Southern China and followed up to 38 weeks of gestation. Data on demography and anthropometry were obtained from a structured questionnaire at enrollment. Iron biomarkers including hepcidin were measured at enrollment and follow-up. Regression models were used to evaluate the association of first-trimester hepcidin with third-trimester ID/IDA risk. Results: Serum hepcidin levels substantially decreased from 19.39 ng/mL in the first trimester to 1.32 ng/mL in the third trimester. Incidences of third-trimester ID and IDA were 46.2 and 11.4%, respectively. Moreover, moderate and high levels of first-trimester hepcidin were positively related to third-trimester hepcidin (log-transformed ß = 0.51; 95% CI = 0.01, 1.00 and log-transformed ß = 0.66; 95% CI = 0.15, 1.17). Importantly, elevated first-trimester hepcidin was significantly associated with reduced risk of third-trimester IDA (OR = 0.38; 95% CI = 0.15, 0.99), but not with ID after adjustment with potential confounders. Conclusion: First-trimester hepcidin was negatively associated with IDA risk in late pregnancy, indicating higher first-trimester hepcidin level may predict reduced risk for developing IDA. Nonetheless, given the limited sample size, larger studies are still needed.

Tumor-Targeting Extracellular Vesicles Loaded with siS100A4 for Suppressing Postoperative Breast Cancer Metastasis.

Introduction: S100A4 promotes the establishment of tumor microenvironment for malignant cancer cells, and knockdown of S100A4 can inhibit tumorigenesis. However, there is no efficient way to target S100A4 in metastatic tumor tissues. Here, we investigated the role of siS100A4-loaded iRGD-modified extracellular vesicles (siS100A4-iRGD-EVs) in postoperative breast cancer metastasis. Methods: siS100A4-iRGD-EVs nanoparticles were engineered and analyzed using TEM and DLS. siRNA protection, cellular uptake, and cytotoxicity of EV nanoparticles were examined in vitro. Postoperative lung metastasis mouse model was created to investigate the tissue distribution and anti-metastasis roles of nanoparticles in vivo. Results: siS100A4-iRGD-EVs protected siRNA from RNase degradation, enhanced the cellular uptake and compatibility in vitro. Strikingly, iRGD-modified EVs significantly increased tumor organotropism and siRNA accumulation in lung PMNs compared to siS100A4-EVs in vivo. Moreover, siS100A4-iRGD-EVs treatment remarkedly attenuated lung metastases from breast cancer and increased survival rate of mice through suppressing S100A4 expression in lung. Conclusions: siS100A4-iRGD-EVs nanoparticles show more potent anti-metastasis effect in postoperative breast cancer metastasis mouse model. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00757-5.

Single-cell and spatial transcriptome analyses revealed cell heterogeneity and immune environment alternations in metastatic axillary lymph nodes in breast cancer.

BACKGROUND: Tumor heterogeneity plays essential roles in developing cancer therapies, including therapies for breast cancer (BC). In addition, it is also very important to understand the relationships between tumor microenvironments and the systematic immune environment. METHODS: Here, we performed single-cell, VDJ sequencing and spatial transcriptome analyses on tumor and adjacent normal tissue as well as axillar lymph nodes (LNs) and peripheral blood mononuclear cells (PBMCs) from 8 BC patients. RESULTS: We found that myeloid cells exhibited environment-dependent plasticity, where a group of macrophages with both M1 and M2 signatures possessed high tumor specificity spatially and was associated with worse patient survival. Cytotoxic T cells in tumor sites evolved in a separate path from those in the circulatory system. T cell receptor (TCR) repertoires in metastatic LNs showed significant higher consistency with TCRs in tumor than those in nonmetastatic LNs and PBMCs, suggesting the existence of common neo-antigens across metastatic LNs and primary tumor cites. In addition, the immune environment in metastatic LNs had transformed into a tumor-like status, where pro-inflammatory macrophages and exhausted T cells were upregulated, accompanied by a decrease in B cells and neutrophils. Finally, cell interactions showed that cancer-associated fibroblasts (CAFs) contributed most to shaping the immune-suppressive microenvironment, while CD8+ cells were the most signal-responsive cells. CONCLUSIONS: This study revealed the cell structures of both micro- and macroenvironments, revealed how different cells diverged in related contexts as well as their prognostic capacities, and displayed a landscape of cell interactions with spatial information.

Circular RNAs in breast cancer diagnosis, treatment and prognosis.

