An Exploratory Phase II Study of Eribulin Re-challenge After Short Term Therapy of 5-Fluorouracil for HER2 Negative, Advanced or Recurrent Breast Cancer.

BACKGROUND/AIM: In our previous study, first-line eribulin (ERI) showed 25 weeks of progression-free survival (PFS). This study investigated the efficacy and safety of ERI re-administration in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: HER2-negative MBC patients who had never received chemotherapy for MBC received first-line ERI for 18 weeks if they did not have disease progression, and then one cycle of S-1 before ERI re-administration. RESULTS: Twelve patients received ERI re-administration. The PFS of re-administered ERI was 13 weeks. Total duration of ERI use was 30 weeks. The incidence and severity of adverse events were consistent with previous reports. CONCLUSION: In the first-line setting, the total PFS of eribulin was extended by S-1 administration before disease progression, compared with that of our previous report.

Interstitial lung disease associated with adjuvant and neoadjuvant chemotherapy in early breast cancer.

BACKGROUND: Interstitial lung disease (ILD) is a rare adverse event in patients receiving adjuvant or neoadjuvant chemotherapy (NAC) for breast cancer. Few studies have reported the frequency of ILD in detail, and only small numbers of cases have been described in the literature. Given these previous findings concerning ILD, we retrospectively examined the clinicopathological characteristics of five cases of ILD who had received epirubicin and cyclophosphamide (EC) and compared their findings with non-ILD cases. METHODS: The present single-center retrospective study included breast cancer patients who underwent adjuvant chemotherapy or NAC at our hospital between January 2014 and January 2021. RESULTS: Thirty-nine patients who had received EC for operable breast cancer were enrolled in this study. ILD developed 5 out of 39 patients (12.8%). The incidence of ILD in patients with non-dose-dense (dd) or dd chemotherapy was statistically significantly different (p = 0.0149). ILD occurred in three patients during dd EC treatment and two during weekly paclitaxel (wPTX) after dd EC. ILD was detected in one patient with high Krebs von den Lungen-6 (KL-6) levels, in two patients with continuous pyrexia, and in two patients from computed tomography imaging, which was taken to estimate the efficacy of chemotherapy, in two patients. Three of the 5 ILD patients underwent bronchoalveolar lavage, and 2 of these patients were diagnosed with Pneumocystis jirovecii pneumonia (PCP). There were no cases of serious ILD that required steroid pulse therapy. CONCLUSIONS: Dd chemotherapy may be associated with an increased ILD frequency, which may reflect developing PCP. Careful monitoring and a timely diagnosis are useful for detecting early-stage ILD.

[Radiation-Induced Undifferentiated Pleomorphic Sarcoma after Breast-Conserving Surgery-A Case Report].

The patient was a 73-year-old woman who had undergone breast-conserving surgery followed by irradiation (50 Gy/25 Fr)to the residual breast for left breast cancer 4 years before. Computed tomography for routine examination revealed a soft tissue mass on her left chest wall. Ultrasonography showed a hypoechoic mass with heterogeneous internal echo, 3.5×3.0×1.5 cm in size. Core-needle biopsy was performed, and histological examination revealed proliferation of spindle-shaped or pleomorphic and highly atypical cells. On immunohistochemistry, the tumor was negative for AE1/AE3, CD34, SMA, desmin, and S-100 and focally positive for CD68. Based on these findings, undifferentiated sarcoma was suspected. The patient underwent wide local excision of the chest wall with a surgical margin of 3-4 cm from the tumor edge. The histological diagnosis was undifferentiated pleomorphic sarcoma. Judging from the clinical course, this tumor was radiation-induced sarcoma. The patient remains disease-free 54 months after the operation.

Neoadjuvant Chemotherapy With Nab-paclitaxel Plus Trastuzumab Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide for HER2-positive Operable Breast Cancer: A Multicenter Phase II Trial.

