Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-positive Breast Cancer.

Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies. SIGNIFICANCE: Estrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.

Sex-based differences and aging in tactile function loss in persons with type 2 diabetes.

BACKGROUND: Recent evidence of significant sex-based differences in the presentation of Type 2 Diabetes Mellitus (DM) and its complications has been found in humans, which may contribute to sex-based differences in reduced functionality and quality of life. Some functionality, such as tactile function of the hands, has significant direct impact on quality of life. The purpose of the current study was to explore the impact of DM and sex on tactile function, with consideration of variability in health state measures. RESEARCH DESIGN AND METHODS: A case-control single time point observational study from 2012-2020 in an ethnically diverse population-based community setting. The sample consists of 132 adult individuals: 70 independent community dwelling persons with DM (PwDM) and 62 age- and sex-matched controls (42 males and 90 females in total). The Semmes-Weinstein monofilament test was used to evaluate tactile sensation of the hands. RESULTS: Tactile sensation thresholds were adversely impacted by sex, age, degree of handedness, high A1c, diagnosis of DM, and neuropathy. Overall, strongly right-handed older adult males with poorly controlled DM and neuropathy possessed the poorest tactile discrimination thresholds. When self-identified minority status was included in a secondary analysis, DM diagnosis was no longer significant; negative impacts of age, neuropathy, degree of handedness, and high A1c remained significant. CONCLUSIONS: The data indicate significant impacts of male sex, age, degree of handedness, self-identified minority status, and metabolic health on the development of poor tactile sensation. This combination of modifiable and non-modifiable factors are important considerations in the monitoring and treatment of DM complications.

Comparison between pancreatoduodenectomy and hepatopancreatoduodenectomy for bile duct cancer.

BACKGROUND/AIMS: Pancreatoduodenectomy has been accepted as a standard operative procedure for distal bile duct cancer with low operative mortality. However, hepatopancreatoduodenectomy has not been accepted as a standard treatment modality for diffuse bile duct cancer. METHODOLOGY: From December 12, 1992 to December 15, 2000, 37 patients with the diagnosis of extrahepatic bile duct adenocarcinoma (cholangiocarcinoma) underwent pancreatoduodenectomy or hepatopancreatoduodenectomy, at the department of surgery, Ibaraki Prefectural Central Hospital and the Cancer Center. The differences in indications and results of both operative procedures were investigated retrospectively. RESULTS: Thirty-day operative mortality was 0% after either pancreatoduodenectomy or hepatopancreatoduodenectomy. One- to 5-year cumulative survival rates for the 24 patients after pancreatoduodenectomy were 76.3%, 41.5%, 41.5%, 41.5%, 41.5%, respectively. One- to 4-year cumulative survival rates for the 13 patients after hepatopancreatoduodenectomy were 48.0%, 32.0%, 32.0%, 16.0%, respectively. There were no statistically significant differences between cumulative survival rates after pancreatoduodenectomy and hepatopancreatoduodenectomy either in all the patients or in patients with UICC stage IV. CONCLUSIONS: Hepatopancreatoduodenectomy should be tried for patients with diffuse bile duct cancer, because only hepatopancreatoduodenectomy has the possibility of a cure at this time.

[Ineffective and recurrent cases of thoracoscopic sympathectomy for hyperhidrosis and intractable pain].

We reported the cases of thoracoscopic sympathectomy, that is, six cases of hyperhidrosis, three of post herpetic neuralgia, and four of reflex sympathetic dystrophy, including recurrent or incompletely resected or ineffective ones. Recently this procedure for hyperhidrosis had been performed frequently because of its effectiveness, less pain, early discharge and cosmetic aspect. For an ineffective case of hyperhidrosis abdominal respiration which emphasized the exhalation and using an upper abdomen decreased the sweating. The balance of autonomic nerve system, toward parasympathetic dominant, was thought to be improved by conscious respiration. The decrease of sweating right after the operation in a case of incomplete resection indicated that intraoperative maneuver could restrict the sympathetic nerve. This procedure for a pain control could be less effective than that for hyperhidrosis, so an adequate preoperative informed consent was thought to be necessary.

[A case of spontaneous hemopneumothorax associated with uncontrolled massive bleeding after inserting thorathic drain].

