[Two Cases of Advanced Recurrent Breast Cancer with Severe Heart Failure Caused By Anthracycline].

Case 1: A 48-year-old woman, had right breast cancer with multiple liver metastases. Seven courses of paclitaxel plus bevacizumab were administered, but due to disease progression, 12 courses of FEC 75(total epirubicin 900 mg/m2)were administered. 2 months after the last FEC administration, the patient developed heart failure and died about 3 months later. Case 2: A 58-year-old woman, was on endocrine therapy after surgery for left breast cancer. Recurrence of lung and bone metastases were appeared 5 years after surgery, 10 courses of FEC 75(total epirubicin 750 mg/m2)were administered due to disease progression. Eight months after the last administration of FEC, the patient developed heart failure and died about 8 months later. Anthracycline induced cardiotoxicity is irreversible and has a severe course. Therefore, anthracycline should be administered with caution.

Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells.

Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated. Dabrafenib strongly inhibited the viability in BRAF mutated cells by demonstrating G0/G1-arrest via the downregulation of MEK/ERK phosphorylation. Upregulated phosphorylation of MEK was observed in RAS mutated cells after dabrafenib treatment and caused VEGF upregulation, but was not related to the cellular proliferation. Trametinib inhibited the cellular viability to variable degrees in every cell by downregulating ERK phosphorylation. Dual blockade by both inhibitors demonstrated clear cytostatic effect in all the cells. OCUT-4 showed the weakest sensitivity to trametinib, no additional effect of either inhibitor in combination with the other, and an increase of SNAI1 mRNA expression after treatment with inhibitors, suggesting a mechanism for resistance. Our findings demonstrated the efficacy of a mutation-selective BRAF inhibitor and a MEK inhibitor in human ATC cells in a genetic alteration-specific manner.

Clinical verification of sensitivity to preoperative chemotherapy in cases of androgen receptor-expressing positive breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) patients testing positive for androgen receptor (AR) expression are thought to be chemotherapy resistant, similar to other hormone receptor-positive breast cancers; however, this has not been substantially validated in the clinic. In this study, we investigated the association between chemotherapy sensitivity and AR expression in patients treated with neoadjuvant chemotherapy (NAC) using standardised chemotherapy criteria and regimens. METHODS: A total of 177 patients with resectable early-stage breast cancer were treated with NAC. Oestrogen receptor, progesterone receptor, HER2, Ki67 and AR status were assessed immunohistochemically. RESULTS: Sixty-one patients were diagnosed with TNBC; AR expression was identified in 23 (37.7%), which was significantly less common than that found in non-TNBC patients (103 of 116; 88.8%; P<0.001). The rate of pathological complete response after NAC was significantly lower (P=0.001), and disease recurrence was more common (P=0.008) in patients with AR-positive compared with those with AR-negative TNBC. In TNBC cases, as expected, the non-recurrence period in cases that were negative for AR expression was significantly extended (P=0.006, log-rank). CONCLUSIONS: Androgen receptor expressions may be useful as biomarkers to predict treatment responses to NAC in TNBC. Moreover, induction of a change in subtype to the AR-negative phenotype was observed after NAC.

Predictive factors for the occurrence of four or more axillary lymph node metastases in ER-positive and HER2-negative breast cancer patients with positive sentinel node: A retrospective cohort study.

INTRODUCTION: Patients with four or more axillary lymph node metastases have benefited from postmastectomy radiotherapy to the supraclavicular region. However, when metastatic sentinel nodes (SNs) are present, information regarding the total number of node metastases cannot be obtained if axillary lymph node dissection (ALND) is omitted from the treatment protocol. It is important to determine the indication for additional chemotherapy in ER-positive and HER2-negative breast cancer patients. We investigated the predictive factors for the occurrence of four or more metastases in patients with ER-positive and HER2-negative breast cancer in the presence of macrometastasis in the SNs. METHODS: We reviewed 83 patients with ER-positive and HER2-negative breast cancer, who had macrometastasis in the SN and had undergone ALND. The clinicopathological findings and prognosis between patients with pN1 disease and those with pN2 disease were also compared. RESULTS: Nineteen percent of patients had pN2-3 disease. The predictive factor for poor prognosis in these patients was the presence of pN2-3 disease. The independent predictive factors for pN2-3 disease were the T stage and the ratio of the number positive SNs to the number of removed SNs (SN ratio). Patients with both T2 tumors and a high SN ratio had a 50% risk of having pN2-3 disease. CONCLUSION: The presence of four or more metastases was found to be the strongest prognostic factor in ER-positive and HER2-negative breast cancer patients with macrometastasis in the SN. The T stage and SN ratio determined before surgery or during surgery were useful in predicting pN2-3 disease in these patients.

