Dynamic change of cancer genome profiling in metachronous bilateral breast cancer with BRCA pathogenic variant.

A 61-year-old woman with BRCA2 pathogenic variant had been treated for 20 years and showed dynamic changes in the genomic profile of her metachronous bilateral breast cancer and metastases. She underwent right breast conservation surgery at age 42-Genome 1, lung metastasis and left axillary lymph node metastasis at age 51, partial excision under local anesthesia for left breast cancer at age 53-Genome 2, left axillary lymph node dissection was added 6 month later-Genome 3. Then, olaparib was administered, and subsequently, left mastectomy was performed for the recurrence of left breast cancer at age 59-Genome 4. Genomic profile of the tumor was analyzed at four points (Genome 1-3 were analyzed by in house breast cancer panel, and Genome 4 was analyzed by Foundation One CDx). Two interesting findings emerged from these analyses. First, the genomic profile revealed that the left axillary lymph node metastasis, considered histologically from right breast cancer, was a metastasis from the left breast cancer. The second finding is that as the disease progressed, mutation profile became more diverse. The profile of the left breast cancer removed after olaparib and other treatments showed reversion mutation of BRCA2 and was diagnosed as tumor mutation burden high. Subsequent response to pembrolizumab was favorable.

Effect of Perioperative Docetaxel-induced Limb Edema on Health-related Quality of Life in Patients with Early-stage Breast Cancer: A Prospective Observational Study.

Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL) is unclear. In this study, we evaluated the effects of edema caused by administration of DTX on HRQOL in patients with early-stage breast cancer. We prospectively investigated patients diagnosed with early-stage breast cancer (stage I-III) who received 4 cycles of DTX as preoperative or postoperative chemotherapy between September 2021 and December 2022 at Yamanashi Prefectural Central Hospital. The circumference of each extremity was measured at each administration of DTX, and limb edema was evaluated by Common Terminology Criteria for Adverse Events version 5.0. HRQOL was evaluated using SF-12 version 2, which has a range of 0-100 (national standard, 50), and compared between the presence and absence of grade 2 or higher edema and between before and after administration of DTX. Twenty patients met the eligibility criteria and were included in the study. There was no difference in the HRQOL score according to whether grade 2 limb edema was present. The median HRQOL summary scores before and after administration of DTX were 51.1 and 50.8 (p=0.763), respectively, for mental health, 52.6 and 49.4 (p=0.005) for physical health, and 38.9 and 37.5 (p=1.000) for role/social health. We found no direct effect of DTX-induced limb edema on HRQOL in patients with early-stage breast cancer. However, HRQOL summary scores indicated that administration of DTX reduced physical health in these patients.

[Successful treatment of acute promyelocytic leukemia with all-trans retinoic acid on hemodialysis for acute renal failure].

All-trans retinoic acid (ATRA) is used as standard induction therapy for acute promyelocytic leukemia (APL), but it is contraindicated for patients on hemodialysis. We present a case of a patient with APL on hemodialysis, intubated, and with marked disseminated intravascular coagulation (DIC) who was successfully treated with ATRA. A 49-year-old man was transferred to our hospital and admitted into the intensive care unit due to renal dysfunction, DIC, and pneumonia. Promyelocytes were noted in the peripheral blood, and he was diagnosed with APL after bone-marrow examination. Because of renal dysfunction, only Ara-C was used but with a reduced dose. The patient's condition improved, and he was extubated and withdrawn from dialysis on the 5th day of hospitalization. The patient suffered from APL syndrome during induction therapy, which necessitated ATRA withdrawal and steroid administration. Remission was achieved after induction therapy, and the patient is currently on maintenance therapy. There are few cases of patients with APL on hemodialysis who were treated with ATRA; hence, it is necessary to review the treatment plan for these patients.

Cystic degeneration during neo-adjuvant chemotherapy predicts squamous metaplasia of triple negative breast cancer: report of two cases.

Neo-adjuvant chemotherapy (NAC) has become a standard treatment for advanced breast cancer because of the advantage of monitoring drug sensitivity and enabling breast-conserving therapy. The changes during NAC are also important to know the biological characteristics of the tumor. We experienced two cases with cystic degeneration and enhancement of the cyst wall during NAC for triple negative breast cancer (TNBC). They were diagnosed to have breast cancer with squamous metaplasia. In case 1, a 37-year-old woman with right breast cancer diagnosed as TNBC, T3N3M0, Stage 3b was treated with NAC. MRI showed a cystic degeneration with a diameter of 3.5 cm and enhancement of the cyst wall, and the other nodules were extinguished. The histopathological finding of the surgical specimen revealed solid tubular carcinoma with squamous metaplasia. In case 2, a 58-year-old woman with right breast cancer diagnosed as HER2 enriched subtype, T2N0M0 stage 2 was treated with NAC containing trastuzumab. The post-NAC MRI showed extinguishment of the mass in the right breast, but showed a cystic lesion with 24 mm in diameter and enhancement of its wall in the left breast. She underwent breast conserving surgery for bilateral breast cancer, and histopathological finding of the surgical specimen indicated complete remission of right breast cancer and squamous cell carcinoma developed in the left breast. These changes are impressive and remind us that there are metaplastic changes (especially for squamous metaplasia) with resistance to chemotherapy.

