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Background: The renin-angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth.Methods: We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs).Results: Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis.Conclusions: The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis. [ABSTRACT FROM AUTHOR]

In order to establish a new echocardiographic index of the severity of mitral stenosis, left ventricular echocardiograms were digitised using manual tracing and a computer. The instantaneous left ventricular dimension was measured in 15 patients with mitral stenosis. The peak rate of change of left ventricular dimension (peak dD/dt) and the normalised peak rate (peak dD/dt/D) during early diastole were significantly lower in mitral stenosis than in normal subjects. Also, the time between the second heart sound and peak dD/dt was significantly shorter in patients with mitral stenosis than in normal subjects. Correlation between the mitral valve area calculated from the Gorlin formula and peak dD/dt/D was good, while valve area was poorly correlated with the EF slope of the anterior mitral leaflet echo. It is suggested that by continuous measurement of left ventricular dimension and of its first derivative, the reduced atrioventricular blood flow in mitral stenosis can be shown, and that peak dD/dt/D during early diastole is a possible index of its severity. [ABSTRACT FROM PUBLISHER]

We present a unique case of metastatic metaplastic breast carcinoma responding dramatically to immunochemotherapy. A 46-year-old Japanese woman with primary metaplastic carcinoma of the breast, which was immunohistochemically confirmed to be triple-negative breast cancer, underwent radical surgery, followed by adjuvant chemotherapy with an anthracycline and a taxane. Since multiple lung metastases were detected two months post-chemotherapy and the primary site was shown to be PD-L1-positive, the immune checkpoint inhibitor (ICI) pembrolizumab plus gemcitabine/carboplatin was initiated. While the treatment was discontinued after 15 days due to suspected drug-induced pneumonitis, the lung metastases significantly shrank with no development of new lesions for three months. The patient remained alive as of approximately 15 months after the recurrence date. This case highlights the potential of immunochemotherapy in treating metaplastic breast carcinomas., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare malignancy. Many cases of BIA-ALCL are identified based on the presence of late-onset effusion and/or masses. Importantly, the United States Food and Drug Administration noted that in all cases diagnosed in patients with textured implants, the patients either had a history of mixed implantation of smooth and textured devices or no clinical history was supplied for review. In Japan, the first case of BIA-ALCL was reported in 2019, and we encountered the third case in Japan in December 2021. There have been a total of five cases of BIA-ALCL previously reported at Japanese academic conferences (Japan Oncoplastic Breast Surgery Society. http://jopbs.umin.jp/medical/index.html ), of which only the first case has been published. Unlike the first case, this patient had clinical features that were highly suggestive of the postoperative chest wall recurrence of breast cancer, with a mass and rash on the skin., Case Presentation: The patient was a 45-year-old woman who had undergone breast reconstruction after breast cancer surgery of the right breast 8 years previously. The patient presented with a mass and skin rash inside the inframammary area, and we suspected a damaged silicone breast implant (SBI) or chest wall recurrence. We examined the mass by a core needle biopsy and made a pathological diagnosis of BIA-ALCL. Imaging findings suggested internal thoracic lymph node swelling and lymphoma infiltration beyond the capsule but no metastatic lesions (cStage III). After en bloc resection of the SBI and lymphoma, adjuvant systemic therapy was performed., Conclusion: We encountered the third case of BIA-ALCL in Japan. This was a case with clinically advanced stage of disease; however, the BIA-ALCL was found to be in remission., (© 2024. The Author(s).)

