Metformin Alters Tumor Immune Microenvironment, Improving the Outcomes of Breast Cancer Patients With Type 2 Diabetes Mellitus.

This study investigated the clinical effect of metformin on breast cancer patients with preexisting type 2 diabetes mellitus (T2DM). We analyzed 177 patients with T2DM who underwent breast cancer surgery and assessed tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) in patients who underwent tumor resection with or without metformin treatment using multiplex immunohistochemistry (IHC). Patients who received metformin either pre- or postoperatively exhibited reduced distant organ recurrence and improved postoperative recurrence-free survival compared to those of patients who did not. Additionally, in a subgroup of 40 patients receiving preoperative systemic therapy, metformin treatment was associated with increased rates of pathological complete response. IHC analysis revealed significantly lower levels of cluster of differentiation (CD) 68(+) CD163(+) M2-type TAMs (p < 0.01) but higher CD3(+) and CD8(+) TIL densities in the metformin-treated group compared with the same parameters in those without metformin treatment, with a significant difference in the CD8(+)/CD3(+) TIL ratio (p < 0.01). Despite the constraints posed by our small sample size, our findings suggest a potential role for metformin in modulating the immunological microenvironment, which may contribute to improved outcomes in diabetes patients with breast cancer.

Efficacy and safety of surgical energy devices for axillary node dissection: a systematic review and network meta-analysis.

Various surgical energy devices are used for axillary lymph-node dissection. However, those that reduce seroma during axillary lymph-node dissection are unknown. We aimed to determine the best surgical energy device for reducing seroma by performing a network meta-analysis to synthesize the current evidence on the effectiveness of surgical energy devices for axillary node dissection for breast cancer patients. We searched MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform Search Portal. Two reviewers independently selected randomized controlled trials (RCTs) comparing electrosurgical bipolar vessel sealing (EBVS), ultrasonic coagulation shears (UCS), and conventional techniques for axillary node dissection. Primary outcomes were seroma, drained fluid volume (mL), and drainage duration (days). We analyzed random-effects and Bayesian network meta-analyses. We evaluated the confidence of each outcome using the CINeMA tool. We registered with PROSPERO (CRD42022335434). We included 34 RCTs with 2916 participants. Compared to the conventional techniques, UCS likely reduces seroma (risk ratio [RR], 0.61; 95% credible interval [CrI], 0.49-0.73), the drained fluid volume (mean difference [MD], - 313 mL; 95% CrI - 496 to - 130), and drainage duration (MD - 1.79 days; 95% CrI - 2.91 to - 0.66). EBVS might have little effect on seroma, the drained fluid volume, and drainage duration compared to conventional techniques. UCS likely reduce seroma (RR 0.44; 95% CrI 0.28-0.69) compared to EBVS. Confidence levels were low to moderate. In conclusion, UCS are likely the best surgical energy device for seroma reduction during axillary node dissection for breast cancer patients.

[Long-Term Survival of a Patient with Triple-Negative Breast Cancer with Hormone Receptor Status Conversion between Primary and Metastatic Tumors].

Patients with triple-negative breast cancer have poor survival after recurrence. However, previous studies have shown that receptor conversion can occur between primary breast tumor and metastatic sites. Herein, we describe the case of a 54- year-old woman with advanced breast cancer, which showed receptor conversion from primary tumor(triple-negative)to distant metastases(Luminal type). The patient had undergone left radical mastectomy and left axillary lymph node dissection at another hospital(pT3N0M0, Stage ⅡB, ER-negative, PgR-negative, and HER2-negative). She was referred to our hospital for adjuvant chemotherapy with 3 courses of 5-fluorouracil, epirubicin, and cyclophosphamide and 3 courses of docetaxel. Around 26 months after the surgery, the follow-up CT scan showed multiple lung nodules. Another 9 months later, her left axillary and mediastinal lymph nodes were enlarged. She received several courses of anticancer chemotherapy. After paclitaxel and bevacizumab were administered as seventh-line chemotherapy, a vacuum-assisted biopsy of the left axillary lymph node was performed to confirm the presence of metastasis. Furthermore, immunohistochemistry results showed that the metastatic tumor was ER-positive, PgR-positive, and HER2-negative. Fulvestrant and palbociclib were then initiated as first-line endocrine therapy. She has been stable for more than 18 months since. It is essential to perform biopsies of metastatic sites for optimal management of patients with metastatic breast cancer.

