Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer were updated and published online in 2023, and adapted, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with early breast cancer. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with breast cancer representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and KSMO. The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with early breast cancer across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling, as well as the age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer.

BACKGROUND: Although 1% has been used as cut-off for estrogen receptor (ER) positivity, several studies have reported that tumors with ER < 1% have characteristics similar to those with 1% ≤ ER < 10%. We hypothesized that in patients with human epidermal growth factor 2 (HER2)-negative breast cancer, a cut-off of 10% is more useful than one of 1% in discriminating for both a better pathological complete response (pCR) rate to neoadjuvant chemotherapy and a better long-term outcome with adjuvant hormonal therapy. Our objectives were to identify a percentage of ER expression below which pCR was likely and to determine whether this cut-off value can identify patients who would benefit from adjuvant hormonal therapy. PATIENTS AND METHODS: Patients with stage II or III HER2-negative primary breast cancer who received neoadjuvant chemotherapy followed by definitive surgery between June 1982 and June 2013 were included. Logistic regression models were used to assess the association between each variable and pCR. Cox models were used to analyze time to recurrence and overall survival. The recursive partitioning and regression trees method was used to calculate the cut-off value of ER expression. RESULTS: A total of 3055 patients were analyzed. Low percentage of ER was significantly associated with high pCR rate (OR = 0.99, 95% CI = 0.986-0.994, P < 0.001). The recommended cut-off of ER expression below which pCR was likely was 9.5%. Among patients with ER ≥ 10% tumors, but not those with 1%≤ER < 10% tumors, adjuvant hormonal therapy was significantly associated with long time to recurrence (HR = 0.24, 95% CI = 0.16-0.36, P < 0.001) and overall survival (HR = 0.32, 95% CI = 0.2-0.5, P < 0.001). CONCLUSION: Stage II or III HER2-negative primary breast cancer with ER < 10% behaves clinically like triple-negative breast cancer in terms of pCR and survival outcomes and patients with such tumors may have a limited benefit from adjuvant hormonal therapy. It may be more clinically relevant to define triple-negative breast cancer as HER2-negative breast cancer with <10%, rather than <1%, of ER and/or progesterone receptor expression.

c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun.

c-Jun N-terminal kinase (JNK) plays a vital role in malignant transformation of different cancers, and JNK is highly activated in basal-like triple-negative breast cancer (TNBC). However, the roles of JNK in regulating cancer stem-like cell (CSC) phenotype and tumorigenesis in TNBC are not well defined. JNK is known to mediate many cellular events via activating c-Jun. Here, we found that JNK regulated c-Jun activation in TNBC cells and that JNK activation correlated with c-Jun activation in TNBC tumors. Furthermore, the expression level of c-Jun was significantly higher in TNBC tumors than in non-TNBC tumors, and high c-Jun mRNA level was associated with shorter disease-free survival of patients with TNBC. Thus, we hypothesized that the JNK/c-Jun signaling pathway contributes to TNBC tumorigenesis. We found that knockdown of JNK1 or JNK2 or treatment with JNK-IN-8, an adenosine triphosphate-competitive irreversible pan-JNK inhibitor, significantly reduced cell proliferation, the ALDH1+ and CD44+/CD24- CSC subpopulations, and mammosphere formation, indicating that JNK promotes CSC self-renewal and maintenance in TNBC. We further demonstrated that both JNK1 and JNK2 regulated Notch1 transcription via activation of c-Jun and that the JNK/c-Jun signaling pathway promoted CSC phenotype through Notch1 signaling in TNBC. In a TNBC xenograft mouse model, JNK-IN-8 significantly suppressed tumor growth in a dose-dependent manner by inhibiting acquisition of the CSC phenotype. Taken together, our data demonstrate that JNK regulates TNBC tumorigenesis by promoting CSC phenotype through Notch1 signaling via activation of c-Jun and indicate that JNK/c-Jun/Notch1 signaling is a potential therapeutic target for TNBC.

Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Randomised clinical trial: efficacy of the addition of a prokinetic, mosapride citrate, to omeprazole in the treatment of patients with non-erosive reflux disease - a double-blind, placebo-controlled study.