AIM: This study was conducted in order to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus trastuzumab followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) in a neoadjuvant chemotherapy (NAC) setting for patients with human epidermal growth factor receptor 2 (HER2)-positive operable breast cancer. PATIENTS AND METHODS: Each patient received four cycles of 260 mg/m2 nab-paclitaxel with 6 mg/kg trastuzumab (8 mg/kg as the loading dose) every 3 weeks (q3w) followed by four cycles of FEC (500/100/500 mg/m2) q3w. The primary endpoint was pathological complete response (pCR) rate. RESULTS: Twenty-nine patients were analyzed for the efficacy and safety of this treatment. All patients completed four cycles of nab-paclitaxel and trastuzumab, and 28 patients completed four cycles of FEC. Twenty-seven patients subsequently underwent surgery. The pCR rate was 74.0%. The most frequent toxicity was sensory neuropathy (96.6%), but grade 3 neuropathy rate was 3.4%. CONCLUSION: Nab-paclitaxel plus trastuzumab followed by FEC in patients with HER2-positive operable breast cancer is considerably effective and well tolerated.

Metachronous solitary mediastinal lymph node metastases of hepatocellular carcinoma treated by video-assisted thoracic surgery twice: Report of a case.

Solitary mediastinal lymph node metastasis of hepatocellular carcinoma (HCC) is rare. We report a case of metachronically solitary mediastinal metastases of HCC treated by video-assisted thoracic surgery (VATS) twice. A 66-year-old man underwent repeated laparoscopic radiofrequency ablation or trans-arterial catheter chemo-embolization against HCC for more than 10 years. The level of alpha fetoprotein protein was elevated, and radiological modalities including FDG-PET revealed solitary mediastinal tumor metachronically. VATS was performed bilaterally twice. The postoperative course was uneventful and there had no recurrence of extra-hepatic metastases and tumor markers are within normal limits at 18 months after second VATS. VATS is a minimally invasive and useful procedure for solitary mediastinal lymph node metastasis of HCC. If primary HCC was controlled and lymph node metastasis was solitary, mediastinum lymphadenectomy using VATS might give good short and long term results.

Safety and Efficacy of Low-dose Nanoparticle Albumin-bound Paclitaxel for HER2-negative Metastatic Breast Cancer.

BACKGROUND/AIM: Nab-paclitaxel (nab-PTX) is an albumin-bound paclitaxel formulation. Although nab-PTX has shown superior efficacy compared to conventional paclitaxel (PTX) in metastatic breast cancer (MBC), chemotherapy-induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In this study, we aimed to estimate the feasibility of the nab-PTX 175 mg/m2/3weeks regimen. PATIENTS AND METHODS: Patients having metastatic or inoperable HER2-negative breast cancer received 175 mg/m2 of nab-PTX every three weeks. The primary endpoint was safety and the secondary endpoints were response and survival. RESULTS: Seventeen patients were enrolled with a median age of 64 years. Ten patients had estrogen receptor positive disease and seven had triple-negative disease. CIPN was observed in seven patients (41%) however, grade 3 CIPN was only seen in one patient (6%). Objective response rate was 41% and progression-free survival was 23 weeks. CONCLUSION: Nab-PTX 175 mg/m2/3wks regimen has a good safety profile and less frequent CIPN. This regimen can contribute to the strategy of MBC treatment.

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer.

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted.

A phase II, multicenter, single-arm trial of eribulin as first-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer.

The treatment goals for metastatic breast cancer (MBC) are prolonging survival and improving the quality of life. Eribulin, a non-taxane tubulin inhibitor, demonstrated improved survival in previous studies and also showed mild toxicity when used in late-line therapy for MBC. We conducted a phase II study to investigate the efficacy of eribulin mesylate as the first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative MBC. This was a phase II, open-label, single-arm, multicenter trial conducted in Japan. Patients with HER2-negative MBC received intravenous eribulin (1.4 mg/m(2) on days 1 and 8 of each 21-day cycle). The primary efficacy outcome was overall response rate (ORR). Secondary outcomes included time to treatment failure, progression-free survival (PFS), overall survival (OS), and safety. A total of 35 patients were enrolled and received a median of 8 (range 1-21) cycles of eribulin therapy. ORR and clinical benefit rate were 54.3 and 62.9 %, respectively. Median PFS was 5.8 months and median OS was 35.9 months. Grade 3 or 4 neutropenia was observed in 63 % of patients. The majority of non-hematological adverse events were mild in severity. The present trial demonstrated that eribulin has antitumor activity comparable with other key established cytotoxic agents with acceptable safety and tolerability. Thus, eribulin as first-line chemotherapy might be beneficial for patients with HER2-negative MBC.

