[A Long-Surviving Case of Locally Advanced Breast Cancer with Multiple Lung Metastasis].

We report a case of right advanced breast cancer with multiple lung metastases in a 66-year-old woman. Her breast cancer( invasive ductal carcinoma, cT4bN1M1, Stage Ⅳ)was resected in October 2007(mastectomy plus axillary lymph node dissection)after local arterial infusion therapy(total dose 5-FU 4,735 mg plus adriamycin 180 mg), which caused bilateral lung arterial embolism due to deep vein thrombosis in right her leg. She had to be treated by anticoagulant therapy, mechanical ventilation and placement of IVC filter before her operation. Subsequent chemo-endocrine therapy(docetaxel 6 courses plus anastrozole)was continued. In October 2008, a CT scan showed disappearance of multiple lung metastases (complete response). In November 2015 (8 years after her operation), a CT scan showed recurrence of multiple lung metastases and endocrine therapy was changed to tamoxifen. A year later, a CT scan showed disappearance of multiple lung metastases(complete response)again and keep a condition of complete response in her breast cancer until May 2023 (15 years after her operation).

[A Case of Recurrent Breast Cancer with Multiple Bone Metastasis Effectively Treated by CDK4/6 Inhibitor in Addition to Aromatase Inhibitor].

We report a case of recurrent breast cancer with multiple bone metastasis in a 62-year-old woman. Her breast cancer (invasive ductal carcinoma, T2N0M0, Stage ⅡA)was resected in 2001(partial mastectomy plus axillary lymph node dissection) with adjuvant chemotherapy(UFT)and irradiation to her left remnant breast. In February 2018, she complained of severe pain in right femoral joint and hip. CT scan showed a left cystic breast tumor(17 cm)and multiple bone metastasis. The core needle biopsy of the costal bone lesion and left mastectomy were performed. These pathological findings were recurrence of the breast cancer(ER+). The endocrine therapy(exemestane, aromatase inhibitor), the administration of denosumab and irradiation to painful bone lesions were performed, but it did not suppress tumor progression. The treatment of letrozole plus palbociclib(CDK4/6 inhibitor)were continued for 3 months from May 2018, and this therapy made her bone lesions smaller, but palbociclib were stopped due to its severe neutropenia. After that, the single administration of letrozole was continued, but the tumor marker did not become normal. In February 2019, abemaciclib was administered in addition to letrozole. One year later, her symptoms improved and her bone metastases have showed partial response.

[A Useful Method of Nipple-Side HydroMARK-Marking before Neoadjuvant Chemotherapy in the Breast Preserving Surgery-A Case Report with pCR of the Triple Negative Breast Cancer].

When the primary breast cancer disappears by neoadjuvant chemotherapy, it is often difficult to detect it during the breast preserving surgery. Before neoadjuvant chemotherapy, preoperative nipple-side HydroMARK-marking, which was made of titanium coil and hydrogel, was a very useful and effective method because of its fine detection by ultrasonography. We report a case of 51-year-old female with the triple negative breast cancer(TNBC). At first, the HydroMARK was inserted between the nipple and the tumor. Its distance was about 10 mm toward the nipple. EC therapy followed by docetaxel was performed for 6 months as neoadjuvant chemotherapy. After that, her left TNBC(T1N0M0, Stage Ⅰ, invasive ductal carcinoma, ER[-], PgR[-], HER2[-])was disappeared in all imagings and resected in August 2018. The HydroMARK was clearly detected by intraoperative ultrasonography and her right breast preserving surgery was completely performed. Its pathological finding was pCR(pathological complete response).

[A Case of Pyloric Stenosis Due to Gastric Metastasis of Breast Cancer].

We report a case of left advanced breast cancer(T4N1M0, Stage ⅢA)in a 67-year-old woman. In August 2010, her breast cancer(triple-negative invasive ductal carcinoma)was resected(mastectomy plus axillary lymph node dissection) with adjuvant chemotherapy(TC)and irradiation to her chest wall. In July 2018, she experienced recurrent vomiting. Gastrointestinal endoscopy(GS)revealed type Ⅳ advanced gastric cancer-like appearance with pyloric stenosis. Pathological findings confirmed hormone-positive gastric metastasis of breast cancer. Systemic chemo-endocrine therapy(EC and anastrozole) was performed, following which her symptoms improved. In May 2019, recurrent vomiting appeared again. Thereafter, systemic chemo-endocrine therapy(paclitaxel plus bevacizumab and fulvestrant)was initiated, and her symptoms showed improvement. In November 2020, she showed obstructive jaundice due to malignant biliary stenosis. She was treated using endoscopic biliary stenting, but died 2 months later. Gastric metastasis is reported rarely in 4% of all breast cancers, and GS should be recommended in cases of recurrent abdominal complaints.