TP53-positive clones are responsible for drug-tolerant persister and recurrence of HER2-positive breast cancer.

PURPOSE: The prognosis of HER2-positive breast cancer has improved with the development of anti-HER2 therapies. In order to further improve the prognosis of HER2-positive breast cancer, it is essential to elucidate the cells that survive during the therapy (drug-tolerant persister DTP). METHODS: Of the 2022 breast cancer patients operated at our institution during 2004-2018, 240 (12%) had HER2-positive breast cancer. Neo-adjuvant chemotherapy including trastuzumab (Tr-NAC) was administered to 94 of them. Forty-six of them were complete remission (CR), and 48 were non-CR. After 6.9 ± 3.7 years of follow-up, all 46 CR cases showed no recurrence (Cohort A), and 48 non-CR cases were divided into 31 cases with no recurrence (Cohort B) and 17 cases with recurrence (Cohort C). In addition to clinical backgrounds, we compared genomic profiles for 27 patients (Cohort A; 15/48, B; 7/31, and C; 5/17) who consented to genomic analysis. RESULTS: Genomic abnormalities of TP53 and PIK3CA were frequently observed in biopsy samples pre Tr-NAC, but we found no differences between CR (Cohort A) and non-CR (Cohorts B + C). Then, we examined both of pre and post Tr-NAC samples of Cohort B (7) and C (5) to see the relationship between recurrence and genomic abnormalities. TP53 mutations were significantly more prevalent in Cohort C (5/5, 100%) than cohort B (3/7, 43%) in the surgical sample after treatment (p = 0.04). PyClone analysis of TP53 mutations showed that the cellular frequency of TP53 clones increased in 4 of 5 patients in Cohort C and none of B. On the other hand, we found no enhancement of PIK3CA mutant clones in Cohort C. CONCLUSIONS: The DTP after Tr-NAC associated with subsequent relapse had TP53 mutations, suggesting that overcoming DTP with TP53 mutations is the most important clinical challenge. TRIAL REGISTRATION: Not applicable.

Benefit of home parenteral nutrition (HPN) and chemotherapy in patients with invasive lobular carcinoma developed peritoneal metastases.

The benefit of home parenteral nutrition (HPN) for patients with malnutrition due to peritoneal metastasis depends on the type of cancer. During the period 1999-2020, we treated 460 patients with metastatic and stage 4 breast cancer, 23 of whom were invasive lobular carcinoma (ILC). Of the 23 patients with ILC, 13 (57%) developed peritoneal metastasis, and 11 died of progression of peritoneal metastasis. Among these 11 patients, 2 patients who underwent surgery due to bowel obstruction, had no improvement, and died 1-4 months after surgery. The prognosis of the other 7 patients under BSC alone was poor, survival time were ranging from 1 to 5 months. The remaining two patients who were able to continue outpatient chemotherapy under HPN were able to prolong their survival time by 18 months and 26 months, respectively. We need to recognize that HPN and chemotherapy may prolong survival time in patients with peritoneal metastasis of ILC, and determine the indication for HPN based on the non-peritoneal life-threatening metastasis, length of treatment, availability of support for HPN management and outpatient chemotherapy, and the patient's willingness to accept it.

[Two Cases of Carcinoma en Cuirasse, as Cutaneous Metastasis of Breast Cancer].

We present 2 cases of carcinoma en cuirasse, an uncommon clinical manifestation of metastatic cutaneous breast cancer. Case 1, a 70-year-old woman, presented with diffuse erythematous, indurated skin lesions that covered her entire anterior chest wall. Skin biopsy revealed tumor cells in the dermis which were ER and PgR positive and HER2 negative. CT showed pleural and pericardial effusion which led to a final diagnosis of cutaneous metastasis from breast cancer. Fulvestrant monotherapy was initiated and maintained a good clinical effect for 40 months. She died of multiple liver metastasis after 53 months from her first visit. Case 2 was a 71-year-old woman, with a 24 month history of a left breast tumor that gradually accompanied erythematous skin indurations and erosion, which spread to her entire left chest wall and contralateral breast. Following skin biopsy and CT, she was diagnosed to have triple negative breast cancer with multiple lymph node and cutaneous metastasis. After 4 cycles of EC, capecitabine was administrated and her skin lesions improved rapidly, including the lymph nodes. She is currently alive after 12 months since her first visit and under chemotherapy against new cutaneous metastasis.