Breast cancer has surpassed lung cancer to become the most common malignancy worldwide. The incidence rate and mortality rate of breast cancer continue to rise, which leads to a great burden on public health. Circular RNAs (circRNAs), a new class of noncoding RNAs (ncRNAs), have been recognized as important oncogenes or suppressors in regulating cancer initiation and progression. In breast cancer, circRNAs have significant roles in tumorigenesis, recurrence and multidrug resistance that are mediated by various mechanisms. Therefore, circRNAs may serve as promising targets of therapeutic strategies for breast cancer management. This study reviews the most recent studies about the biosynthesis and characteristics of circRNAs in diagnosis, treatment and prognosis evaluation, as well as the value of circRNAs in clinical applications as biomarkers or therapeutic targets in breast cancer. Understanding the mechanisms by which circRNAs function could help transform basic research into clinical applications and facilitate the development of novel circRNA-based therapeutic strategies for breast cancer treatment.

Multivariable Models Based on Baseline Imaging Features and Clinicopathological Characteristics to Predict Breast Pathologic Response after Neoadjuvant Chemotherapy in Patients with Breast Cancer.

Introduction: Currently, the accurate evaluation and prediction of response to neoadjuvant chemotherapy (NAC) remains a great challenge. We developed several multivariate models based on baseline imaging features and clinicopathological characteristics to predict the breast pathologic complete response (pCR). Methods: We retrospectively collected clinicopathological and imaging data of patients who received NAC and subsequent surgery for breast cancer at our hospital from June 2014 till September 2020. We used mammography, ultrasound, and magnetic resonance imaging (MRI) to investigate the breast tumors at baseline. Results: A total of 308 patients were included and 111 patients achieved pCR. The HER-2 status and Ki-67 index were significant factors for pCR on univariate analysis and in all multivariate models. Among the prediction models in this study, the ultrasound plus MRI model performed best, producing an area under curve of 0.801 (95% CI 0.749-0.852), a sensitivity of 0.797, and a specificity of 0.676. Conclusion: Among the multivariable models constructed in this study, the ultrasound plus MRI model performed best in predicting the probability of pCR after NAC. Further validation is required before it is generalized.

circ_0041732 Promotes Breast Cancer Progression.

Breast cancer is quite a prevalent cancer worldwide, and it is the leading cause of cancer-related deaths among female populations worldwide. Increasingly more efforts have been made in exploration of circular RNA functions in various malignancies. In this study, the primary target was to verify the putative influences of circ_0041732 on breast cancer progression and the corresponding regulatory mechanism. In addition to measurement of RNAs and proteins, functional assays were done to examine the changes in cell proliferation and cell cycle, and the potential association among genes was investigated by mechanism assays. According to experimental results, significant upregulation of circ_0041732 was confirmed in breast cancer tissues and cell lines. E2F4 was proved to transcriptionally modulate circ_0041732. Moreover, circ_0041732 was validated to accelerate breast cancer cell proliferation and impede G2-M arrest and cell apoptosis, and the oncogenic role of circ_0041732 in breast cancer was further verified via in vivo experiments. circ_0041732 could sponge miR-541-3p to enhance expression levels of RelA and GLI4, thus activating NFκB and Hedgehog pathways and affecting breast cancer cell proliferation, cell cycle, and apoptosis. In all, E2F4-mediated circ_0041732 could activate RelA/NFκB and GLI4/Hedgehog signaling pathways via modulation on miR-541-3p/RelA/GLI4 to promote breast cancer progression. IMPLICATIONS: E2F4-mediated circ_0041732 upregulation resulted in the activation of NFκB and Hedgehog pathways via sponging miR-541-3p and enhancing expression levels of RelA and GLI4, thus affecting breast cancer cell proliferation, cell cycle, and cell apoptosis.

Research on DCE-MRI Images Based on Deep Transfer Learning in Breast Cancer Adjuvant Curative Effect Prediction.

Breast cancer is a serious threat to women's physical and mental health. In recent years, its incidence has been on the rise and it has become the top female malignant tumor in China. At present, adjuvant chemotherapy for breast cancer has become the standard mode of breast cancer treatment, but the response results usually need to be completed after the implementation of adjuvant chemotherapy, and the optimization of the treatment plan and the implementation of breast-conserving therapy need to be based on accurate estimation of the pathological response. Therefore, to predict the efficacy of adjuvant chemotherapy for breast cancer patients is to find a predictive method that is conducive to individualized choice of chemotherapy regimens. This article introduces the research of DCE-MRI images based on deep transfer learning in breast cancer adjuvant curative effect prediction. Deep transfer learning algorithms are used to process images, and then, the features of breast cancer after adjuvant chemotherapy are collected through image feature collection. Predictions are made, and the research results show that the accuracy of the prediction reaches 70%.