[Fluorescence Detection System for Intraoperative Identification of the Parathyroid Glands in a Patient with Thyroid Cancer with a Right Non-Recurrent Inferior Laryngeal Nerve].

Intraoperative identification of the parathyroid gland is very important during thyroid and parathyroid surgery.Recently, intrinsic fluorescence of the parathyroid gland was identified and reported.We report the case of a 45-year-old woman with thyroid papillary cancer.Before surgery, neck and chest CT showed a thyroid tumor(20mm)of the right lobe and an aberrant right subclavian artery.Her thyroid cancer(T1N1M0, Stage Ⅰ)was resected in December 2017(right lobectomy and lymph node dissection).During surgery, her parathyroid glands were visually inspected by the surgeon as well as by a ready-made photodynamic eye(PDE-neo)system.Diagnosis was performed using the intraoperative fast pathological method.Her inferior laryngeal nerve was non-recurrent(Toniato ⅡA).This photodynamic eye(PDE-neo)system is an effective and useful method that decreases the operation time and enables faster detection of the parathyroid gland.

[A Case Report of Recurrent Bleeding and Massive Malodorous Effusion Due to Skin Invasion of Advanced Breast Cancer Successfully Treated with Mohs' Paste].

We report a case involving a 65-year-old woman with skin invasion and destruction by left large breast cancer(T4cN0M0, Stage ⅢB). She had severe anemia with recurrent bleeding on the cancer surface and needed blood transfusion, and massive malodorous effusion from the skin lesion resulted in hypoalbuminemia and recurrent bacteremia. Metronidazole gel treatment for malodorous effusion and postmenopausal hormonal therapy were administered at first. After using Mohs' paste 4 times with 1- or 2-week intervals, the bleeding and effusion stopped, and the primary cancer tumor almost disappeared. Bacteremia also improved with antibiotics, and amelioration of distress was observed. Following this, systemic chemotherapy was performed. Mohs' paste was a very useful method for symptom management of malignant skin lesions with bleeding and massive effusion.

[A Case Report of Continuous Bleeding due to Severe Skin Metastases of Breast Cancer Successfully Treated Using Mohs Paste].

We report a case of severe skin metastases of advanced right breast cancer in an 84-year-old woman. The tumor (T4bN3cM0, Stage III C)was resected in June 2011(BT+AX)after blood transfusion for severe anemia. Radiotherapy to the right chest wall and supraclavicular lymph nodes was performed, and adjuvant hormonal therapy was administered. Local recurrences in the skin of the right chest wall appeared and were resected in December 2011. Nine months later, continuous bleeding from the progressed, widespread skin metastases needed recurrent blood transfusion. After using Mohs paste twice, the bleeding stopped almost completely. Mohs paste was very useful for stopping bleeding in locally advanced, unresectable skin metastasis.

EpCAM-targeted therapy for human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies and the identification of new effective therapies for HCC is urgently needed. We have previously identified EpCAM, one of the hepatic stem/progenitor markers, as a prognostic predictor of patients who received curative hepatectomy for HCC. In this preclinical study, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. METHODS: In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. RESULTS: In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU (p < 0.05). Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13 (p < 0.05), VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13 (p < 0.0005, <0.01, respectively). In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control (p = 0.016). Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control (p = 0.0011). CONCLUSIONS: Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and novel approach for the treatment of HCC with a poorer prognosis.

[A case of cardiac tamponade due to pericarditis carcinomatosa of breast cancer successfully treated via pericardiocentesis and systemic chemo-endocrine therapy].

We report a case of lung and bone metastases of right advanced breast cancer in a 33-year-old woman. Her breast cancer (T4bN1M1, StageIV)was resected in December 2003 (mastectomy [BT] plus axillary lymph node dissection [AX]) after local arterial infusion therapy and subsequent systemic chemo-endocrine therapy was initiated and continued. In June 2007, a computed tomography (CT) scan revealed cardiac tamponade due to pericarditis carcinomatosa. Pericardiocentesis was performed, and the bloody effusion was drained immediately. Subsequently, the sysytemic chemo-endocrine therapy was modified. In 2009, multiple cerebellar metastases were discovered and treated via whole brain irradiation. In 2010, multiple liver metastases appeared, and they were treated by intravenous (IV) administration of nab-paclitaxel. In 2011, superior vena cava syndrome appeared gradually, and it was treated via venous metallic stenting. In 2012, epidural spinal cord compression appeared gradually, and it was treated via irradiation. In November 2012, the patient died because of lymphangitis carcinomatosa; her prognosis was good, as it was approximately 5 years after the pericardiocentesis.

