Pembrolizumab response in stage IV luminal-type breast cancer with high microsatellite instability: a case report.

BACKGROUND: Pembrolizumab (PEM), an immune checkpoint inhibitor (ICI), is often used for triple-negative breast cancer, but can also be used to treat solid tumors that exhibit high microsatellite instability (MSI-High). However, patients with breast cancer rarely have MSI-High, the use of PEM in such cases in clinical practice is uncertain due to lack of sufficient supporting data. Here, we report the case of a premenopausal woman in who received PEM for MSI-High luminal-type breast cancer. CASE PRESENTATION: A 40-year-old premenopausal Asian woman was diagnosed with stage IIA (T2N0M0) breast cancer and had an Oncotype DX recurrence score of 38. After surgery, she received 4 courses of chemotherapy with docetaxel and cyclophosphamide. After 3 months of tamoxifen therapy, the patient complained of abdominal pain due to right iliac metastasis, and biopsy of the metastatic lesion showed of luminal type; she was sequentially treated with fulvestrant, a CDK4/6 inhibitor, and an anticancer drug (TS1), but over the next year, metastasis to the bone and para-aortic lymph nodes increased. Tumor was MSI-High; PEM was started, and after three courses, bone metastases were reduced, para-aortic lymph node metastases resolved, opioids were discontinued, and the patient returned to society; PEM was administered for 1 year with no worsening of bone metastases on imaging. Asymptomatic brain metastasis less than 1 cm was detected and gamma knife was performed. Six months after completion of PEM, the patient is working with no new lesions. CONCLUSION: We report a case of luminal-type breast cancer with bone metastases and MSI-High, which was treated with PEM and showed a rapid therapeutic response.

Ductal carcinoma in situ of the breast arising in encapsulated mammary hamartoma†;†A case report.

Mammary hamartoma is benign lesion and relatively rare. 17 cases of breast cancer associated with a hamartoma had been previously documented in the literature. We describe herein a case of noninvasive ductal carcinoma of the breast arising in hamartoma in a woman of 60's. The discordance of images of the mass between mammogram and ultrasonogram can lead us to detect the carcinoma within the hamartoma in our case. J. Med. Invest. 67 : 368-371, August, 2020.

Influence of human serum albumin on the bile acid-mediated inhibition of liver microsomal type 1 11ß-hydroxysteroid dehydrogenase.

The influence of human serum albumin (HSA) on the bile acid-mediated inhibition of liver microsomal type 1 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) was studied in vitro. A rat liver microsomal fraction was prepared, and the 11ß-HSD1 enzyme activity in the presence of various concentrations of bile acids and HSA was determined using hydrocortisone as the substrate. The products of the reaction were extracted and analyzed using high-performance liquid chromatography. The magnitude of the inhibition decreased with the addition of HSA in a dose-dependent manner. Four percent human albumin decreased the inhibitory effects of 100 µM chenodeoxycholic acid and lithocholic acid from 89.9 ± 5.6 to 54.5 ± 6.1% and from 83.8 ± 4.8 to 20.8 ± 4.2%, respectively. In contrast, ursodeoxycholic acid and deoxycholic acid showed no inhibitory effect on the enzyme activity in the presence of 4% human serum albumin, and the addition of 1% γ-globulin to the assay mixture in the presence of bile acids did not affect the enzyme activity. Our in vitro study showed that the addition of HSA ameliorated the inhibition of 11ß-HSD1 and that the magnitude of the change is dependent on the species of bile acid, presumably based on the numbers of hydroxyl groups. These results suggest that HSA seems to protect the bile acid-mediated inhibition of 11ß-HSD1 in the healthy subject. On the other hand, in the patients with obstructive biliary diseases, not only elevated serum bile acid but also the accompanying hypoalbuminemia is important to evaluate the pathophysiology of the bile acid-mediated inhibition of 11ß-HSD1 of the disease.

Predictor of neurologic dysfunction after elective thoracic aorta repair using selective cerebral perfusion.

