A patient with stage IIIB advanced breast cancer who is still alive 24 years after surgery: a case report and remarks on the treatment strategies.

Background: In recent years, a number of agents possessing novel mechanisms, such as cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors and PIK3CA inhibitors, have been developed for the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor type negative (HER2-) advanced or recurrent breast cancer. As a result, the treatment strategies for advanced or recurrent breast cancer have changed significantly. The combination of CDK 4/6 inhibitors administration and endocrine therapy is now widely used in the treatment of HR+ HER2- recurrent breast cancer with improved outcomes. In 2021, abemaciclib was approved as post-operative adjuvant combination therapy with endocrine therapy for HR+ HER2- advanced breast cancer and is expected to suppress postoperative recurrence. A range of new agents are being developed in addition to CDK4/6 inhibitors that provided more options of treatment strategies for advanced or recurrent breast cancer, which in turn could improve outcomes. However, the prognosis for the recurrent HR+ HER2- breast cancer remains poor, overall survival (OS) is still very low and a complete cure is difficult even with the treatments. Case Description: In 1998, 24 years ago, neoadjuvant chemotherapy (NAC) and the concept of subtypes were not even widespread, the number of available drugs was far fewer than today, the clinical treatment guidelines had not been established. Nevertheless, we experienced a case of HR+ HER2- advanced breast cancer, stage IIIB at the initial diagnosis, which was consistently treated with the aim of complete cure and with the various treatments available at the time, resulting in long-term survival. 24 years have passed since the initial surgery, the patient has continued to do well despite repeated recurrences and remissions. Conclusions: We report here a case of long-term survival in advanced breast cancer of 24 years after surgery, and remark for future treatment strategies that not bound by the conventional treatment policy that emphasizes quality of life without aiming for complete cure.

Isolation of Aspergillus oryzae mutants producing low levels of 2,4,6-trichloroanisole.

Musty or moldy off-odor in sake severely reduces its quality. Such off-odor is caused by 2,4,6-trichloroanisole (TCA), a compound that is produced by Aspergillus oryzae during sake production by O-methylating the precursor 2,4,6-trichlorophenol (TCP). TCP suppresses the growth of fungi, including A. oryzae, although TCA does not. Therefore, strains that are unable to convert TCP to TCA should be sensitive to TCP in the medium. Nevertheless, A. oryzae with a disrupted O-methyltransferase gene (ΔomtT) grew in a medium containing TCP. In agar medium, we observed no growth difference between the ΔomtT strain and a non-disrupted transformant; however, a significant growth delay was observed with the ΔomtT strain grown in liquid medium containing 0.5 µg/mL of TCP. This strain was more sensitive to low concentrations of TCP, suggesting that omtT contributes to the conversion (detoxification) of TCP in liquid culture. We generated A. oryzae RIB 40 mutants by ultraviolet irradiation and then cultured them in liquid medium containing TCP to obtain strains that did not produce moldy odor. The slow-growing strains were cultured in agar plates and then used to make koji with added TCP. We obtained three strains with lower TCA-producing ability and with sufficient hydrolase activities for sake brewing.

Growth characteristics of Aspergillus oryzae in the presence of 2,4,6-trichlorophenol.

During the making of rice-koji for sake production, 2,4,6-trichlorophenol (TCP) is O-methylated to 2,4,6-trichloroanisole (TCA) by the koji-mold, Aspergillus oryzae, resulting in a musty/moldy off-odor, which significantly reduces the quality of sake. Thus, we aim to develop A. oryzae strains with a less-efficient ability to produce TCA. TCP is a fungicide that suppresses the growth of fungi, whereas TCA does not. The exact effects of TCP on the growth of A. oryzae are unknown. However, it is assumed that a strain with low TCP conversion ability will be sensitive to TCP concentration. In this study, we investigated the effects of the different concentrations of TCP on the growth suppression of A. oryzae. As the TCP concentration in the media increased, the growth rate, and conidia formation of A. oryzae slowed down. No growth was observed in liquid culture (for 1 day at 30°C) containing more than 30 µg/mL of TCP and in agar culture (for 7 days at 30°C) containing more than 50 µg/mL of TCP. However, A. oryzae was able to grow on alpha rice containing higher concentrations of TCP. The results in agar culture are consistent with the effects of TCP on other Aspergillus species.

Decline of T cell-related immune functions in cancer patients and an attempt to restore them through infusion of activated autologous T cells.