Melatonin inhibits triple-negative breast cancer progression through the Lnc049808-FUNDC1 pathway.

Melatonin has been reported to have tumor-suppressive effects via comprehensive molecular mechanisms, and long non-coding RNAs (lncRNAs) may participate in this process. However, the mechanism by which melatonin affects the function of lncRNAs in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is still unknown. Therefore, we aimed to investigate the differentially expressed mRNAs and lncRNAs in melatonin-treated TNBC cells and the interaction mechanisms. Microarray analyses were performed to identify differentially expressed mRNAs and lncRNAs in TNBC cell lines after melatonin treatment. To explore the functions and underlying mechanisms of the mRNAs and lncRNAs candidates, a series of in vitro experiments were conducted, including CCK-8, Transwell, colony formation, luciferase reporter gene, and RNA immunoprecipitation (RIP) assays, and mouse xenograft models were established. We found that after melatonin treatment, FUNDC1 and lnc049808 downregulated in TNBC cell lines. Knockdown of FUNDC1 and lnc049808 inhibited TNBC cell proliferation, invasion, and metastasis. Moreover, lnc049808 and FUNDC1 acted as competing endogenous RNAs (ceRNAs) for binding to miR-101. These findings indicated that melatonin inhibited TNBC progression through the lnc049808-FUNDC1 pathway and melatonin could be used as a potential therapeutic agent for TNBC.

Treatment and Outcome of 341 Papillary Breast Lesions.

BACKGROUND: Papillary breast lesions constitute a pathological heterogeneous group and display diverse clinical and imaging features. This study was conducted to analyze the upgrade rate of intraductal papilloma diagnosed on core needle biopsy and to assess the possible risk factors associated with upgrade to higher-risk lesions. We also examined the long-term outcomes in patients who received resection of the papillary lesions. MATERIALS AND METHODS: The clinical and pathology records of 324 female patients who were diagnosed with papillary lesions based on core needle biopsy (CNB) from February 2010 to October 2016 at our institution were retrospectively analyzed. Patients were grouped by initial diagnosis into two groups (papilloma with or without atypia) and followed-up for long-term outcomes. For the upgrade to higher-risk lesions after excision, upgraded lesions were compared with benign papillomas for the collected variables. RESULTS: A total of 341 lesions were included for final analysis, and all were available for follow-up. Papillomas with or without atypia diagnosed by CNB were found in 9 and 332 lesions, respectively. Papillomas without atypia on CNB were treated by open excision (n = 265) or vacuum-assisted biopsy (VAB) (n = 67), which yielded similar event-free rate (p = 0.19). The upgrade rate of this group to higher-risk lesions was 9.9%. Peripheral (p = 0.011) lesions in postmenopausal (p = 0.001) or older (p = 0.001) patients with papillomas without atypia based on CNB showed significantly higher upgrade rates. Papillomas with atypia on CNB were all managed by open excision, and concurrent malignancy was found in two lesions. CONCLUSION: In conclusion, our results support benign papillary lesions based on CNB require further treatment. Peripheral lesions occurring in older or postmenopausal women are at higher risk for upgrade.

BCL11A enhances stemness and promotes progression by activating Wnt/ß-catenin signaling in breast cancer.

Background: Breast cancer has become the most common malignant disease threatening women's health. The cancer stem cell (CSC) has been recognized as a small subpopulation of cancer cells possesses stem cell properties, which is crucial in tumorigenicity, tumor invasion, drug resistance, and metastasis. The BCL11A plays a crucial role in breast cancer progression. To investigate the effect of BCL11A, a functional oncogene, we focused on its maintenance ability of stemness in breast cancer stem cells. Methods: We assessed the BCL11A expression level in tumor and non-tumor tissues using RT-qPCR and IHC. We subsequently established BCL11A-modulating breast cancer cell lines MDA-MB-231 and MCF-7. CCK8, colony formation assays, and xenograft model were used to determine the effect of BCL11A on tumorigenicity. Transwell assay and lung metastasis model in vivo were conducted to validate its function in metastasis. Its effect on stemness was assessed by flow cytometry and mammosphere formation. Western blot further characterized the importance of Wnt/ß-catenin signaling in BCL11A-regulated cancer cell stemness. Results: A higher level of BCL11A was detected in clinical breast cancer samples. BCL11A promoted tumor formation, cancer cell mobility, spheroid forming, and epithelial-mesenchymal transition by activating the Wnt/ß-catenin signaling. In addition, BCL11A was associated with lung metastasis and increased the breast cancer cells stemness. BCL11A high expression (BCL11Ahigh) cancer cells exhibited stem cell-like properties compared with BCL11Alow cells, including a higher percentage of CD24low/CD44high subpopulation, self-renewal spheroids formation, and higher tumorigenicity. Our studies demonstrated that the Wnt/ß-catenin signaling activated by BCL11A plays a potential role in the initiation of the renewal of breast cancer stem cells. Conclusions: BCL11A not only functions in breast cancer carcinogenesis but also enhanced the stemness of breast cancer through activating Wnt/ß-catenin signaling, and may become a potential target for breast cancer treatment.