Breast tuberculosis presenting with intractable mastitis: a case report.

BACKGROUND: Breast tuberculosis, also known as tuberculous mastitis, is an extremely rare form of tuberculosis. It accounts for <0.1% of all breast diseases and <2% of all cases of tuberculosis. It is often misdiagnosed as breast cancer, which can potentially lead to a delayed diagnosis. CASE PRESENTATION: A 69-year-old Japanese woman presented with a tumor-mimicking lesion in her right breast, followed by intractable mastitis with a fistula formation. The time until the correct diagnosis of tuberculosis of the breast and sternal bone was 14 months. CONCLUSIONS: Although rare, it is important to recognize that tuberculous mastitis can present as refractory abscesses/mastitis or mass lesions that mimic carcinomas in women of reproductive age and elderly people. Breast tuberculosis should always be considered in the differential diagnoses, particularly in patients with a history of tuberculosis and those living in areas where tuberculosis is endemic.

Neoadjuvant chemotherapy for primary sarcoma of the breast: a case report.

BACKGROUND: Primary sarcoma of the breast is rare. Surgery has been the only curative treatment available. Recently, neoadjuvant chemotherapy including anthracycline/ifosfamide has been reported effective for patients with high-risk sarcomas in a prospective trial. CASE PRESENTATION: A 52-year-old Japanese woman presented with a mass in her left breast. The 10 cm tumor was fixed to her chest wall on examination. A skin biopsy was performed which showed leiomyosarcoma. Neoadjuvant chemotherapy was given and the tumor became mobile. A mastectomy and axillary dissection were performed with surgically negative margins. After neoadjuvant chemotherapy, the amount of necrosis was profoundly influenced by chemotherapy, and the histological effect of neoadjuvant chemotherapy was assessed in reference to pre-neoadjuvant chemotherapy magnetic resonance imaging. CONCLUSION: In contrast to many other cancers, the evaluation of various treatments and of the histological effect of neoadjuvant chemotherapy for sarcoma has been difficult due to the rarity of these tumors. We report the case of a patient with a breast sarcoma, treated with neoadjuvant chemotherapy and discuss the appropriate pathological evaluation and therapeutic management.

Comparison between the antiemetic effects of palonosetron and granisetron in breast cancer patients treated with anthracycline-based regimens.

Chemotherapy-induced nausea and vomiting is a serious adverse side-effect of anthracycline-based chemotherapy regimens, in patients with breast cancer. A combination of three drugs, 5-hydroxytryptamine (5-HT3) receptor antagonist, aprepitant and dexamethasone, is recommended for antiemetic therapy. Palonosetron (PALO), a novel 5-HT3 receptor antagonist has been identified to be effective against delayed nausea and vomiting. In this study, the results of PALO for patients who received anthracycline-based chemotherapy were compared with that of granisetron (GRA) using a crossover study design. This study evaluated the efficacy of antiemetics in the first cycle of chemotherapy, as well as the second and third cycles. A total of 21 patients and 19 patients were assigned to PALO and GRA treatment groups during the first cycle of chemotherapy, respectively. The patients switched to the other antiemetic drug for the second chemotherapy cycle (PALO followed by GRA or GRA followed by PALO). The patients could select PALO or GRA antiemetics for the third cycle, according to their preference. A total of 21 patients selected PALO and 18 patients selected GRA in the third cycle, and one patient was withdrawn from the study as their third cycle questionnaire was not obtained. No significant differences between PALO and GRA were identified in first and second cycles. However, during the third cycle, a significant difference was observed in acute-phase complete control of emetic events between the PALO and GRA groups, which was defined as no emetic episode, no additional antiemetic treatment and no more than mild nausea, between PALO and GRA. These results demonstrated that changing antiemetics may affect the efficacy of antiemetics. This study indicates that alteration of antiemetic regimens, including drug combination and order, may improve the efficacy of antiemetic treatment.

High-sensitivity troponin T as a marker to predict cardiotoxicity in breast cancer patients with adjuvant trastuzumab therapy.