We developed a scoring system that can combine several immunological parameters and express the immune status of individuals as a simple numeral. T cell immune score was obtained by using 5T cell-related parameters: number of T cells, ratio of CD4(+)T cells to CD8(+)T cells, number of naïve T cells, ratio of naïve T cells to memory T cells, and T cell proliferative index (TCPI). TCPI was calculated by using number of T cells and their proliferative activity. We assessed T cell immune score in 103 patients with colorectal cancer and 51 healthy age-matched controls. The results were as follows: (1) T cell-immune score of patients in stages I-IV before surgery was significantly decreased as compared with controls. (2) The number of regulatory T cells in patients in stages I-IV gradually increased with disease progression. (3) T cell immune score was strongly suppressed after surgery, but were recovered to the initial level within a month. (4) Furthermore, restoration of immunological function was attempted in cancer patients by infusion of activated autologous T cells. The effectiveness was confirmed by an increase of TCPI in many cancer patients.

[A case of peritoneal dissemination caused by recurrent hilar cholangiocarcinoma treated with intraperitoneal infusion of cisplatin (CDDP) and systemic chemotherapy].

Six years and 9 months ago, a 72-year-old man underwent left hepatectomy for a hilar cholangiocarcinoma(T2N0M0: Stage II A). At 3 years and 2 months after surgery, he was admitted for rectal tumor and reoperation. From surgery, it was diagnosed as peritoneal metastases of the cholangiocarcinoma, and an intraperitoneal infusion port was placed. He was treated with gemcitabine administered iv at day 1 and CDDP ip at day 8 every 3 or 4 weeks for 2 years. Then, gemcitabine was changed to docetaxel because of elevation of CA19-9. Both docetaxel iv and CDDP ip were administered for one and half years. For 3 years and 4 months, 12.2 g of CDDP, 28.0 g of gemcitabine and 920 mg of docetaxel were administered. As serum CA19-9 elevated again, he has been treated with S-1 and docetaxel ip for 3 months. This case indicates that intraperitoneal application of CDDP with systematic chemotherapy was effective for carcinomatous peritonitis without serious side effects.

[A case of pericardial tamponade caused by recurrent breast cancer treated with intrapericardial and intrapleural infusion of cisplatin (CDDP)].

Breast cancer rarely metastasizes to the pericardial cavity to cause cardiac tamponade. We have recently experienced a case of pericardial tamponade due to recurrent breast cancer. A 41-year-old woman who underwent modified radical mastectomy for a right breast cancer (T(1)N(3)M(0), Stage IIIA) 8 years and 8 months ago, was admitted for dyspnea and cough. Chest X-ray and CT scan revealed cardiomegaly and right pleural effusion, and cardiac echogram showed marked retention of pericardial effusion. A diagnosis of cardiac tamponade was made, and pericardiocentesis and thoracentesis were carried out immediately. Based on cytodiagnosis of pericardial and pleural effusion, the diagnosis was pericardial and intrapleural metastases of the breast cancer. Dyspnea was improved by pericardiocentesis and thocacentesis. Both intrapericardiac and intrathoracic instillation of CDDP prevented reaccumulation of pericardial and pleural effusion. After local chemotherapy with CDDP, systemic chemotherapy of CPT-11 was started. Thereafter the patient was discharged from the hospital and recovered her daily activities. This case indicates that intrapericardiac application of CDDP was effective for carcinomatous cardiac tamponade without serious side effects.

A plant growth retardant related to chlamydocin and its proposed mechanism of action.

A comparison of the plant growth retardant activity of the chlamydocin analogues, compound 1, six derivatives from 1 and 2, and two synthetic analogues revealed that there are two types of retardant in chlamydocin analogues. One, for example in compound 1, requires an oxygen atom at C-8 of the 2-aminodecanoic acid moiety to show retardant activity. The other, for example in compound 8, requires no oxygen atom at C-8 but requires a specific alkyl group chain length for activity. To determine the differences in mode of action of both types of retardant, rice seedlings were separately treated with compounds 1 and 8, and after appearance of dwarfism, their endogenous ABA and GA(1) levels were determined and compared to those of the control. Treatment with 1 (10 nmol/plant) increased ABA levels 4 times higher than that of the control and decreased GA(1) levels to 20% of that of the control. Treatment with 8 (30 nmol/plant) did not affect the ABA level but decreased GA(1) content to 5% of that of the control.

Fungal melanin inhibitor and related compounds from Penicillium decumbens.

Two polyketides, decumbenones A and B, and versiol were isolated from the culture filtrate of the fungus, Penicillium decumbens. Their respective structures were 1-(2,8-dihydroxy-1,2,6-trimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-3-hydroxy-1-propanone and 1-(2,8-dihydroxy-1,2,6-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-3-hydroxy-1-propanone based on NMR spectroscopic data, chemical conversion, and X-ray analysis. Decumbenone A inhibited melanization in Magnaporthe grisea, the rice blast pathogen, whereas decumbenone B like versiol did not.