[A case report of liver metastasis of breast cancer successfully treated by hepatic arterial infusion of docetaxel and systemic administration of nab-paclitaxel].

We report the case of an effectively treated 50-year-old woman with liver metastasis of left breast cancer. Her breast cancer (T2N0M0, Stage IIA) was resected in November 1998 (radical mastectomy+axillary lymph nodes dissection). After this operation, tamoxifen(TAM 20 mg daily) was administered. In February 2002, a solitary liver metastasis(S5, 4 cm in diameter) was found by computed tomography(CT) scan. Hepatic arterial infusion of docetaxel(DOC 20 mg weekly)was started. In March 2003, the solitary liver metastasis had become smaller and showed partial remission (PR), but DOC intravenous injection(iv) therapy(40 mg weekly) was started because lung metastases appeared. Therefore, epirubicin+ cyclophosphamide therapy, DOC ia therapy (120 mg triweekly), and anastrozole (1 mg daily) were continued. However, in March 2005, she refused chemotherapy. In January 2011, a CT scan showed progressive disease of multiple liver and lung metastases. Nab-paclitaxel(PTX) iv therapy(400 mg triweekly) and exemestane(25 mg daily) were administered. In March 2012, a CT scan showed PR of the metastatic breast cancer. She has continued to receive nab-PTX iv therapy as an outpatient.

[Loco-regional chemotherapy at the outpatient clinic for gastric cancer patients with home enteral nutrition].

In over the 10 years from 2000-2010, 21 gastric cancer patients received loco-regional chemotherapy with home enteral nutrition (HEN) at an outpatient clinic because of insufficient oral intake. These loco-regional chemotherapy regimens consisted of 5 intra-aortic chemotherapies, 4 hepato-arterial infusions and 12 intra-peritoneal chemotherapies. Five out of 8 cases that had measurable lesions showed PR, and 3 cases revealed PD. The patients received HEN with peptide central formula, 400-1,200 kcal/day in night time. The average duration of HEN was 12.9 months. The post-operative nutritional management was needed for continuation and securing of outpatient chemotherapy. The author reported an experience of the outpatient loco-regional chemotherapy with HEN for the gastric cancer patients who could not eat a sufficient volume of food.

Importin-α1 as a novel prognostic target for hepatocellular carcinoma.

BACKGROUND: Perturbations in the nuclear microenvironment, including transport systems, play a critical role in malignant progression, but the nuclear import abnormalities remain unclear in hepatocarcinogenesis. We analyzed the role of importin in hepatocellular carcinoma (HCC). METHODS: Gene expression profiling of the importin family was performed in HCC tissues. The significance of importin protein expression was analyzed in vitro as well as clinicopathologically. RESULTS: According to the microarray profiles, the importin-α1 was dominantly overexpressed in HCC tissues as compared to the adjacent noncancerous tissues. By means of human HCC cell lines, a knockdown of importin-α1 by its siRNA greatly reduced cellular proliferation by 15.2-26.6% (P < 0.005). Immunohistochemical analysis on tissue samples demonstrated cancer-specific overexpression in 36.3% of HCCs. The overexpression of importin-α1 was correlated statistically with high levels of alfa-fetoprotein ( P = 0.0017), the tumor number (P = 0.0116), histological dedifferentiation (P = 0.0054), tumor morphology (P = 0.0433), portal vein invasion (P = 0.0007), hepatic vein invasion (P = 0.0081), Fc (P = 0.0367), Fc-inf (P = 0.0122), and the tumor, node, metastasis stage (P = 0.0026); this resulted in a significantly poorer prognosis in both overall survival (P = 0.0164) and recurrence-free survival (P = 0.0101). Multivariate analysis of recurrence-free survival revealed importin-α1 expression to be a statistically significant factor (P = 0.0361). In addition, early recurrence after curative resection was observed more frequently in the importin-α1-positive group as compared to the negative group (P = 0.0023). The multivariate analysis identified importin-α1 as the only independent predictor of early recurrence after HCC resection (odds ratio = 5.291, P = 0.0191). CONCLUSIONS: Because importin-α1 might be closely associated with HCC progression, further analysis should be pursued to evaluate it as a novel prognostic target.