A 31-year-old man admitted to our hospital complaining of right chest pain. Chest X-ray on admission revealed a collapsed lung and an air fluid line in the right thorax. A chest tube drainage was carried out, but hemorrhagic pleural fluid was drainaged. Forty minutes later, an anemia developed and chest X-ray showed increased massive right pleural collection. Therefore, emergent surgery was performed. An operation under thoracoscopic guidance was converted into thoracotomy because of massive blood clots and fresh bleeding. A bleeding originating from the branch of 1st intercostal artery and a bulla on upper lobes were noted. The artery was coagulated with electrocoutary and ligated using Endo-loop. This artery is not congenital abnormal one but collateral expanded one of which the elastic lamina is thickened. Spontaneous hemopneumothorax is life-threatening, emergent operation should be undergone.

[Treatment for advanced colorectal carcinoma with 5-fluorouracil plus low-dose leucovorin].

From July 1992 to May 1996, 16 patients with non-curative postoperative or recurrent colorectal carcinomas were treated with 5-fluorouracil (5-FU) plus leucovorin (LV) systemic chemotherapy. LV was given at a dose of 20 mg/m2/d immediately followed by 5-FU at 370 mg/m2/d. LV was given by rapid intravenous (i.v.) injection and 5-FU by rapid or drip i.v. for 5 consecutive days. Courses were repeated once every 4 weeks for two months and then once every 5 weeks. All patients took 3 or more courses. The toxicity was tolerable, but one patient needed hospitalization because of severe gastro-intestinal toxicity. We observed 3 PR cases, no CR and an overall response rate of 19%. The response duration was 6 to 8 months, averaging 7.3 months, and median survival was 12 months. It was possible to perform this chemotherapy on an outpatient basis, so we think this chemotherapy is superior to in-hospital chemotherapy considering the issue of quality of life. However, the response rate was low and its duration was short. We must investigate chemotherapy further with new and more powerful chemical modulations to increase the response rate and to prolong the response duration.

Hepatocellular carcinoma with a solitary adrenal metastasis and poor hepatic functional reserve: report of a case.

A 54-year-old man with a 15-year history of liver disease, was found by his family physician to have multiple tumors in the right lobe of the liver and a large right retroperitoneal tumor. He was referred and admitted to our institute where a preoperative diagnosis of liver cirrhosis complicated by hepatocellular carcinoma and probable right adrenal metastasis was made. Because his hepatic functional reserve was so poor, only resection of the right adrenal tumor with a splenectomy for hypersplenism and a cholecystectomy for the prevention of cholecystitis secondary to the scheduled transcatheter arterial embolization was performed. The patient was discharged in good clinical condition 5 weeks after surgery.

The effect of nifedipine, a calcium channel blocker, on liver ischemia in dogs.

This study was undertaken in order to determine whether the administration of nifedipine, a calcium channel blocker, could protect the liver from ischemic damage and to investigate its effect on the hepatic cellular energy status and cardio-vascular system after 60 minutes of hepatic ischemia in dogs. The ischemia was induced by temporarily clamping the portal vein and hepatic artery. One group of animals (n = 17) received nifedipine (5 micrograms/kg body weight) intravenously 15 minutes before the induction of liver ischemia, which was continued at a dose of 0.2 microgram/kg body weight/min throughout the ischemic period, and for an additional 30 minutes afterwards. Control dogs (n = 16) were not given nifedipine and survival was observed over seven days. The survival rate was 83 per cent in the nifedipine treated animals and 0 per cent in the control animals. Serum glutamic oxaloacetic transaminase levels were greatly increased following ischemia, and they were significantly lowered with the nifedipine treatment. The hepatic energy charge decreased remarkably during the hepatic ischemia, however it increased gradually after declamping but did not returned to its preoperative value in either group until one hour later and then it was higher in the nifedipine treated animals than in the control animals. Cardiac index and portal venous blood flow ratio remained higher in the nifedipine treated animals than in the control animals, after the ischemic period. These results suggest that nifedipine may have a powerful cytoprotective effect and that the period of warm hepatic ischemia could be prolonged with its use.

Internal stenting of the hepaticojejunostomy and pancreaticojejunostomy in patients undergoing pancreatoduodenectomy to promote earlier discharge from hospital.