Nestin expression as an independent indicator of poor prognosis for patients with anaplastic thyroid cancer.

The protein nestin, a neuronal stem cell marker, has been reported to indicate a poor prognosis in various tumours. Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies in humans, and its molecular background has not been identified. The present study evaluated the expression of nestin and its significance in ATC. Tissue samples from 23 patients with ATC were subjected to immunohistochemical staining and the staining intensity of nestin in the cytoplasm was evaluated. The expression of nestin in the tumour cytoplasm was confirmed in 6 of the 23 tissue samples (26.1%). Between the nestin-positive group (n=6) and the nestin-negative group (n=17), there were no significant differences in the clinicopathological factors of the patients. However, the nestin-positive group exhibited significantly worse prognoses than the nestin-negative group (median survival time, 86.5 vs. 306 days; P<0.01, log-rank test). The multivariate analysis indicated that nestin expression was a prognostic indicator for the ATC patients (hazard ratio, 5.59; 95% confidence interval, 1.63-19.50; P<0.01), which is independent of the known clinical indicators. Nestin expression has the potential to be an independent indicator of a poor prognosis for patients with ATC.

Partial mastectomy using manual blunt dissection (MBD) in early breast cancer.

BACKGROUND: Breast-preserving surgery (Bp) and sentinel lymph node biopsy (SNB) are established as standard treatment for axillary lymph node-negative early breast cancer. METHODS: A surgical technique using manual blunt dissection (MBD), in which use of electrocautery, an ultrasonically activated scalpel, and ligation is minimized, is described. This involves an approach from small incisions in the axilla or areola to avoid injury to skin flaps, and with adequate mobilization of the breast, so that regardless of the tumor site, surgical wounds are not noticeable. The usefulness and tolerability of this surgical technique were examined. RESULTS: This surgical technique was evaluated in 233 patients. Surgery could be performed rapidly, with a mean operative time of 67 ± 21 min and a low mean blood loss of only 35 ± 28 ml. There was little need for postoperative analgesia, and surgery was well tolerated without postoperative bleeding or wound infection. CONCLUSION: Our proposed technique for partial mastectomy using MBD provides good curative and cosmetic results.

Identification of tumour-reactive lymphatic endothelial cells capable of inducing progression of gastric cancer.

BACKGROUND: Tumour cells and stromal cells interact in the tumour microenvironment; moreover, stromal cells can acquire abnormalities that contribute to tumour progression. However, interactions between lymphatic endothelial cells (LECs) and tumour cells are largely unexamined. In this study, we aimed to determine whether tumour-specific LECs inhabit the tumour microenvironment and examine their influence on this microenvironment. METHODS: We isolated normal LECs (NLECs) from a non-metastatic lymph node and tumour-associated LECs (TLECs) from cancerous lymph nodes. We examined proliferative and migratory potency, growth factor production, and gene expression of each type of LEC. Moreover, we developed a co-culture system to investigate the interactions between gastric cancer cells and LECs. RESULTS: When compared with NLEC, TLECs had an abnormal shape, high proliferative and migratory abilities, and elevated expression of genes associated with inflammation, cell growth, and cell migration. NLECs co-cultured with gastric cancer cells from the OCUM12 cell line acquired TLEC-like phenotypes. Also, OCUM12 cells co-cultured with TLECs expressed high levels of genes responsible for metastasis. CONCLUSIONS: Our results demonstrated that LECs interacted with tumour cells and obtained abnormal phenotypes that could have important roles in tumour progression.