Arabidopsis sos1 mutant in a salt-tolerant accession revealed an importance of salt acclimation ability in plant salt tolerance.

An analysis of the salinity tolerance of 354 Arabidopsis thaliana accessions showed that some accessions were more tolerant to salt shock than the reference accession, Col-0, when transferred from 0 to 225 mM NaCl. In addition, several accessions, including Zu-0, showed marked acquired salt tolerance after exposure to moderate salt stress. It is likely therefore that Arabidopsis plants have at least two types of tolerance, salt shock tolerance and acquired salt tolerance. To evaluate a role of well-known salt shock tolerant gene SOS1 in acquired salt tolerance, we isolated a sos1 mutant from ion-beam-mutagenized Zu-0 seedlings. The mutant showed severe growth inhibition under salt shock stress owing to a single base deletion in the SOS1 gene and was even more salt sensitive than Col-0. Nevertheless, it was able to survive after acclimation on 100 mM NaCl for 7 d followed by 750 mM sorbitol for 20 d, whereas Col-0 became chlorotic under the same conditions. We propose that genes for salt acclimation ability are different from genes for salt shock tolerance and play an important role in the acquisition of salt or osmotic tolerance.

A novel abi5 allele reveals the importance of the conserved Ala in the C3 domain for regulation of downstream genes and salt tolerance during germination in Arabidopsis.

Abscisic acid (ABA) signal transduction during Arabidopsis seed development and germination requires a Group A bZIP transcription factor encoded by ABA INSENSITIVE5 (ABI5). In addition to the basic leucine zipper DNA binding domain, Group A bZIPs are characterized by three N-terminal conserved regions (C1, C2 and C3) and one C-terminal conserved region (C4). These conserved regions are considered to play roles in ABI5 functions; however, except for the phosphorylation site, the importance of the highly conserved amino acids is unclear. Here, we report a novel abi5 recessive allele (abi5-9) that encodes an intact ABI5 protein with one amino acid substitution (A214G) in the C3 domain. The abi5-9 plants showed ABA insensitivity during germination and could germinate on medium containing 175 mM NaCl or 500 mM mannitol. Em1 and Em6--both encoding late embryogenesis abundant (LEA) proteins and directly targeted by ABI5 regulation--were expressed at very low levels in abi5-9 plants compared with the wild type. In yeast, the abi5-9 protein exhibited greatly reduced interaction with ABI3 compared with ABI5. These data suggest that Ala214 in ABI5 contributes to the function of ABI5 via its interaction with ABI3.

Parathyroid hormone-related protein expression, in combination with nodal status, predicts bone metastasis and prognosis of breast cancer patients.

Parathyroid hormone-related protein (PTHrP) has been known to play an important role in the formation of meta-static lesions in the bone. However, there remains controversy over its practical role in predicting the occurrence of bone metastasis and the prognosis of breast cancer patients. In this study, we attempted to investigate the clinical value of PTHrP expression status in the primary lesions of breast cancer patients. We immunohistochemically investigated PTHrP expression in surgically resected specimens from 125 primary breast cancer patients whose clinicopathological background and long-term prognosis were available. Positive PTHrP staining was demonstrated in 79 (63.2%) tumors. PTHrP was expressed significantly more frequently in the tumors of premenopausal patients. Bone metastases were significantly more common in patients with T4 tumors, with a positive node, with distant metastasis and with PTHrP-positive tumors. Multivariate logistic analysis revealed positive PTHrP expression as an independent risk factor for predicting bone metastasis. PTHrP expression was significantly related to a shorter overall survival. Bone metastasis was found significantly more frequently (28.3%) in PTHrP- and node-positive cases than in double-negative cases, and the rate was more pronounced in postmenopausal cases (32.1%). Expression of PTHrP in primary lesions, in combination with positive nodal status, is indicative of an increased risk of bone metastasis in breast cancer patients.