Clinical characteristics and prognosis of patients with lung adenosquamous carcinoma after surgical resection: results from two institutes.

BACKGROUND: Adenosquamous carcinoma (ASC) is a mixed glandular and squamous cell carcinoma (SCC) with more aggressive behavior than the other histologic subtypes of lung cancer. We aim to evaluate the prognosis of patients with ASC after surgical resection. METHODS: We reviewed records of patients who underwent surgical resection for lung cancer in two institutes between January 2010 and December 2015. Survival data were collected with a median follow-up of 59 (range from 10 to 85) months. Kaplan-Meier survival curve was determined for all patients. RESULTS: Patients with ASC accounted for 1.6% of all NSCLC patients (33 males, 25 females). The cumulative postoperative 3- and 5-year survival rates were 56% and 48%, respectively. Overall survival (OS) was significantly lower in ASC patients than in adenocarcinoma (AC) patients operated during the same period (P<0.01). Patients with ASC containing acinar predominant AC had better survival than those with non-acinar predominant ASC (P=0.03). No difference of OS was found in patients with or without visceral pleural invasion (VPI), vascular invasion (VI) or EGFR mutation status. Multivariate analysis showed gender, pathological subtype, and TNM staging to be independent prognostic factors. CONCLUSIONS: We demonstrated that ASC were uncommon and aggressive lung tumors. Predominant histological subtype of AC might be an independent prognostic factor for ASC. Further prospective studies are warranted to clarify the characteristics of this rare tumor.

[Single-port video-assisted thoracoscopic surgery for pulmonary diseases: analysis of 158 cases].

OBJECTIVE: To assess the clinical value of single-port video-assisted thoracoscopic surgery (VATS) for treatment of pulmonary diseases. METHODS: From October, 2009 to December, 2013, 105 patients with pulmonary diseases were scheduled for single-pore VATS for pulmonary lobectomy (19 patients), wedge resection of the lung (34 patients), and bullae resection and pleurodesis for spontaneous pneumothorax or pulmonary bleb (52 patients). RESULTS: Of the 105 patients, 101 patients underwent single-port VATS; the procedure was converted to open thoracotomy in 1 patient and to conventional three-port VATS in 2 patients. The operative time was 50.6∓36.8 min (20-200 min) with intraoperative blood loss of 70∓56.9 ml (10-300 ml), thoracic drainage time of 4.2∓3.2 days (2-14 days), and postoperative hospital stay of 5.4∓3.8 days (3-16 days). Postoperative complications of the procedures included prolonged air leakage (6 cases) and atelectasis (2 cases). All the other patients recovered smoothly without serious complications. CONCLUSION: Single-port VATS is a safe and efficient procedure that allows rapid postoperative recovery and is a method of choice for selected patients with pulmonary diseases.

[Intercostal video-mediastinoscopy: a report of 701 cases].

OBJECTIVE: To summarize the experience of intercostal video-mediastinoscopy (VMS) in treatment for mediastinal masses, malignant pleural effusion and palmar hyperhidrosis. METHODS: The clinical data of 701 patients received intercostal VMS from November 2001 to June 2007 were summarized retrospectively. Forty-eight patients with mediastinal masses and 46 patients with suspected malignant pleural effusion underwent intercostal VMS pleural biopsy (39 cases with talc pleurodesis) and 607 patients with palmar hyperhidrosis underwent bilateral intercostals VMS thoracic sympathectomy. RESULTS: No mortality and morbidity were reported in this group. Definitive pathologic diagnosis had been made through VMS mediastinal masses biopsy in mediastinal masses and pleural biopsy in pleura effusion. The efficiency of talc pleurodesis was 100% for 39 cases. The symptoms of sweating of hands in 607 patients with palmar hyperhidrosis disappeared completely, all patients' hands became dry with a 1.5 degrees C to 3.0 degrees C increase of the skin temperature immediately after operation. No recurrence occurred during the follow-up. CONCLUSION: VMS is a simple, convenient and alternative procedure for the treatment of mediastinal masses, malignant pleural effusion and palmar hyperhidrosis.