Significant cytostatic effect of everolimus on a gefitinib-resistant anaplastic thyroid cancer cell line harboring PI3KCA gene mutation.

We previously demonstrated the efficacy of gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), on an anaplastic thyroid cancer (ATC) cell line. We also observed that gefitinib was not effective in regulating cell growth in a different ATC cell line that exhibited an altered EGFR-initiated signal transduction pathway. In the present study, we attempted to regulate the downstream effector of EGFR-Akt-mammalian target of rapamycin (mTOR) pathway by an mTOR inhibitor, everolimus. A total of 8 ATC cell lines were employed, 7 of which were established in our institute. OCUT-2 was known to carry a mutation in the phosphoinositide-3-kinase, catalytic, α polypeptide gene (PI3KCA) and to be gefitinib-resistant, whereas ACT-1 exhibited a remarkable growth arrest by gefitinib. All the cell lines were tested for the cytotoxic effect of everolimus. The mechanisms of cellular toxicity were investigated by EGFR stimulation, cell cycle and concurrent exposure to paclitaxel. In OCUT-2, but not in any of the other cell lines, everolimus achieved a significant growth inhibition (inhibition of 30 and 50% was achieved by concentrations of 0.8 and 5 nM, respectively). The growth in OCUT-2 was inhibited by everolimus, even with concordant EGFR stimulation. This effect was demonstrated by a G2M cell cycle arrest. An additive effect of everolimus onto the cytotoxic effect of paclitaxel was demonstrated at a dose of 1-2 nM. A significant growth inhibitory effect of everolimus on the gefitinib-resistant ATC cell line was demonstrated, suggesting a possible correlation between the efficacy of everolimus and PI3KCA gene mutation and the significance of molecular-targeted therapy in the management of ATC.

Nonfunctional adrenocortical carcinoma initially presenting as retroperitoneal hemorrhage.

BACKGROUND: Acute adrenal hemorrhage is an uncommon entity. Although trauma is the most common cause of adrenal hemorrhage, non-traumatic etiologies have also been reported. We report an unusual case of a spontaneously ruptured adrenocortical carcinoma that initially presented as a critical massive retroperitoneal hemorrhage. The case was treated successfully using a combination of emergency interventional radiology and elective surgery. CASE PRESENTATION: A 47-year-old woman was transported to our hospital because of the sudden onset of severe pain in her left lower back. The shadow of a tumor-like soft mass accompanied by bleeding was observed in the upper pole of the left kidney, together with vascular leakage from the middle suprarenal artery on computed tomography. Transcatheter embolization of the left middle adrenal artery was administered based on a diagnosis of acute adrenal hemorrhage. Further observation indicated that the bleeding was caused by rupture of an adrenocortical carcinoma. Left adrenalectomy was subsequently carried out via laparotomy. CONCLUSIONS: We experienced an unusual case of acute massive adrenal hemorrhage caused by the rupture of a non-functional adrenocortical carcinoma, which was treated successfully by ambulatory transcatheter embolization therapy and elective surgery.

Ambulatory sentinel lymph node biopsy preceding neoadjuvant therapy in patients with operable breast cancer: a preliminary study.

BACKGROUND: Sentinel lymph node biopsy (SNB)-oriented stepwise treatment under local anesthesia has been performed in the outpatient-ambulatory setting in patients receiving neoadjuvant therapy (NAT). We retrospectively reviewed our preliminary experience of ambulatory SNB in breast cancer patients scheduled to undergo NAT to evaluate the usefulness and feasibility of this method as a minimally invasive, stepwise treatment protocol. METHODS: We retrospectively identified 56 patients with breast cancer without obvious nodal involvement who were scheduled to receive NAT before breast surgery. SNB was performed under local anesthesia in an ambulatory outpatient setting before the initiation of NAT. RESULTS: The average number of removed sentinel lymph nodes was 1.9. Identification of the sentinel node was possible in all cases, and macrometastasis was observed in six cases (10.7%). Micrometastasis was observed in five cases, while isolated tumor cells were noted in six cases. There were no delays in the initiation of NAT as a result of complications of SNB. CONCLUSIONS: This pilot study demonstrated the safety and feasibility of ambulatory SNB prior to NAT. Further studies are warranted to assess the strict indications, patient satisfaction, and medical economics of this procedure.

