Neoadjuvant chemotherapy using nanoparticle albumin-bound paclitaxel plus trastuzumab and pertuzumab followed by epirubicin and cyclophosphamide for operable HER2-positive primary breast cancer: a multicenter phase II clinical trial (PerSeUS-BC04).

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) is a promising antibody partner for anti-human epidermal growth factor receptor 2 (HER2). We performed neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer (BC) using nab-PTX plus trastuzumab (T-mab) and pertuzumab (P-mab), followed by epirubicin and cyclophosphamide (EC). METHODS: In this multicenter phase II clinical trial (January 2019-July 2020), patients with stage I (T1c)-IIIB HER2-positive primary BC were treated with four cycles of nab-PTX plus T-mab and P-mab, followed by four cycles of EC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints were clinical response rate (RR), adverse events (AE), and tumor-infiltrating lymphocytes (TILs) in biopsy samples. RESULTS: In total, 43 patients were enrolled (mean age, 54 years). Twenty-two patients had HER2, and 21 patients had luminal/HER2-subtypes. The overall pCR rate was 53.5% (23/43, 95% CI: 42.6-64.1%, p = 0.184), whilst the pCR for HER2 was 68.2% (15/22, 95% CI: 45.1-86.1) and 38.1% for luminal/HER2 (8/21, 95% CI: 18.1-61.6%). The RR was 100% [clinical (c) CR:25, partial response (PR): 18]. AEs (≥ G3) included neutropenia (23.3%), leukopenia (7.0%), liver dysfunction (7.0%), and peripheral neuropathy (4.7%) when nab-PTX was administered. EC administration resulted in leukopenia (34.2%), neutropenia (31.6%), and febrile neutropenia (15.8%). The TILs in preoperative biopsy samples were significantly higher in pCR compared to non-pCR samples. CONCLUSION: Nab-PTX plus T-mab and P-mab induced a high pCR rate in HER2-positive BC, particularly in the HER2-subtype. Given that AEs are acceptable, this regimen is safe and acceptable as NAC for HER2-positive BC.

[Analysis of Neoadjuvant Chemotherapy for HER2-Positive Breast Cancer in Our Department].

We investigated neoadjuvant chemotherapy for patients with human epidermal growth factor receptor 2(HER2)-positive breast cancer. Twenty-eight patients with HER2-positive breast cancer received neoadjuvant chemotherapy from January 2011 to December 2017. Of the 28 patients, pathological complete response(pCR)was achieved in 14 patients. The pCR rate for the docetaxel(DTX)-containing regimen was 47.4%, whereas that for the nanoparticle albumin-bound paclitaxel(nab- PTX)-containing regimen was 71.4%. Therefore, nab-PTX-containing therapy may be more effective than a DTX-containing regimen for patients with HER2-positive breast cancer.

Combination therapy of 5-fluorouracil with rapamycin for hormone receptor-negative human breast cancer.

AIM: To determine a novel chemotherapeutic concept for hormone receptor-negative and HER2-positive breast cancer, a high progression form of the disease for which treatment has been difficult. A combination therapy of 5-fluorouracil (5-FU) with rapamycin (Rap) was examined. MATERIALS AND METHODS: The growth inhibitory effect of treatment was evaluated by an MTT assay and cellular signal/apoptotic pathways were investigated by Western blotting and Hoechst 33342 staining. RESULTS: Rap was shown to induce an inhibitory effect on the phosphorylation of mTOR and p70S6K. The expression of thymidine synthase (TS) was decreased by Rap. The addition of 5-FU to Rap was found to increase cell death. The Hoechst 33342 assay showed that apoptosis was increased by the combination of 5-FU and Rap in comparison to 5FU alone. CONCLUSION: 5-FU is more effective in combination with the TS-reducing action of Rap, even for highly HER2-expressing breast cancer cells.

Effect of hepatocyte growth factor on progression of liver metastasis in colorectal cancer.

BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most common cancers worldwide, and a strategy to assess and control liver metastasis will be critical to control patient prognosis. To evaluate therapeutic approaches, the biological responses associated with hepatectomy were studied with a focus on hepatocyte growth factor (HGF). METHODOLOGY: In 54 patients with metastatic liver tumors due to CRC, c-Met expression was estimated by western blotting from resected tissue specimens. Serum HGF levels were measured by an ELISA method and compared with other liver function serum factors. RESULTS: The preoperative serum level of HGF was found to be related to ICGR15, ALP, CHE and AST, but after hepatectomy, the change was not correlated with other liver function factors. From an evaluation of pre-operative liver condition using ICGR15, an increasing rate (post/pre) of AST, ALT, ALP and HGF was observed to be higher in cases with positive outcomes. In cases with normal pre-operative levels of serum HGF, the increasing rate (post/pre) of HGF after surgery was higher than in cases with abnormally high pre operative values (3.07 +/- 0.87 and 2.38 +/- 0.74, respectively; p = 0.0102). In cases where tumors recurred within 6 months (early recurrence cases), the c-Met value in tumor tissue was higher than in cases with no recurrence, even in cases where there was no tendency for an increasing rate of HGF. In addition, multiplying data serum HGF increasing rate by c-Met value in tissue was significantly higher in early recurrence cases than in cases with no recurrence, (3.96 +/- 0.62 and 3.00 +/- 1.16 respectively; p = 0.0135). A similar finding was also detected following curative operations involving multiple tumor resection (3.93 +/- 0.64 vs. 2.84 +/- 1.24 for early and no recurrence, respectively; p = 0.0147). CONCLUSION: The present study demonstrated that cancer with high c-Met expression and under high level of its ligand, HGF, led to recurrence soon after hepatectomy, leading to unfavorable patient prognosis. If pathological or biochemical factors from resected specimens could help identify patients with a high risk of relapse, innovative adjuvant chemotherapy protocols could be initiated.

Clinical evaluation of modified reconstruction method after pancreatoduodenectomy.

BACKGROUND/AIMS: The new reconstruction procedure after pancreatoduodenectomy (PD) is described to evaluate its usefulness. METHODOLOGY: The jejunum was made for an end-to-side choledochojejunostomy, and the cut proximal jejunum for approximately 20 cm was led to the pancreatic stump for end-to-end anastomosis with telescoping. Approximately 20 cm of jejunum was created with a side-to-end anastomosis with the stomach, and end-to-side jejuno-jejunostomy for Roux-en Y reconstruction. As a postoperative course, separated loop method (SL, n=38) was evaluated by comparing pancreatogastrostomy (PG, n=31) and Imanaga method (IM, n=26). RESULTS: On SL, PG and IM cases, the high amylase level in drainage fluid was noted in 2.6%, 6.5% and 19.2%, respectively. The delayed gastric emptying was seen in PG and IM, but not in SL. Serum albumin levels were similar, but cholinesterase and total cholesterol levels were significant better in SL. CONCLUSIONS: SL method is safe for complications after PD.

A modified reconstruction method to prevent critical complications after pancreatoduodenectomy.

BACKGROUND/AIMS: A new method of reconstructing the pancreatic stump after pancreatoduodenectomy (PD) is necessary to improve the postoperative mortality rate. Thus, we modified the pancreatoenteric procedure to reduce anastomotic leakage from the pancreatic stump after PD, and we conducted a study to evaluate the usefulness of the new procedure on the basis of patients' postoperative condition. METHODOLOGY: We compared the postoperative condition of 21 patients who underwent PD with the new separated loop (SL) reconstruction (6 men, 11 women; mean age, 67.7+/-7.2 years) to that of 31 patients (12 men, 19 women; mean age, 66.8+/-10.3 years) who underwent PD with pancreatogastrostomy (PG). In the SL reconstruction procedure, the proximal jejunum is brought up behind the colon, and an end-to-side choledochojejunostomy is made with a single layer of interrupted sutures. Approximately 20cm of the jejunum is fitted with a fixed stomach tube for postoperative enteral feeding, and the cut proximal jejunum is positioned next to the pancreatic stump. A pancreatic tube is inserted into the lumen of the pancreatic duct and fixed without closing the pancreatic duct. Pancreatojejunostomy is achieved as an end-to-end anastomosis with the pancreatic stump telescoping into the proximal jejunum. Approximately 20cm of the jejunum is anastomosed side-to-end to the stomach, and end-to-side jejunojejunostomy is made to complete a Y-type reconstruction. Each patient's postoperative condition was also assessed on the basis of serum albumin (ALB), cholinesterase and total cholesterol (T-CHO) levels on postoperative days (PODs) 14 and 28. RESULTS: A high level of amylase in drainage fluid was noted in two (6.5%) and delayed gastric emptying in four (12.9%) of the patients in the PG group. There were no complications in the SL group. Postoperative levels of ALB on POD 14 and T-CHO on POD 28 were significantly higher than in the PG group. CONCLUSIONS: The SL method is safe and does not induce complications after PD. Our results indicate that this method may provide a favored outcome.