Kikuchi-Fujimoto disease mimicking tuberculous lymphadenitis.

A 28-year-old woman was referred to our hospital for treatment of tuberculous lymphadenitis, after presenting with fever, left cervical lymphadenopathy, and a positive interferon-gamma release assay (QuantiFERON®-TB Gold In-Tube; QFT) result. Surprisingly, biopsy specimens of the cervical lymph nodes showed necrotic lesions with prominent nuclear debris and a proliferation of histiocytes, consistent with Kikuchi-Fujimoto disease (KFD). A diagnosis was made of KFD complicated by latent tuberculosis infection (LTBI), and all symptoms had resolved completely two months post-diagnosis. KFD may be misdiagnosed as tuberculous lymphadenitis, and antibiotics unnecessarily prescribed. Careful attention should therefore be paid when diagnosing cervical lymphadenopathy.

[A case of breast cancer with postoperative metastasis to the supraclavicular lymph nodes-recurrence-free survival achieved by surgical excision following chemotherapy].

The patient, a 58-year-old woman, underwent a partial excision of the right breast and an axillary lymph node dissection in October 2004. The histopathological findings were: solid tubular carcinoma with metastasis to 17 axillary lymph nodes; triple negative-type breast cancer. As adjuvant therapy, FEC60 was administered 6 times, followed by radiotherapy applied to the residual breast and the right supraclavicular fossa. In Novermber 2007, she noted a tumorous growth above the right clavicle. The pathological diagnosis via fine needle biopsy was adenocarcinoma. An oral antineoplastic agent was given for about 6 months, but did not alter the lymph nodes. No distant recurrence was noted during this time. In August 2008, the right supraclavicular lymph nodes were dissected. The patient has been under observation without treatment, but no signs of recurrence have been noted. It was thought that excision of the recurrent supra-clavicular lymph nodes should be considered after careful examination in some individual cases.

Extended sleeve lobectomy for interlobar lymph node metastasis invading the bronchus from peripheral lung cancer.

Although extended sleeve lobectomy has been used as an alternative to pneumonectomy for the treatment of centrally located lung cancer, the validity of this surgical procedure is unclear in patients with peripheral lung cancer with interlobar lymph node metastasis invading the bronchus. We herein report four patients with peripheral lung cancer in the left lower lobe who underwent extended sleeve lobectomy consequent to interlobar lymph node metastasis. The tumor and metastasized lymph node was extirpated en bloc with division of the main bronchus and upper division bronchus, and those bronchi were anastomosed using the telescope method. All patients were doing well without recurrence. Extended sleeve lobectomy may be applicable to patients with peripheral lung cancer with interlobar lymph node metastasis invading the bronchus to avoid pneumonectomy.

[Combination chemotherapy of S-1/low-dose CDDP/lentinan for advanced gastric cancer].

Eight patients with inoperable advanced gastric cancer were treated with combination chemotherapy of S-1, low-dose cisplatin(CDDP)and Lentinan. S-1 80 mg/ m² was orally administered for 2 weeks followed by 1-week rest, CDDP 15 mg/ m² and Lentinan 2 mg/body were given intravenously on day 1 and 8. One complete response and four partial responses were observed for an overall response rate of 63%(5 of 8 patients). Only one patient developed over grade 3 toxicity leukocytopenia. Many patients could be maintained by long-term continuous treatment. Since combination chemotherapy of S-1/low-dose CDDP/Lentinan for advanced gastric cancer was very tolerable, it could be used for a long time.

[A case of the local advanced gastric cancer which became a resection possible in S-1/CDDP/lentinan neoadjuvant chemotherapy].