T-stage and positive sentinel nodes ratio are the useful factors to predict non-sentinel node metastasis in breast cancer patients with macro-metastasis in the sentinel node.

INTRODUCTION: Current guidelines recommend completion axillary lymph node dissection (cALND) in case of a sentinel lymph node (SN) metastasis larger than 2 mm (macrometastasis). However in many patients of those, the non-sentinel lymph nodes (NSN) contain no further metastasis, indicating that axillary lymph node dissection provides no benefit. To identify cases who could have undergone omission of the ALND with confidence, we have retrospectively evaluated the predictive factors of NSN metastasis with positive macrometastasis in the SN. METHODS: This study was based on a retrospective database of 420 patients who underwent sentinel lymph node biopsy (SNB) for breast cancer, of whom 61 patients had SN macrometastasis intra- and postoperatively. We examined predictive factors of NSN involvement in 51 cases of these 61 patients who underwent cALND. All clinical and histological variables were analyzed according to NSN status, by using Mann-Whitney U test, univariate and multivariate logistic regression model. RESULTS: T stage and the proportion of involved SNs among all identified SNs (SN ratio) were correlated with NSN metastasis. Univariate and multivariate analysis showed that T stage and SN ratio were the independent predictive factor of NSN metastasis. The area under ROC curve for SN ratio was 0.71. The best cut off value of SN ratio was 0.667. Negative predictive value to NSN metastasis in cases with both T2 and more than 0.667 of SN ratio was 85.7%. CONCLUSION: In patients with invasive breast cancer and macrometastasis of SN, T stage and SN ratio were useful for prediction of NSN metastasis.

[A Case of Spontaneous Regression of Breast Cancer with Multiple Lung Metastases].

Spontaneous regression of any malignant tumor is a rare event, occurring in about 1 of 60,000-100,000 cases of malignant tumor. We report a case of spontaneous regression of breast cancer with multiple pulmonary metastases. The patient was a 73-year-old woman who complained of a left mammary mass. A tumor, approximately 2.2 cm in diameter, was palpated, and breast cancer was suspected based on ultrasound examination. Histopathological findings of the core needle biopsy specimen indicated invasive ductal carcinoma. The patient underwent partial mastectomy with axillary lymph node dissection. It was a stage ⅡB (pT2N1 [sn] M0) tumor. CT performed after adjuvant therapy confirmed the presence of multiple pulmonary metastases 6 years after surgery. We started anti-cancer therapy with TS-1; however, it was discontinued because an adverse event occurred. Half a year later, tumor shrinkage was confirmed after a recurrence. Four years and 6 months after the treatment was discontinued, the tumor continued to regress spontaneously.

E-cadherin expression and cell proliferation in the primary tumor and metastatic lymph nodes of papillary thyroid microcarcinoma.

Although papillary thyroid microcarcinoma (PTMC) has an excellent prognosis, certain cases exhibit aggressive clinical manifestations. In this study, we assessed the expression of E-cadherin and Ki-67 in primary PTMC tumors and metastatic lymph nodes, in order to investigate the mechanism underlying the mainly indolent but potentially malignant nature of PTMC. A total of 93 PTMC patients treated in our institute were included in this study. All primary tumors and 57 metastatic lymph nodes were immunohistochemically stained and a total of 73 tumors (78.5%) were positive for E-cadherin. E-cadherin expression was significantly less common at the invasive front (58.1%, P<0.01) compared to that at the center of the tumor. Tumors that had lost E-cadherin expression at the invasive front frequently presented with lymph node metastasis (70.6%). Small tumors (≤5 mm diameter) expressed E-cadherin significantly more frequently compared with larger tumors (P=0.04); however, no other particular characteristic was found to correlate with the status of E-cadherin expression in the primary tumors. E-cadherin expression was detected in 49 (86.0%) of the 57 metastatic foci and correlated significantly with the expression status at the invasive front of the tumor (P=0.02). The Ki-67 index was universally low and was not correlated with the clinicopathological characteristics or the E-cadherin expression of the tumors. These results suggested that cancer cells in the metastatic lymph nodes exhibit indolent characteristics, similar to those of the primary PTMC. However, the metastatic cancer cells may have already completed the process of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), suggesting an innate malignant potential.