Mucoepidermoid carcinoma is the most prevalent malignancy in the salivary gland and is sporadic in the breast. Here, we report a case of breast mucoepidermoid carcinoma with a rare CREB-regulated transcription coactivator 3-mastermind-like transcriptional coactivator 2 ( CRTC3-MAML2 ) fusion. A 23-year-old female was admitted to our hospital with a left breast palpable mass. Histologic findings of the core-needle biopsy indicated breast cancer. The section revealed a squamoid tumor-cell proliferation with enlarged nuclei and eosinophilic cytoplasm among smaller intermediate cells and abundant cystic spaces containing secretory materials. The features were compatible with mucoepidermoid carcinoma in low-grade, confirmed by detecting the CRTC3-MAML2 fusion using reverse transcription polymerase chain reaction and direct sequencing. We only administered tamoxifen postoperatively without other adjuvant therapy because her tumor partially expressed hormonal receptors. No signs indicate a recurrence or metastasis in our over 3 year follow-up. The genetic analysis helps in definitively diagnosing breast mucoepidermoid carcinoma, and the treatment strategy should be considered based on the histologic findings., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs., Methods and Results: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models., Conclusion: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: Osteopenia, the loss of bone mineral density (BMD), was recently reported as a prognostic factor in various cancers. However, the prognostic significance of preoperative osteopenia in breast cancer remains unclear. This study aimed to clarify the clinical significance of preoperative osteopenia in breast cancer., Patients and Methods: We retrospectively analyzed the relationship between osteopenia and clinical factors and prognosis in 532 patients with pathological Stage I-III primary breast cancer between 2009 and 2017. Osteopenia was assessed by measuring the average pixel density (Hounsfield unit) in the midvertebral core of the 11 th thoracic vertebra on enhanced preoperative computed tomography., Results: Osteopenia was diagnosed in 186 (35.0%) patients. The recurrence-free survival (RFS) rate was significantly worse in the osteopenia group than in the non-osteopenia group (p=0.0275), but there was no significant difference in overall survival (OS) between the two groups. When evaluated by menopausal status, RFS and OS were significantly worse in the osteopenia group than in the non-osteopenia group (p=0.0094 and p=0.0264, respectively) in premenopausal patients. However, there were no significant differences in RFS and OS between the two groups among postmenopausal patients. In premenopausal patients, osteopenia was an independent prognostic factor for RFS in a multivariate analysis (p=0.0266)., Conclusion: Preoperative osteopenia was independently associated with recurrence of breast cancer., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a marker of systemic inflammation with a prognostic impact in patients with various cancers, including breast cancer. The aim of this study was to investigate the relationships between the preoperative NLR and breast cancer prognosis in the patients before and after menopausal age, and its relationship with other prognostic factors., Methods: A total of 1868 patients with clinical Stage I-III primary breast cancer were enrolled. The associations between clinicopathological factors and the preoperative NLR were analyzed, and relapse-free survival (RFS) and overall survival (OS) were estimated., Results: Statistical analyses stratified by the menopausal status revealed that a high NLR was significantly associated with worse RFS (P < 0.001) and OS (P = 0.001) in postmenopausal patients, but not in premenopausal patients. Although the postmenopausal patients with relapsed cancer tended to have higher NLR levels than those without relapse (P = 0.079), NLR levels of premenopausal patients with relapsed cancer were significantly lower than that of relapse-free patients (P = 0.024). In postmenopausal patients, a high NLR was only associated with worse RFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (P < 0.001), in those managed without adjuvant chemotherapy (P = 0.003); this association was not observed in patients who received adjuvant chemotherapy., Conclusions: The preoperative NLR can be a useful prognostic marker, especially in postmenopausal breast cancer patients. The relationships between the NLR and breast cancer prognosis may be more evident when patients are assessed according to their menopausal status., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Tramadol, a weak opioid anesthetic, is used for pain management in patients with cancer, but the effects of tramadol on cancer via µ-opioid receptor are still unknown. We assessed the effects of tramadol on pancreatic ductal adenocarcinoma using transgenic mice ( LSL-Kras G12D/+ ; Trp53 flox/flox ; Pdx-1 cre/+ )., Methods: Six-week-old transgenic mice were orally administered 10 mg/kg/day tramadol (n=12), 10 mg/kg/day tramadol and 1 mg/kg/day naltrexone (n=9), or vehicle water (n=14) until the humane endpoint. Cancer-related pain and plasma cytokine levels were assessed by the mouse grimace scale and cytokine array, respectively. Tumor status was determined histopathologically. Tramadol's effects on proliferation and invasion in pancreatic ductal adenocarcinoma cell lines were studied in vitro., Results: Tramadol with/without naltrexone improved mouse grimace scale scores while decreasing inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. Proliferative Ki-67 and cyclins decreased by tramadol, while local M1-like tumor-associated macrophages increased by tramadol, which was blocked by naltrexone. Meanwhile, tramadol with/without naltrexone reduced juxta-tumoral cancer-associated fibroblasts and M2-like tumor-associated macrophages. Tumor-associated neutrophils, natural killers, and cytotoxic T cells were not altered. Tramadol decreased the proliferative and invasive potentials of pancreatic ductal adenocarcinoma cell lines via decreasing cyclins/cyclin-dependent kinases, which was partially reversed by naltrexone., Conclusions: These findings imply that tramadol might be a useful anesthetic for pancreatic ductal adenocarcinoma: inhibiting the proliferation and invasion along with increasing antitumor M1-like tumor-associated macrophages via the µ-opioid receptor, while improving cancer-associated pain possibly through the antitumor effects with the decrease of inflammatory cytokines., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The local renin-angiotensin system promotes angiogenesis and proliferation via vascular endothelial growth factor or epidermal growth factor receptor expression. In this study, we aimed to evaluate the impact of angiotensin system inhibitors (ASIs) on long-term outcomes in patients undergoing surgical resection of pancreatic ductal adenocarcinoma (PDAC)., Methods: A single institutional retrospective analysis was performed using the medical records of patients who underwent pancreatic resection with curative intent for PDAC between January 2005 and December 2018. Patient characteristics and surgical outcomes were compared between patients taking ASIs and those who are not., Results: A total of 272 patients were included in the study and classified into the ASI group (n = 121) and the non-ASI group (n = 151). The median overall survival times in the ASI group and non-ASI group were 38.0 and 34.0 months ( P = 0.250), and the median recurrence-free survival times were 24.0 and 15.0 months ( P = 0.025), respectively. Multivariate analysis for recurrence-free survival identified the use of ASIs ( P = 0.020), CA19-9 level >500 IU/L ( P = 0.010), positive lymph node metastasis ( P < 0.001), and no adjuvant chemotherapy ( P < 0.001) as independent prognostic factors., Conclusions: The use of ASI may improve long-term outcomes after surgery for PDAC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To investigate the efficacy of virtual monochromatic spectral computed tomography imaging (VMI) in the preoperative evaluation for intraductal spread of breast cancer., Materials and Methods: Twenty-four women who underwent spectral CT and were pathologically diagnosed with ductal carcinoma with a ≥ 2-cm noninvasive component were retrospectively enrolled in Group 1. Twenty-two women with 22 lesions pathologically diagnosed with ductal carcinoma in situ or microinvasive carcinoma were enrolled in Group 2. We compared the contrast-to-noise ratios (CNRs) of the lesions on conventional 120-kVp CT images and 40-keV VMIs in Group 1. Two board-certified radiologists measured the maximum diameters of enhancing areas on 120-kVp CT, 40-keV VMI, and MRI in Group 2 and compared with histopathological sizes., Results: The quantitative assessment of Group 1 revealed that the mean ± SD of the CNRs in the 40-keV images were significantly greater than those in the 120-kVp images (5.5 ± 1.9 vs. 3.6 ± 1.5, p < 0.0001). The quantitative assessment of Group 2 demonstrated that the lesion size observed in the conventional 120-kVp CT images by both readers was significantly underestimated as compared to the histopathological size (p = 0.017, 0.048), whereas both readers identified no significant differences between the lesion size measured on 40-keV VMI and the histopathological data. In a comparison with MRI, 40-keV VMI provided measurement within a 10-mm error range in more lesions as compared to the conventional 120-kVp CT., Conclusion: VMI improves the evaluation of intraductal spread and is useful for the preoperative evaluations of breast cancer., (© 2023. The Author(s).)