Gene expression signature of the gross morphology in hepatocellular carcinoma.

OBJECTIVE: To evaluate the gene expression signature of hepatocellular carcinoma (HCC) in relation to the gross morphology. BACKGROUND: Eggel's nodular type of HCC is morphologically subclassified into the single nodular (SN) type, the single nodular type with extranodular growth (SNEG), and the confluent multinodular (CM) type, but their biomolecular differences remain unclear. METHODS: The clinicopathological characteristics and genome-wide gene expressions were analyzed in 275 patients with nodular-type HCC (124 SN-type, 91 SNEG-type, and 60 CM-type) who received curative hepatectomy. RESULTS: Significantly poor prognosis was recognized in CM types in overall survival (P = 0.0020) and recurrence-free survival (P = 0.0066). Analysis of the genome-wide expression patterns revealed significant difference of CM-type HCC from either SN- or SNEG-type HCC. In particular, a stem cell marker EpCAM was dominantly expressed in CM-type HCC. Immunohistochemical studies confirmed the specific expression of EpCAM in HCC cancer cells of CM type. In multivariate analysis, the gross morphology of CM type was significantly associated with EpCAM expression (P = 0.0092), α-fetoprotein (P = 0.0424), "lens culinaris agglutinin-reactive fraction of α-fetoprotein" level (P = 0.0288), and the portal vein invasion (P = 0.0150). Furthermore, EpCAM was predictive for poor prognosis in overall and recurrence-free survivals of patients with CM-type HCC (P = 0.0082 and P = 0.0043, respectively). CONCLUSION: Our studies suggest that the distinct signature of gene expression is closely related to morphological progression in HCC. Especially, EpCAM might play a critical role in the aggressiveness of CM-type HCC.

Analogy between sphere forming ability and stemness of human hepatoma cells.

Increasing evidence suggests that cancers contain a small subset of cancer-initiating cells, so-called cancer stem cells (CSCs) that are capable of regenerating a tumor after chemoradiation therapy. Sphere forming ability is known to be one of properties of CSCs, but the significance remains unclear. The present study focused on sphere formation of human hepatoma cells in three-dimensional culture in order to evaluate the analogy between sphere forming ability and stemness of cancer cells in vitro. Under three-dimensional culture condition, HepG2, Hep3B and PLC/PRF/5 cells demonstrated the sphere formation while SK-Hep1 and Huh-7 cells did not. The population of G0/G1 phase increased in the spheres compared with the monolayer (67 vs. 38%). In spite of no significant difference in stem cell surface markers (CD44, CD90, CD133, EpCAM and ABCG2), remarkable up-regulation of p27 CDK inhibitor was observed in sphere forming cells. Immunofluorescence analysis revealed the nuclear expression of p27 in the whole of the sphere, but weak expression of p21 only at the peripheral area. The spheres acquired chemoresistance to cisplatin compared with the monolayers (58.9 vs. 16.2 µM in IC50). This model was useful for assessment of the role of cell-cycle quiescence in the stemness and chemoresistance of cancer cells.

The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma.

BACKGROUND & AIMS: We previously identified that high Aurora B expression was associated with hepatocellular carcinoma (HCC) recurrence due to tumor dissemination. In this preclinical study, a novel inhibitor of Aurora B kinase was evaluated as a treatment for human HCC. METHODS: AZD1152 is a selective inhibitor of Aurora B kinase. Twelve human HCC cell lines were analyzed for Aurora B kinase expression and the in vitro effects of AZD1152. The in vivo effects of AZD1152 were analyzed in a subcutaneous xenograft model and a novel orthotopic liver xenograft model. RESULTS: Aurora B kinase expression varied among the human HCC cell lines and was found to correlate with inhibition of cell proliferation, accumulation of 4N DNA, and the proportion of polyploid cells following administration of AZD1152-hydroxyquinazoline-pyrazol-anilide (AZD1152-HQPA). AZD1152-HQPA suppressed histone H3 phosphorylation and induced cell death in a dose-dependent manner. Growth of subcutaneous human HCC xenografts was inhibited by AZD1152 administration. In an orthotopic hepatoma model, treatment with AZD1152 significantly decelerated tumor growth and increased survival. Pharmacobiological analysis revealed that AZD1152 induced the rapid suppression of phosphohistone H3, followed by cellular apoptosis in the liver tumors but not in the normal tissues of the orthotopic models. CONCLUSIONS: Our preclinical studies indicate that AZD1152 is a promising novel therapeutic approach for the treatment of HCC.