[A case of squamous cell lung carcinoma that was difficult to distinguish from squamous cell carcinoma of the breast].

A 74 -year-old man was hospitalized for chest pain. Chest computed tomography showed a 4 × 8 cm-sized tumor pressing on the left pectoralis major muscle. Subsequent imaging showed progression of the tumor along with rib erosion and intrapleural invasion. The patient was admitted to our hospital for a follow-up examination of the tumor. Bronchoscopy results were normal. Ultrasound-guided percutaneous needle biopsy was performed. Histopathology indicated squamous cell carcinoma on the basis of the presence of keratin pearls. We therefore diagnosed the patient with squamous cell lung carcinoma fStage IIb (T3N0M0) and subsequently administered chemoradiotherapy owing to the inoperable status of the lesion. We report a case of squamous cell lung carcinoma that was difficult to differentiate from squamous cell carcinoma of the breast, along with a review of the literature.

[Clinical experience with a handheld vacuum-assisted biopsy system (VACORA® )for mammary lesions].

We evaluated the usefulness and safety of a handheld vacuum-assisted biopsy system (VACORA®) in 253 lesions suspected to be malignant. Biopsy samples were successfully obtained from 252 lesions, and no complications occurred that required other treatments during or after the biopsy. The definitive diagnosis rate using VACORA / ®was 89.3% (226/253). For 27 lesions, biopsy using Mammotome®or open biopsy was performed because a diagnosis could not be made with the VACORA® system, despite a category 4 result on ultrasonography. The lesions that were diagnosed as benign using the VACORA® system did not manifest malignant features during the observation period (1-36 months). We considered the VACORA® biopsy system as an effective technique that has both convenience and high diagnostic accuracy.

[Clinical experience of nab-Paclitaxel treatment in 31 patients with breast cancer].

Nanoparticle albumin-bound paclitaxel (nab-PTX, Abraxane®) does not require premedication, and it can be used for patients with alcohol intolerance. We administered nab-PTX to 31 patients with breast cancer between October 2010 and April 2013. Eighteen patients had progressive, recurring breast cancers and 13 patients had locally advanced operable breast cancers. The treatment schedules were 175 or 260 mg/m² every 3 weeks (q3w). No patient experienced an allergic reaction. Grade 1-3 sensory neuropathies were observed in 20 patients; however, no patient experienced grade 4 neuropathy. In patients with locally advanced, operable breast cancer, 1 patient treated with 175 mg/m² q3w had a partial response (PR), while of the patients treated with 260 mg/m² q3w, 10 patients showed a PR, and 1 patient had stable disease (SD). Of the patients with progressive, recurring breast cancer, 2 patients showed a PR and 4 patients had SD when treated with 175 mg/m² q3w, whereas 1 patient displayed a PR and 1 patient had SD when treated with 260 mg/m² q3w. Our investigation suggests that nab-PTX is well tolerated, even by patients with advanced breast cancer.

[Eribulin chemotherapy after taxane treatment in advanced metastatic breast cancer].

Clinical outcomes, including adverse events, in 52 advanced breast cancer patients treated with eribulin chemotherapy after taxane treatment (TX) were analyzed to confirm the effectiveness and safety of this treatment.The objective response rate (ORR) in patients was 34.6% (TX group 31.6%, non-TX group 36.4%). There were no significant differences in overall survival, time to treatment failure, or progression-free between three TX and non-TX groups. Further, adverse events did not differ between groups expression of neutropenia of Grade 3 or more. On the other hand, the number of patients with sensory peripheral neuropathy of Grade 1 or more was significantly more in the TX group than in the non-TX group. Eribulin chemotherapy was effective for the treatment of advanced breast cancer regardless of a history of taxane treatment.In addition, sensory peripheral neuropathy is a possible complication that can occur in advanced breast cancer patients treated with eribulin chemotherapy with taxane treatment history.