BACKGROUND: Proton pump inhibitors (PPIs) are less effective in non-erosive reflux disease (NERD) patients than in reflux oesophagitis patients. Whether the addition of prokinetics to PPIs improves NERD patients' symptoms remains unknown. AIM: To evaluate the efficacy of mosapride in NERD patients when used with PPI. METHODS: A total of 200 NERD patients were randomised to one of two arms: omeprazole (10 mg once daily) plus mosapride citrate (5 mg three times a day) (treatment arm) and omeprazole plus placebo (placebo arm). The primary endpoint was the rate of responders [visual analogue scale (VAS) was zero or <1 cm] after 4 weeks of treatment. The secondary endpoints were changes in the VAS score and the safety profile. RESULTS: There was no significant difference between the rates of responders in both arms in intent-to-treat (ITT) and per-protocol (PP) analysis. The change in the VAS score in treatment arm was significantly better than placebo arm in PP analysis (-4.0 ± 0.2 and -3.3 ± 0.2, mean ± S.E.M.) (N.S. in ITT analysis). The rate of adverse events was similar in both groups. CONCLUSION: The addition of mosapride to omeprazole was not more effective than omeprazole alone.

Possible paracrine growth of adenocarcinoma of the stomach induced by granulocyte colony stimulating factor produced by squamous cell carcinoma of the oesophagus.

Synchronous cancers of the oesophagus and stomach diagnosed in a patient showing pronounced leucocytosis were examined for production of granulocyte colony stimulating factor (G-CSF) and expression of G-CSF receptor. Whereas enzyme immunoassay of tissue extracts showed that the oesophageal carcinoma produced G-CSF, the gastric cancer did not. However, the gastric tumour showed G-CSF receptor expression on immunohistochemical examination of sections. These findings suggest that the oesophageal cancer promoted gastric cancer growth by paracrine mechanisms involving G-CSF.

[Percutaneous transcatheter thermotherapy (PTCT): use of hotwire for local tumor control].

We developed a Hotwire for use in percutaneous transcatheter thermotherapy (PTCT) for local tumor control. The Hotwire has a temperature sensor and a heater, and is inserted into the hepatic artery through a Y-connector and an angiocatheter. It can then warm fluid from the Y-connector to 45 degrees C under electorical control PTCT was performed on liver tumors using 4 mg of MMC and 10 mg Epirubicin. The antitumor effects and indications for PTCT were investigated in patients with unresectable liver tumors, including 3 patients who had hepatocellular carcinoma (HCC) with intraportal invasion and collateral vessels, one patient with liver metastasis of rectal cancer, and two gastric cancer patients. In all patients, tumor marker levels decreased (PIVKA-II; 8.5-->0.9, 2.9-->0.9, AFP; 1154-->753, CEA; 300-->226, TPA; 6319-->4227, 3312-->943), and CRP levels were markedly elevated with tumor fever. The only adverse reaction to PTCT was nausea and vomiting in one female patient. We repeated PTCT 6 times for giant HCC, and performance status was improved (2-->0). In conclusion, PTCT using the Hotwire is useful for treating hypervascular tumors limited to the liver, especially HCC with intraportal invasion and collateral vessels.

Eight cases of gastric tumors with calcification.

Gastric tumors with calcification have been considered to be relatively rare. We treated 8 cases of tumors involving calcification, 4 cases of gastric carcinomas and 4 other cases of submucosal tumors with ulceration. These cases are reported along with a review of the cases reported in Japan.

[Clinical evaluation of the long-term treatment with chlormadinone acetate in patients with benign prostatic hypertrophy].

Fifty patients with benign prostatic hypertrophy were treated with chlormadinone acetate (CMA) at the dose of 50 mg/day for 12 months. Subjective symptoms and objective findings were evaluated before, and after 4 and 12 months of treatment. Better improvement was observed in all of the subjective symptoms and in almost all the parameters of objective findings, in proportion to the period of CMA treatment. Generally speaking, 12 months of treatment was more effective than 4 months of treatment. Two patients had impotence (4.0%). Both of them complained of side effects within 4 months after treatment, but they were not severe. In conclusion, long-term treatment of benign prostatic hypertrophy with CMA was useful.

[Expression of c-H-ras, c-erb B1 and c-erb B2 gene products in human bladder cancer].