Clinical Significance of Past History of Breast Cancer Screening for the Prognosis of Triple Negative Breast Cancer.

BACKGROUND/AIM: This study examined the prognostic impact of the past history of breast cancer screening within the last 2 years (PH-BCS), for patients with triple negative breast cancer (TNBC), a subtype that carries extremely poor prognosis. PATIENTS AND METHODS: Eighty-six consecutive cases with TNBC, who underwent surgery at our faculty from 2009 to 2015, were divided into two groups according to PH-BCS. Prognostic analyses for disease-free survival and overall survival between the two groups were performed. RESULTS: The positive PH-BCS group (n=44) had a significantly better prognoses than the negative PH-BCS group (n=42) (p<0.001). No recurrent cases were observed in the positive PH-BCS group. In the negative PH-BCS group, tumor and node status and chemotherapy were indicated as significant prognostic factors, and further step-wise multivariate analysis revealed only node status as a significant prognostic factor. CONCLUSION: Breast cancer screening at least every 2 years may improve the prognosis of TNBC.

Effect of oral immunotherapy in children with milk allergy: The ORIMA study.

BACKGROUND: This study was aimed at evaluating the efficacy and safety of oral immunotherapy (OIT) in children with severe cow's milk allergy. METHODS: The subjects comprised 28 children (aged 3-12 years) with allergic symptoms that were induced by ≤ 10 mL of cow's milk in an oral food challenge test (OFC). The subjects were randomly allocated to the treatment group (n = 14) and control group (n = 14); the former received rush immunotherapy for 2 weeks, followed by a gradual increase of cow's milk volume to 100 mL for 1 year, and the latter completely eliminated cow's milk for 1 year. Both groups underwent an OFC with 100 mL of cow's milk after 1 year. RESULTS: The treatment group had significantly higher rates of a negative OFC [7/14 (50%) vs. 0/14 (0%), p < 0.01] compared with the control group. The cow's milk-specific IgE level significantly decreased in the treatment group (p < 0.01) but not in the control group (p = 0.63). During the study period, adrenaline was required in 6/14 patients (43%) of the treatment group and in 0/14 patients (0%) of the control group. Long follow-up data were available at the 2-year point after the study for 8 in the treatment group and 7 (87.5%) of these continued to ingest milk (>100 mL). CONCLUSIONS: The effect of immunotherapy was 50%, but the incidence of adverse events was not low. Further studies focusing on safety is necessary to standardize OIT for cow's milk allergy.

Phospho­STAT1 expression as a potential biomarker for anti­PD­1/anti­PD­L1 immunotherapy for breast cancer.

In the present study, we evaluated the mechanisms of programmed death ligand 1 (PD­L1) expression in the breast cancer microenvironment, focusing on the role of interferon­Î³ (IFN­Î³), and the clinical indications for anti­programmed cell death 1 (PD­1) /anti­PD­L1 immunotherapy. We evaluated PD­L1 expression in 4 breast cancer cell lines in the presence of 3 types of inhibitors, as well as IFN­Î³. The expression of phosphorylated signal transducer and activator of transcription 1 (p­STAT1), one of the IFN­Î³ signaling pathway molecules, was analyzed using immunohistochemistry (IHC) in relation to PD­L1 and human leukocyte antigen (HLA) class I expression on cancer cells and tumor­infiltrating CD8­positive T cells in 111 patients with stage II/III breast cancer. Using The Cancer Genome Atlas (TCGA) database, the correlation of the IFN­Î³ signature with PD­L1 expression was analyzed in breast invasive carcinoma tissues. As a result, the JAK/STAT pathway via IFN­Î³ was mainly involved in PD­L1 expression in the cell lines examined. IHC analysis revealed that the PD­L1 and HLA class I expression levels were significantly upregulated in the p­STAT1­positive cases. TCGA analysis indicated that the PD­L1 expression and IFN­Î³ signature exhibited a positive correlation. On the whole, these findings suggest that PD­L1 and HLA class I are co­expressed in p­STAT1­positive breast cancer cells induced by IFN­Î³ secreted from tumor infiltrating immune cells, and that p­STAT1 expression may be a potential biomarker for patient selection for immunotherapy with anti­PD­1/anti­PD­L1 monoclonal antibodies.

Feasibility of Combination Therapy with Nab-paclitaxel Plus Gemcitabine in Patients with Recurrent Pancreatic Cancer.