The humanized monoclonal antibody trastuzumab has been in routine use for chemotherapy for human epidermal growth factor receptor II (HER2)-positive breast cancer. A major adverse effect of trastuzumab is cardiotoxicity. Well-established biomarkers or echocardiographic parameters to predict trastuzumab-induced cardiotoxicity have not yet been determined. We attempted to identify useful biomarkers and/or echocardiographic parameters to predict trastuzumab-induced cardiotoxicity. We prospectively investigated the cases of 19 women who received chemotherapy including anthracyclines and trastuzumab for HER2-positive breast cancer. We measured cardiac biomarkers and echocardiographic parameters before their chemotherapy and every 3 months up to 15 months until the end of the adjuvant trastuzumab therapy. We divided the patients into two groups: group R was the nine patients who showed a reduction of left ventricular ejection fraction (LVEF) ≥5%, and group N was the 10 patients who showed a reduction of LVEF <5%. The high-sensitivity troponin T (hs-TnT) level at 6 months was significantly higher in group R than in group N (11.0 ± 7.8 pg/mL vs. 4.0 ± 1.4 pg/mL, p < 0.01). The hs-TnT level with a cutoff value of 5.5 pg/mL at 6 months had 78% sensitivity and 80% specificity for predicting a reduction of LVEF at 15 months. In our evaluation of echocardiographic parameters at baseline, the diastolic function was more impaired in group R than in group N. The hs-TnT and echocardiographic parameters of diastolic function could be useful to predict trastuzumab-induced cardiotoxicity.

Long-term oral polyamine intake increases blood polyamine concentrations.

Although the intracellular de novo synthesis of the polyamines decreases with age, there is no similar trend in blood polyamine levels, but rather there is wide individual variability. We hypothesized that dietary polyamines attenuate a decrease in blood polyamine levels with age and augment the previously observed individual variability. The effect of a polyamine rich diet, in both mice and humans, on blood polyamine concentrations was examined in this study. Jc1:ICR male mice were fed test diets containing 3 different polyamine concentrations. Healthy human male volunteers added 50 to 100 g of the polyamine-rich fermented soybean product, natto, to their daily intake. After 26 wk, the mean blood spermine concentration in mice receiving the test diet with high polyamine concentrations was 10.1+/-2.4 micromol/L, while the mean concentrations found in mice fed with a diet with normal or low polyamine concentrations were 5.2+/-0.9 and 4.7+/-0.5 micromol/L, respectively (p<0.05). A mean daily intake of 66.4+/-3.7 g (range=46.4-89.3 g) of natto for 2 mo by human volunteers increased the mean blood spermine concentration by a factor of 1.39 (n=10) (p<0.01), while in control volunteers (n=7), asked to exclude polyamine-rich foods from their diet, blood spermine concentration remained unchanged. The individual variability of blood polyamine levels was enhanced after polyamine intake in mice and, to a lesser extent, in humans. The long-term oral intake of enhanced polyamine diets increases blood polyamine levels in both mice and humans.

Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development.

CONTEXT: Natriuretic peptide receptor-B (NPR-B, GC-B in rodents; gene name NPR2) is a guanylyl cyclase-coupled receptor that mediates the effect of C-type natriuretic peptide. Homozygous mutations in human NPR-B cause acromesomelic dysplasia, type Maroteaux (OMIM 602875), an autosomal recessive skeletal dysplasia. NPR-B has an intracellular kinase homology domain (KHD), which has no kinase activity, and its functional significance in vivo is currently unknown. OBJECTIVE: We examined the functional significance of a novel NPR-B KHD mutation in humans. PATIENTS AND METHODS: A 28-yr-old Japanese male presented with marked short stature (118.5 cm, -9.3 sd). His limbs showed marked shortening in the middle and distal segments. His parents had relatively short stature with height z-scores of -2.75 and -0.98 (his father and mother, respectively). Direct sequencing of coding region of the NPR2 gene of the family was performed. The mutant receptor activity was investigated by saturation binding assay and cGMP measurement. Additionally, interaction between the mutant and wild type allele was investigated by the titration experiments. RESULTS: We identified a novel missense mutation L658F in KHD of NPR-B in homozygous and heterozygous states in the patient and his parents, respectively. The mutation conferred normal binding affinity for C-type natriuretic peptide but no discernible ligand-induced cGMP production. Furthermore, L658F mutant impaired wild-type NPR-B-mediated cGMP production in a dose-dependent manner, suggesting that short stature found in L658F heterozygote can be caused by its dominant-negative effect. CONCLUSIONS: This study provides the first evidence that intact KHD of NPR-B is essential for skeletal development.

Distribution of lymph node metastasis in T1 sigmoid colon carcinoma: should we ligate the inferior mesenteric artery?