To investigate the expression of c-H-ras (p21), c-erb B1 (EGFR) and c-erb B2 (p185) gene products in human bladder cancer, immunohistochemical studies using monoclonal antibodies to these proteins were performed on formaline fixed (within 15 hours)-paraffin sections of tumor tissues from 20 patients with bladder cancer, normal appearing adjacent bladder (non-tumor) tissues from 11 of the 20 patients, and normal bladder tissues from 3 patients who died of non-cancerous diseases as control. p21 Positive staining was demonstrated in the superficial cells of urothelium in 1 of 3 controls, also in 5 of 20 tumor tissues compact cells without vacuole in cells which have an increased nuclear/cytoplasmic ratio. Seven of 11 non-tumor tissues indicated positive staining either in superficial layer only or in whole layers of urothelium, and 1 of the latter group reacted with the monoclonal antibody to human bladder cancer produced in our laboratory. EGFR was found in 5 of 20 tumor tissues and 7 of 11 non-tumor tissues, but not in controls. Most EGFR positive tissues also indicated p21 positivity except in 1 of the tumor tissues. p185 Positive staining was demonstrated in 9 of 20 tumor tissues and 5 of 11 non-tumor tissues, but not in the controls. Furthermore, 5 of 6 tumor tissues from the patients with lymph node metastasis indicated p185 positivity. These results suggest that both p21 and EGFR may have a role in transformation and that p185 has a role in the development of metastasis in some urothelial malignancies.

Elevated content and secretion of gut GLI in VMH-lesioned rats.

Gut glucagon-like immunoreactivity (GLI), a supposed intestinal growth factor in the plasma and gastrointestinal tract, and weight of the gastrointestinal tract, an intestinal growth indicator, were examined in ventromedial hypothalamic (VMH)-lesioned rats 1 week after VMH lesions. Postprandial plasma gut GLI in VMH-lesioned rats was significantly higher than that in control rats. The content of gut GLI in all gastrointestinal sections except the duodenum in VMH-lesioned rats was significantly greater than that in control rats. Gel chromatography in the lower portion of the small intestine in which GLI content was the highest of all sections revealed the same pattern in both VMH-lesioned and control rats with two peaks of similar molecular size. Weight of all gastrointestinal sections except the cecum in VMH-lesioned rats significantly increased. These results demonstrated that both gut GLI secretion and production were enhanced in VMH-lesioned rats. The elevated gut GLI release may accelerate growth of the gastrointestinal tract in these animals.

[Histological study on intravesical instillation of Bacillus Calmette Guerin (BCG) and adriamycin for BBN-induced bladder tumor in rats].

We evaluated histological changes induced by intravesical instillation of Bacillus Calmette Guerin (BCG) and doxorubucin hydorochloride (Adriamycin, ADM) for transitional cell carcinoma of the experimental bladder tumor. We administered rats N-butyl-N (4-hydroxybutyl) nitrosamine (BBN) by mixing it in the drinking water, and performed intravesical instillation of BCG, ADM or physiological saline solution as control in the 16th and 17th weeks and sacrificed in the 18th week after BBN exposure, and observed histological changes by light microscopy and electron microscopy. In the BCG group, the enlargement of the intercellular spaces of superficial tumor cells was found, and electron microscopic findings revealed a decrease or disappearance of the junctional complex. In the ADM group, hydrolytic and vacuolated cytoplasm was revealed. But such change as that in the BCG group was not found in the ADM and control groups. These results indicate that BCG may enlarge the intercellular spaces by changing the junctional complex, and lead to desquamate the tumor cells from the superficial cell layer.

[Serious complications of intravesical bacillus Calmette-Guerin therapy in patients with bladder cancer].