OBJECTIVES: This study was undertaken to determine the factors that influence postoperative neurological dysfunction after selective cerebral perfusion (SCP). DESIGN: From 1995 to August 2004, 60 patients were evaluated for the presence of cerebro-vascular disease (CVD), and then underwent thoracic aortic operations using SCP. Perioperative factors were evaluated by multivariate analyses. RESULTS: Hospital mortality rate was zero. Sixteen patients (26.7%) proved to have CVD. Permanent neurological dysfunction (PND) appeared in three patients (5.0%) and transient neurological dysfunction (TND) in two (3.3%). Univariate analysis revealed superficial temporal artery (STA) pressure during SCP (p = 0.0410) to be a significant risk factor for PND. Variables that achieved values of p < 0.2 (aortic cross-clamp time, presence of CVD, old cerebral infarction, presence of clots or atheroma) were examined with multivariate analysis and the presence of CVD (p = 0.038) and STA pressure during SCP (p = 0.032) were independent risk factors for PND. Multivariate analysis for TND did not show any risk factor. CONCLUSIONS: The presence of CVD was indicated as an independent risk factor for PND after thoracic aortic operations using SCP.

Selective delayed management of blunt traumatic left common carotid artery injury using hypothermic circulatory arrest.

Most traumatic carotid artery aneurysms occur at or close to its bifurcation, and traumatic aneurysm of the intrathoracic carotid arteries are rare. We describe a case of false aneurysm at the origin of the left common carotid artery (LCCA) after blunt trauma. A 53-year-old man suffered a blow from a broken steel plate, which flew from a working concrete crusher over his neck when he looked down the machine. Chest computed tomography revealed aneurysm of the LCCA, and aortic arch arteriography demonstrated a false aneurysm of about 3 x 5 cm at the origin of the LCCA, with loss of arterial continuity and abnormal tortuosity above the aneurysm. An ascending aorta to LCCA bypass graft was placed during the cooling period of cardiopulmonary bypass, and mattress sutures were placed in the normal aorta to close the origin of the LCCA under hypothermic circulatory arrest because of the extreme danger of dissection. The LCCA was transected partially at its origin from the aorta. We speculated that the direct lifting force which caused the carotid artery to move upward might produce a tear at the junction of the LCCA and the aortic arch.

Destabilization of Na(v)1.7 sodium channel alpha-subunit mRNA by constitutive phosphorylation of extracellular signal-regulated kinase: negative regulation of steady-state level of cell surface functional sodium channels in adrenal chromaffin cells.

In cultured bovine adrenal chromaffin cells expressing Na(v)1.7 isoform of voltage-dependent Na(+) channels, treatment (> or = 6 h) with serum deprivation, PD98059, or U0126 increased cell surface [(3)H]saxitoxin ([(3)H]STX) binding by approximately 58% (t(1/2) = 12.5 h), with no change in the K(d) value. Immunoblot analysis showed that either treatment attenuated constitutive phosphorylation of extracellular signal-regulated kinase (ERK) 1 and ERK2 but not of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) 1 and JNK2. The increase of [(3)H]STX binding and the attenuated phosphorylation of ERK1 and ERK2 returned to the control nontreated levels after the addition of serum or the washout of PD98059- or U0126-treated cells. Simultaneous treatment of serum deprivation with PD98059 or U0126 did not produce an additional increasing effect on [(3)H]STX binding, compared with either treatment alone. In cells subjected to either treatment, veratridine-induced maximum (22)Na(+) influx was augmented by approximately 47%, with no change in the EC(50) value; Ptychodiscus brevis toxin-3 enhanced veratridine-induced (22)Na(+) influx by 2-fold, as in nontreated cells. Serum deprivation, PD98059, or U0126 increased Na(+) channel alpha- but not beta(1)- subunit mRNA level by approximately 50% between 3 and 24 h; cycloheximide, an inhibitor of protein synthesis, increased alpha-subunit mRNA level and nullified additional increasing effect of either treatment on alpha-subunit mRNA level. Either treatment prolonged half-life of alpha-subunit mRNA from 17.5 to approximately 26.3 h without altering alpha-subunit gene transcription. Thus, constitutively phosphorylated/activated ERK destabilizes Na(+) channel alpha-subunit mRNA via translational event, which negatively regulates steady-state level of alpha-subunit mRNA and cell surface expression of functional Na(+) channels.