Background & Aims: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation., Methods: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders., Results: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively., Conclusions: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Abstract: Mirogabalin, a selective voltage-gated calcium channel α2δ ligand, improves peripheral neuropathic pain; however, its effects on patients with cancers including pancreatic ductal adenocarcinoma (PDAC) remain unknown. We analyzed the effects of mirogabalin on a KPPC ( LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+ ) mouse model of PDAC. Six-week-old KPPC mice received oral mirogabalin (10 mg/kg/day) (n = 10) or vehicle water (n = 14) until the humane end point. Cancer-associated pain was evaluated using the scores of hunching and mouse grimace scale (MGS). Tumor status and plasma cytokine levels were determined using histopathological analysis and cytokine array, respectively. The effects of mirogabalin on the proliferative ability of PDAC cell lines were determined. The scores of the hunching and MGS improved after mirogabalin administration with a decrease in the plasma levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interferon-γ. Although no significant difference in the survival rate was observed, mirogabalin significantly increased pancreatic tumor size and proliferative index of Ki-67 and cyclins. Local arginase-1 + M2-like tumor-associated macrophages and CD31 + tumor blood vessels increased after mirogabalin administration. By contrast, the number of α-smooth muscle actin + cancer-associated fibroblasts, desmoplastic stroma, and CD8 + T cells decreased. Local myeloperoxidase + tumor-associated neutrophils and CD45R + B cells were unaltered. Mirogabalin enhanced the proliferative ability of PDAC cell lines with the upregulation of cyclins and cyclin-dependent kinases; however, it inhibited the potential of pancreatic stellate cells in vitro. Therefore, our results suggest that mirogabalin improves cancer-associated pain but enhances the proliferative potential of PDAC in vitro and in vivo., (Copyright © 2023 International Association for the Study of Pain.)

Background/aim: Tumour lysis syndrome (TLS) is a life-threatening oncological emergency. TLS is rare and associated with a higher mortality rate in solid tumours than in haematological malignancies. Our case report and literature review aimed to identify the distinctive features and hazards of TLS in breast cancer., Case Report: A 41-year-old woman complained of vomiting and epigastric pain and was diagnosed with HER2-positive, hormone-receptor-positive breast cancer with multiple liver and bone metastases and lymphangitis carcinomatosis. She had several risk factors for TLS: high tumour volume, high sensitivity to antineoplastic treatment, multiple liver metastases, high lactate dehydrogenase levels, and hyperuricaemia. To prevent TLS, she was treated with hydration and febuxostat. One day after the first course of trastuzumab and pertuzumab, she was diagnosed with disseminated intravascular coagulation (DIC). After 3 further days of observation, she was relieved of DIC and administered a reduced dose of paclitaxel without life-threatening complications. The patient achieved a partial response after four cycles of anti-HER2 therapy and chemotherapy., Conclusion: TLS in solid tumours is a lethal situation and can be complicated by DIC. Early recognition of patients who are at risk of TLS and initiation of therapy is essential to avoid fatal situations., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)