Side effects and serious complications of intravesical bacillus Calmette-Guérin (BCG) therapy were reviewed in 120 patients with transitional cell carcinoma of the urinary bladder from October, 1983 to June, 1989 at Hirosaki University Hospital. As local side effects, 102 patients (85.0%) had bladder irritability with frequency and/or micturition pain, and 46 patients (38.3%) had hematopyuria. As systemic side effects, fever in 43 patients (35.8%), elevation of serum GOT, GPT in 9 patients (7.5%), and malaise in 3 patients (2.5%) were seen. Serious complications were observed in 7 patients. 4 patients had a severely contracted bladder with decreased compliance less than 50 ml, 2 patients had persistent arthritis and one patient had interstitial pneumonia. In all 4 patients with a contracted bladder partial cystectomy was performed before or after intravesical BCG therapy, and three of them received more than ten times instillation of BCG. It was suggested that contracted bladder most likely occurred after frequent BCG instillations in addition to decreased bladder compliance. Contracted bladder was irreversible in 2 patients. Histopathologically, there was marked fibrosis in the muscular layer of the bladder without tuberculous inflammatory changes. It might depend on the severity of fibrosis in the muscular layer whether contracted bladder was reversible or not. Persistent arthritis was nonspecific inflammation with negative culture results for mycobacteria in the joint fluid in 2 patients. In one patient with interstitial pneumonia, fiberoptic bronchoscopy with transbronchial lung biopsy demonstrated marked fibrosis of alveolar septums and increased lymphocyte count without tuberculous inflammatory changes. The pathogenesis of this complications is considered to be a hypersensitivity reaction to BCG.

Eccrine syringofibroadenomatous hyperplasia in a patient with bullous pemphigoid: a case report and review of the literature.

A 76-year-old man with multiple erythematous lesions on his palms and soles which appeared following bullous pemphigoid (BP) is the subject of this case report. The lesions were not raised above the normal skin level, and there were no nodules on the erythematous lesions. The lesions had the histologic appearance of eccrine syringofibroadenoma. This condition is considered to be not a true tumor but a hyperplasia of eccrine sweat ducts following recurrent subepidermal blister formation in BP.

[Prophylactic intravesical BCG for bladder tumor after surgery of upper tract urothelial carcinoma].

We report the result of prophylactic intravesical instillation of BCG after surgery of upper tract urothelial carcinoma. The BCG Tokyo 172 strain was given preoperatively and/or postoperatively, as a rule, in a dose of 80 mg in 30 ml saline instilled into the bladder. Only one (14.3%) of the 7 patients with intravesical BCG developed bladder tumor at 14 month after surgery, while (45.4%) of 11 patients who did not receive intravesical BCG suffered from bladder tumor within 2 years after surgery. Prophylactic intravesical instillation of BCG reduced significantly (p less than 0.005) the recurrence of bladder tumor after the surgery of renal pelvis and ureteral tumor.

[Clinical analysis of renal cell carcinoma with intravenous tumor thrombus].

We reviewed treatment and prognosis in 7 operative and 7 non-operative cases of renal cell carcinoma with venous tumor thrombosis formation, 14 cases in total. Treatment after around 1983 involved the use of biological response modifier (BRM), chiefly interferon (IFN), and operation by thoracoabdominal approach. Before that, chemotherapy, radiotherapy and operation by peritoneal approach were used, with many cases judged inoperable. Even in non-operative cases, life-prolongation was frequently achieved by embolization of the renal artery and administration of various BRMs. On the other hand, in cases judged operable which were always treated by resection, early postoperative death sometimes occurred. These facts brought home to us the difficulty of choosing appropriate treatment. Though it is hard to determine the relative merits of various treatments from the present data, since the series is small and contains cases from 1963 onwards, the clinical and pathological pictures should be carefully evaluated for each case, and the most suitable course of treatment should be selected individually. We describe a non-operative case in which a combined use of embolization, IFN-gamma and tumor necrosis factor (TNF) elicited a lasting partial response, and an operative case in which postoperative complications such as pulmonary infarction and renal failure occurred after operation under extracorporeal circulation and patient died at 2 months after operation.

Electron microscopic findings in benign deoxycorticosterone and 11-deoxycortisol-producing adrenal tumor.

The ultrastructural characteristics of a benign adrenal adenoma that produces deoxycorticosterone and 11-deoxycortisol were examined by transmission electron microscopy. Both large, round mitochondria with a few cristae in the peripheral portion and spherical or oval mitochondria with sacrotubular cristae were observed in adenoma cells. The development of agranular or granular endoplasmic reticulum varied from cell to cell. In some cells, many vacuoles and collagenous fibers were also seen. Thus, the adrenal tumor we examined was composed of the cells derived from the fascicular zone, which are associated with Cushing's syndrome, and the cells of the glomerular zone observed in association with primary aldosteronism.