Differential effects of bupivacaine enantiomers, ropivacaine and lidocaine on up-regulation of cell surface voltage-dependent sodium channels in adrenal chromaffin cells.

In cultured bovine adrenal chromaffin cells, (+/-)-bupivacaine inhibited veratridine-induced 22Na(+) influx (IC(50) 6.8 microM). The IC(50) of (+)-bupivacaine (2.8 microM) was 6.2-, 7.4-, and 17.1-fold lower than those of (-)-bupivacaine (17.3 microM), (-)-ropivacaine (20.6 microM), and lidocaine (47.8 microM). Chronic (i.e. 3-h) treatment of cells with (+/-)-bupivacaine increased cell surface [3H]saxitoxin ([3H]STX) binding capacity by 48% (EC(50) of 233 microM; t(1/2)=7.4 h), without changing the K(d) value. Treatment for 24 h with either (+)- or (-)-bupivacaine, or (-)-ropivacaine elevated [3H]STX binding, whereas 24-h treatment with lidocaine had no effect. The rise of [3H]STX binding by (+/-)-bupivacaine was prevented by cycloheximide, an inhibitor of protein synthesis, or brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network; however, (+/-)-bupivacaine did not increase Na(+) channel alpha- and beta(1)-subunit mRNA levels. In cells subjected to (+/-)-bupivacaine treatment (1 mM for 24 h) followed by 3-h washout, veratridine-induced 22Na(+) influx was enhanced, even when measured in the presence of ouabain, an inhibitor of Na(+),K(+)-ATPase. Ptychodiscus brevis toxin-3 potentiated veratridine-induced 22Na(+) influx by 2.3-fold in the (+/-)-bupivacaine-treated cells, as in non-treated cells. These results suggest that lipophilic bupivacaine enantiomers or (-)-ropivacaine acutely inhibit Na(+) channel gating, whereas its chronic treatment up-regulates cell surface expression of Na(+) channels via translational and externalization events.

Distinct effects of ketone bodies on down-regulation of cell surface insulin receptor and insulin receptor substrate-1 phosphorylation in adrenal chromaffin cells.

Treatment (>/=24 h) of cultured bovine adrenal chromaffin cells with ketoacidosis-related concentrations (>/=3 mM) of acetoacetate (but not beta-hydroxybutyrate, acetone, and acidic medium) caused a time- and concentration-dependent reduction of cell surface (125)I-insulin binding by ~38%, with no change in the K(d) value. The reduction of (125)I-insulin binding returned to control nontreated level at 24 h after the washout of acetoacetate-treated cells. Acetoacetate did not increase the internalization rate of cell surface insulin receptor (IR), as measured in the presence of brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network. Acetoacetate (10 mM for 24 h) lowered cellular levels of the immunoreactive IR precursor molecule (approximately 190 kDa) and IR by 22 and 28%, respectively. Acetoacetate decreased IR mRNA levels by approximately 23% as early as 6 h, producing their maximum plateau reduction at 12 and 24 h. The half-life of IR mRNA was shortened by acetoacetate from 13.6 to 9.5 h. Immunoprecipitation followed by immunoblot analysis revealed that insulin-induced (100 nM for 10 min) tyrosine-phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 56% in acetoacetate-treated cells, with no change in IRS-1 level. These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis, thereby retarding insulin-induced activation of IRS-1.

Regulation of voltage-dependent sodium channel expression in adrenal chromaffin cells: involvement of multiple calcium signaling pathways.