A 61-year-old man with esophagus invasive advanced gastric cancer and peritoneum dissemination underwent three courses of S-1/CDDP/Lentinan (LNT) combination neoadjuvant chemotherapies (T3N1P1H0, Stage IV) (It is S-1 80 mg/m2,CDDP 15 mg/m2 and LNT 2 mg/body twice/week for two weeks) since down staging was obtained. We performed the surgery of total gastrectomy, splenectomy, D2 lymph node dissection, and Roux-en Y reconstruction in March 2008. With the surgical examination, there was no ascites and peritoneal dissemination. Although there was serious infiltration, we were able to remove it. In the histopathological effect judgment, it was Grade 1b. We changed the therapy to S-1 alone after the same chemotherapy for six months. One year after the operation, he is still alive one year after the surgery.

Diagnosis of parathyroid carcinoma using immunohistochemical staining against hTERT.

The differential diagnosis of parathyroid carcinoma from benign adenoma is often difficult when its typical clinicopathological features are absent, even with the aid of various molecular markers. We recently demonstrated that telomerase activation through hTERT expression is a unique characteristic that is limited to parathyroid carcinoma and not seen in benign tumors. In the present study, we investigated hTERT expression in parathyroid tumors using immunohistochemistry in an attempt to determine its clinical utility. There was no evidence of immunoreactivity in the 4 normal parathyroid glands and the 18 typical adenomas. In contrast, one atypical adenoma stained positively and homogeneously, and the disease recurred three times clinically. All of the 6 carcinomas demonstrated a clear positive nuclear staining of hTERT. Every hTERT-positive tumor showed a high Ki-67 index, i.e., greater than 4%. Nucleolin, an hTERT-binding protein, was abundantly and homogeneously expressed in all specimens examined independent of the pathological diagnosis and hTERT or Ki-67 expression. Therefore, it is possible that immunostaining with an anti-hTERT antigen (NCL-L-hTERT) individually may distinguish parathyroid carcinoma from benign tumors.

[A case report of primary duodenal adenocarcinoma with marked lymph node metastases responding to chemotherapy with S-1 plus CDDP combination].

The patient was a 48-year-old female who underwent combination chemotherapy of S-1 plus CDDP after diagnosis of primary duodenal adenocarcinoma with marked lymph node metastases. The regimen was as follows: 80 mg/m2 of S-1 on days 1-21 orally and 60 mg/m2 of CDDP on day 8 intravenously. One course lasted for 5 weeks. After 5 courses, metastasized lymph nodes were remarkably reduced. This case suggests that the combination of S-1 and CDDP may be an effective regimen for advanced primary duodenal adenocarcinoma.

Clinical significance of intra-tumoral sinusoidal structures showing lympho-endothelial immunoreactivity in breast cancer.

The lymphatic system is known as one of the most important pathways in the disease progression of breast cancer. In this study, we investigated lymphatic systems intra-tumorally, and found a unique structure displaying lymphoendothelial immunoreactivity. These incomplete vessel-like structures that formed sinusoids and specifically reacted with the D2-40 antibody, were found in the tumor stroma and were often infiltrated by cancer cells. To show the clinical significance of these intra-tumoral sinusoidal structures (ISS), we examined 113 specimens of surgically resected breast cancer. In multivariate logistic regression analysis, lymph node status (p=0.024) and disease recurrence (p=0.008) were the independent factors that correlated with the existence of ISS. Positive ISS detection in the tumor correlated more strongly with lymph node metastases than positive lymphovascular invasion by cancer cells. Furthermore, a significant correlation with frequent recurrence and poorer survival were recognized in patients with ISS (p<0.001, log-rank test). The evaluation of ISS by needle-biopsied specimens was as accurate as that with surgical specimens, and a significant correlation between the positive ISS evaluated by biopsy and positive lymph node status (p=0.020) was found. In conclusion, ISS are unique structures which play a crucial role in disease progression through lymphatic systems in breast cancer. In a clinical setting, the detection of ISS by biopsy specimen should be considered as a method for determining prognosis instead of a whole tumor examination.