Internal stenting of the hepaticojejunostomy and pancreaticojejunostomy was performed in 11 consecutive patients undergoing pancreatoduodenectomy between July 1992, and July 1994, to promote earlier discharge from hospital. Although minor leakage of the pancreaticojejunostomy occurred in 4 patients, this resolved within a short period and all 11 patients were able to be discharged by the 29th postoperative day in good health and without any intubation. Follow-up abdominal X-ray and computed tomography (CT) scans proved that all 22 of the stenting tubes had spontaneously fallen out by the 176th postoperative day. No complication related to the stenting tubes occurred in any of our patients.

Application of three-dimensional spiral computed tomographic angiography prior to hepatectomy for hepatocellular carcinoma.

A newly developed method of spiral computed tomography (CT) angiography was employed for 19 consecutive hepatocellular carcinoma (HCC) patients who underwent hepatectomy. Fine images of the intrahepatic vascular structure, portal venous branches and hepatic veins, and HCC nodules were obtained in 16 patients. A more accurate and easier understanding of the relationship between the intrahepatic vascular structure and the HCC nodules was provided by this spiral CT angiography compared with any other imaging modality.

Expression of Bcl-2 in human breast cancer: correlation between hormone receptor status, p53 protein accumulation and DNA strand breaks associated with apoptosis.

The expression of Bcl-2, a suppressor of apoptotic cell death, was investigated in 52 invasive carcinomas of the breast using reverse transcription-polymerase chain reaction and immunohistochemical methods. After consideration of both sets of results, 42 tumors (80.8%) were confirmed to be positive (Bcl-2(+)) and 10 (19.2%) were judged negative (Bcl-2(-)) for Bcl-2 expression. Related factors (p53 protein accumulation, hormone receptor status and apoptotic cell index) were also examined using immunohistochemical and in situ end-labeling methods to elucidate their correlations with Bcl-2 expression. Bcl-2 expression correlated significantly with the hormone receptor status, whereas it showed significant inverse correlations with p53 accumulation and the apoptotic index. It was concluded that estrogen and mutant p53 are related to the regulation of Bcl-2 expression and that the ability to prevent tumor cell death due to Bcl-2 can be developed by breast cancers.

Determination of estrogen receptor in primary breast cancer using two different monoclonal antibodies, and correlation with its mRNA expression.

Estrogen receptor (ER) protein status was investigated in the MCF-7 cell line and 70 invasive ductal carcinomas of the breast. This was achieved by immunohistochemical assay (IHA) using two different monoclonal antibodies (ER-1D5 and AER311), which are able to recognize either the amino or carboxyl terminal. The staining results were assessed in terms of index score, and compared with the ERalpha mRNA expression, which was determined by reverse transcription-polymerase chain reaction for the positions of exons 5 and 7. MCF-7 showed similar immunoreactions with both antibodies, and expressed the wild-type (WT) ER mRNA coexpressing deletions of exons 5 and 7. Although there was a significant difference between the ER-1 D5 and AER311 indices in the tissue samples (20.5 +/- 27.2 and 5.7 +/- 16.4; P < 0.001), in the majority of cases ER mRNA expression patterns were similar to that of MCF-7, and WT ER mRNA was expressed in all cases that yielded PCR products. It was concluded that a number of palpable breast cancers lack the carboxyl terminal of the ER protein, regardless of WT ER mRNA expression. These results suggest that the incidence of WT ER mRNA in such cancers is lower than that in the MCF-7 cell line, or that WT ER is less stable.

Pulmonary artery reconstruction using a great saphenous vein autograft in the treatment of bronchogenic cancer.

Sleeve resection of the pulmonary artery, followed by reconstruction with or without bronchoplasty, for bronchogenic carcinoma located at a major lobar orifice has been reported as an alternative to pneumonectomy in patients with poor respiratory functional reserve. We describe herein what is, to our knowledge, the first report of a successful pulmonary arterial reconstruction using a saphenous vein autograft. This operation was performed in a 63-year-old man with poor pulmonary functional reserve who was diagnosed as having a large bronchogenic cancer in the left lower lobe of the lung, located close to the pulmonary hilum. First, a left lower lobectomy was performed with segmental resection of the pulmonary artery, from the basal artery to the lingular artery, after which pulmonary arterial continuity was reconstructed using a saphenous vein autograft. The patient had an uneventful recovery and remains well without any sign of recurrence 4 months after his operation.

Comparison of hepatectomy and transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma: necessity for prospective randomized trial.