The density and electrical activity of cell surface voltage-dependent Na(+) channels are key determinants regulating the neuronal plasticity including development, differentiation, and regeneration. Abnormalities of Na(+) channels are associated with various neurological diseases. In this paper, we review the regulatory mechanisms of cell surface Na(+) channel expression mediated by Ca(2+) signaling pathways in cultured bovine adrenal chromaffin cells. Sustained, but not transient, elevation of intracellular Ca(2+) concentration reduced the number of cell surface Na(+) channels. The reduction of Na(+) channels was suppressed by an inhibitor of calpain, a Ca(2+)-dependent protease, and by an inhibitor of protein kinase C (PKC). The activation of conventional PKC-alpha and novel PKC-epsilon reduced cell surface Na(+) channels by the acceleration of internalization of the channels and by the increased degradation of Na(+) channel alpha-subunit mRNA, respectively. On the contrary, the activation of PKC-epsilon increased Na(+) channel beta(1)-subunit mRNA level. The inhibition of calcineurin, a Ca(2+)/calmodulin-dependent protein phosphatase 2B, by immunosuppressants upregulated cell surface Na(+) channels by both stimulating externalization and inhibiting internalization of the channels without changing Na(+) channel alpha- and beta(1)-subunit mRNA levels. Thus, the signal transduction pathways mediated by intracellular Ca(2+) modulate cell surface Na(+) channel expression via multiple Ca(2+)-dependent events, and the changes in the intracellular vesicular trafficking are the important mechanisms in the regulation of Na(+) channel expression.

Serum deprivation-induced upregulation of voltage-dependent sodium channels in adrenal chromaffin cells: selective involvement of extracellular signal-regulated kinase pathway.

In the present study, we investigated whether activation of the MAPK family could regulate the cell surface expression of Na channels in cultured bovine adrenal chromaffin cells. The results suggest that constitutively activated ERK (but not p38 or JNK), by various extracellular stimuli, down-modulates the density of cell surface Na channels, which was mediated via the destabilization of Na channel alpha-subunit mRNA.

Down-regulation of cell surface insulin receptor and insulin receptor substrate-1 phosphorylation by inhibitor of 90-kDa heat-shock protein family: endoplasmic reticulum retention of monomeric insulin receptor precursor with calnexin in adrenal chromaffin cells.

Treatment (>/=6 h) of cultured bovine adrenal chromaffin cells with geldanamycin (GA) or herbimycin A (HA), an inhibitor of the 90-kDa heat-shock protein (Hsp90) family, decreased cell surface (125)I-insulin binding. The effect of GA was concentration (EC(50) = 84 nM)- and time (t(1/2) = 8.5 h)-dependent; GA (1 microM for 24 h) lowered the B(max) value of (125)I-insulin binding by 80%, without changing the K(d) value. Western blot analysis showed that GA (>/=3 h) lowered insulin receptor (IR) level by 83% (t(1/2) = 7.4 h; EC(50) = 74 nM), while raising IR precursor level by 100% (t(1/2) = 7.9 h; EC(50) = 300 nM). Pulse-label followed by reducing and nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that monomeric IR precursor (~190 kDa) developed into the homodimeric IR precursor (approximately 380 kDa) and the mature alpha(2)beta(2) IR (~410 kDa) in nontreated cells, but not in GA-treated cells; in GA-treated cells, the homodimerization-incompetent form of monomeric IR precursor was degraded via endoplasmic reticulum (ER)-associated protein degradation. Immunoprecipitation followed by immunoblot analysis showed that IR precursor was associated with calnexin (CNX) to a greater extent in GA-treated cells, compared with nontreated cells. GA had no effect on IR mRNA levels and internalization rate of cell surface IRs. In GA-treated cells, insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 77%, with no change in IRS-1 level. Thus, inhibition of the Hsp90 family by GA or HA interrupts homodimerization of monomeric IR precursor in the ER and increases retention of monomeric IR precursor with CNX; this event retards cell surface expression of IR and attenuates insulin-induced activation of IRS-1.