OBJECTIVE: In standard oncological sigmoid colectomy, the inferior mesenteric artery is ligated either at its origin or at the level of the left colic artery. However, in patients with early-stage carcinoma, the distribution of metastatic nodes may be limited. The aim of this study was to clarify the prevalence and distribution of lymph node metastasis in T1 sigmoid colon carcinoma and to determine the adequate range of lymph node dissection. MATERIALS AND METHODS: The study included 121 consecutive patients treated for T1 sigmoid colon carcinoma. Clinicopathologic factors associated with nodal metastasis and the distribution of metastatic nodes were analyzed. RESULTS: Of 121 patients, 12 (10%) had nodal involvement. The depth of invasion and the presence of lymphatic and vascular invasion were significantly associated with nodal metastasis. Of these 12 patients, 11 (92%) had lymph node metastasis confined to pericolic nodes. Nodes along the sigmoidal artery were involved in one patient. There was no involved node along the superior rectal artery or at the root of the inferior mesenteric artery. CONCLUSIONS: Lymph node dissection for T1 sigmoid colon carcinoma should be limited to the root of the sigmoidal artery, and the inferior mesenteric artery should be preserved.

Predictive factors for lymph node metastasis in T1 stage colorectal carcinomas.

PURPOSE: Selective endoscopic resection may cure early colorectal cancer (T1), but the management is controversial. There is concern about the small risk of lymph node metastasis, which will not be treated by endoscopic resection alone. The authors sought predictive markers of lymph node metastasis to assist patient management. METHODS: The authors retrospectively analyzed consecutive cases of T1 stage colorectal cancer resected using endoscopic resection or bowel surgery over the period 1979 to 2000. The risk of lymph node metastasis was analyzed using logistic regression model for the markers selected by univariate analysis: the type of initial treatment, depth of submucosal invasion, lymphatic channel invasion, differentiation of histology, and invasive front histology. RESULTS: Two hundred seventy-eight patients were available for study. Twenty-one had lymph node metastasis. Depth of submucosal invasion (> or = 2,000 microm) and lymphatic channel invasion significantly predicted risk of lymph node metastasis in multivariate analysis. When these two factors were adopted for the prediction of lymph node metastasis, sensitivity, specificity, positive predictive value, and negative predictive value were 100, 55.6, 15.6, and 100 percent, respectively. CONCLUSIONS: Depth of submucosal invasion and lymphatic channel invasion were accurate predictive factors for lymph node metastasis. These two factors could be used in selecting appropriate cases for surgery after endoscopic resection.

A two-color laser photolysis method for determining reaction rates of short-lived intermediates by product analysis: application to the o-quinodimethane problem.

A time-delayed, two-color pulse laser photolysis technique was used for a kinetic study of short-lived transient species through product analysis, the determination of the rate constant of the cycloaddition of o-quinodimethane (1) and maleic anhydride (2) in room-temperature solutions. o-Quinodimethane (1) was generated from 1,2-bis[(phenylseleno)methyl]benzene (3) by the irradiation of a pulse of a KrF excimer laser (248 nm) in the presence of excess 2, and a successive pulse of a XeCl excimer laser (308 nm) was irradiated to the reaction mixture after varied delay times from 0 to 0.1 s for the decomposition of the remaining 1 to quench the cycloaddition reaction. The rate constant of the cycloaddition of 1 and 2 was 2.1 x 10(5) M(-1) s(-1), which was obtained by the analysis of the delay-time dependence of the product yields.

Large substituent effect on the photochemical rearrangement of 1,6-(N-Aryl)aza-[60]fulleroids to 1,2-(N-Arylaziridino)-[60]fullerenes.

Large substituent effects were observed in the rates and reaction mechanisms of the photochemical rearrangement of N-arylaza-[60]fulleroid 1 to N-arylaziridino-[60]fullerene 2, in which the difference of the rates between the fastest and the slowest (>2160-fold) was attained only by changing the aryl group from 1-naphthyl to 2-naphthyl. The decreasing order of the reaction rates in relation to the substituents was 1-naphthyl (1b) > 1-pyrenyl (1d) > phenyl (1a) > 2-naphthyl (1c). The reactions proceeded via triplet states of the fulleroids and a triplet sensitization of the reaction by rearranged product 2b was observed in the case of 1b. The slow reactions of 1a,c were interpretated by the participation of charge-separated species in the excited triplet states, which was supported by nanosecond transient absorption spectra.