Transcatheter arterial chemoembolization is now widely used in cases of surgically unresectable hepatocellular carcinoma. However, it is unclear whether patients with surgically resectable hepatocellular carcinoma should always be treated with hepatectomy as opposed to transcatheter arterial chemoembolization. Sixty-six patients with hepatocellular carcinoma underwent hepatectomy, whereas 29 patients with more advanced hepatocellular carcinoma were treated with transcatheter arterial chemoembolization at our hospital from 1984 to 1990. All cases were associated with cirrhosis of Child class A or B. All of them underwent hepatectomy or transcatheter arterial chemoembolization for the first time. Their outcomes were determined on March 31, 1991. The backgrounds and survival curves for hepatectomy and transcatheter arterial chemoembolization were compared in both Child A and Child B patients. For both Child A and B patients, no significant difference was found between hepatectomy and transcatheter arterial chemoembolization with respect to age, sex, cause of underlying cirrhosis, liver function assessed by indocyanine green test and maximum diameter of the main tumor. The incidence of multiple hepatocellular carcinoma, more advanced hepatocellular carcinoma (TNM stage III or IV) or both was significantly higher in the transcatheter arterial chemoembolization group than in the hepatectomy group for both Child A and Child B patients. The survival curves of both the hepatectomy and the transcatheter arterial chemoembolization groups showed no significant difference for both Child A and Child B patients. A prospective study is therefore warranted to elucidate whether hepatectomy or transcatheter arterial chemoembolization is more effective for treating resectable hepatocellular carcinoma associated with cirrhosis.

Postoperative recurrence of hepatocellular carcinoma.

Sixty-nine patients with hepatocellular carcinoma underwent curative hepatic resections as primary cases from 1981 to 1986. Seven patients died in the hospital after operation. The other 62 patients left the hospital and were closely followed for 25 to 78 months. Recurrence of carcinoma became obvious in 41 (66%) of 62 patients. The clinical and pathologic features of these 41 patients were not significantly different from those of the other patients. Recurrent tumors were found in the residual liver in 38 patients (93%), in the bone in 2 (5%), and in the lung in 1 (2%). Recurrence was diagnosed within 1 year, between 1 and 2 years, and more than 2 years after the operation in 22 (56%), 10 (26%), and 7 (18%) patients, respectively. It was difficult to determine the exact time of recurrence in two patients. There was a significant negative correlation between the size of primary tumor and time until recurrence; the larger the primary tumor, the shorter the time until recurrence. Among the 29 patients who underwent local excisions for their primary tumors, 19 recurrences were observed. Eighteen were found in the residual liver, in the same segment as the primary tumor, or in one near it. Larger hepatic resection for primary tumors is thus advocated to prevent recurrence.

Hepatoid adenocarcinoma of the stomach.

Although gastric cancer occurs frequently in Japan, few cases of hepatoid adenocarcinoma, a cancer with an extremely poor prognosis, have been reported. Here, we describe a 67-year-old Japanese man referred to our hospital with suspected gastric cancer. Gastrointestinal fiberscopy revealed an elevated lesion with a central depression on the lesser curvature, extending from the antrum to the body of the stomach. On the preoperative examinations, abdominal computed tomography scan, magnetic resonance imaging, and abdominal ultrasonography revealed multiple metastases to the liver and no cirrhotic change. The serum level of alpha-fetoprotein (AFP) was markedly elevated (10,084 ng/ml). After a diagnosis of AFP-producing gastric cancer with multiple liver metastases was made, total gastrectomy, without liver resection, was performed. Microscopically, the tumor showed two main histological features. The main part of the tumor resembled moderately differentiated hepatocellular carcinoma, and the rest showed fetal-type adenocarcinoma. Some parts of the hepatoma-like lesion showed periodic acid-Schiff (PAS)-positive granules. Furthermore, the tumor showed diffuse immunohistochemical positivity for AFP, alpha-1 antitrypsin, and alpha-1 antichymotrypsin. According to these histopathological findings, the tumor was diagnosed as hepatoid adenocarcinoma of the stomach. Although anastomotic leakage occurred postoperatively and the liver metastases have increased in size, the patient remains alive 11 months after the operation. Because of the poor prognosis for this histological type of tumor, accurate diagnosis of hepatoid adenocarcinoma is important, and long-term follow-up is required. We describe this rare case of hepatoid adenocarcinoma of the stomach, and review the literature concerning the clinicopathological aspects.