BACKGROUND/AIM: Nab-paclitaxel plus gemcitabine (nab-P+Gem) is one of most reliable and effective regimens for borderline or unresectable pancreatic cancer (PC). However, the feasibility and clinical benefits of this regimen have never been evaluated for patients with recurrent PC after pancreatectomy. The aim of this study was to investigate the feasibility of combination therapy with nab-paclitaxel plus gemcitabine (nab-P+Gem) for patients with recurrent PC. PATIENTS AND METHODS: Twenty-two patients with recurrent PC received an intravenous infusion of nab-P (125 mg/m2) and Gem (1,000 mg/m2) on days 1, 8, and 15 of a 4-week cycle. The primary end-point of this study was completion of the 4 cycles. The secondary end-points were the safety, efficacy, and disease control rate. RESULTS: The treatment completion rate of the 4 cycles was 90.9%. The objective response rate was 13.6% and the disease control rate was 63.6%. The median progression-free survival was 7.2 months. The most common grade 3 or higher hematological toxicity was neutropenia (72.7%). There was no treatment-related death. Furthermore, the chemotherapeutic effects varied with the time of recurrence. CONCLUSION: Combination nab-P+Gem therapy was well-tolerated and effective in patients with recurrent PC.

[A Case of Triple Negative Breast Cancer Successfully Treated with S-1].

A 73-year-old woman noticed a mass in her right breast about 1 year ago and consulted our hospital for an enlarged mass of about 10 cm in diameter.She was diagnosed with locally advanced triple negative breast cancer, and we initiated S-1 treatment as neoadjuvant chemotherapy.After 4 chemotherapy courses, computed tomography showed that the primary tumor had shrunk.Therefore, right mastectomy and axillary dissection were performed, and UFT was administered after surgery.She is currently alive with no recurrence 18 months after surgery.

Successful laparoscopic partial gastrectomy and spleen-preserving distal pancreatectomy for gastric duplication cyst connecting with the pancreatic tail.

INTRODUCTION: Gastrointestinal duplication cyst is a congenital rare disease that may occur in any region from mouth to anus. Among them, gastric duplication cysts are very rare. CASE REPORT: Here we report A 23-year-old Japanese man who visited our hospital to evaluate an abdominal tumor. Abdominal computed tomography showed a well-circumscribed homogenous low-density mass measuring 6.2 × 6.0 cm between the pancreatic tail and the upper posterior wall on the gastric greater curvature, and the mass seemed to originate from the pancreatic tail. We found intraoperatively that the mass adhered to the stomach and pancreatic tail strongly, so we performed laparoscopic partial gastrectomy and spleen-preserving distal pancreatectomy. Pathological findings showed that the lining epithelium of the cystic mass consisted of the gastric foveolar epithelium with fundic glands. Furthermore, the pancreatic tissue of the pancreatic tail and the muscular layer of the cystic mass were intermingled. DISCUSSION: GDCs are usually diagnosed at a younger age and in adults, they are very rare. Therefore, surgical resection is considered to be the best treatment due to the difficulty of diagnosis, and also that it mimics a pancreatic cystic tumor, and malignant transformation. Complete resection of the cyst is the ideal technique and laparoscopic surgery should be selected whenever possible. CONCLUSION: We experienced a case of GDC continuous to both stomach and pancreatic tail. Laparoscopic surgery is safety and useful even if GDC is continuous with both the stomach and the pancreas.

Loss of osteoblast Runx3 produces severe congenital osteopenia.

Congenital osteopenia is a bone demineralization condition that is associated with elevated fracture risk in human infants. Here we show that Runx3, like Runx2, is expressed in precommitted embryonic osteoblasts and that Runx3-deficient mice develop severe congenital osteopenia. Runx3-deficient osteoblast-specific (Runx3(fl/fl)/Col1α1-cre), but not chondrocyte-specific (Runx3(fl/fl)/Col1α2-cre), mice are osteopenic. This demonstrates that an osteoblastic cell-autonomous function of Runx3 is required for proper osteogenesis. Bone histomorphometry revealed that decreased osteoblast numbers and reduced mineral deposition capacity in Runx3-deficient mice cause this bone formation deficiency. Neonatal bone and cultured primary osteoblast analyses revealed a Runx3-deficiency-associated decrease in the number of active osteoblasts resulting from diminished proliferation and not from enhanced osteoblast apoptosis. These findings are supported by Runx3-null culture transcriptome analyses showing significant decreases in the levels of osteoblastic markers and increases in the levels of Notch signaling components. Thus, while Runx2 is mandatory for the osteoblastic lineage commitment, Runx3 is nonredundantly required for the proliferation of these precommitted cells, to generate adequate numbers of active osteoblasts. Human RUNX3 resides on chromosome 1p36, a region that is associated with osteoporosis. Therefore, RUNX3 might also be involved in human bone mineralization.

Common blue nevus with satellite lesions needs a differential diagnosis from malignant melanoma.

Malignant blue nevus is rare, and a common blue nevus rarely needs a differential diagnosis from malignant melanoma. Although a melanocytic nevus with a satellite lesion is usually suggestive of a peripherally disseminating malignant melanoma, very few cases of blue nevus with satellite lesions have been reported thus far. To our knowledge, this is the seventh case of a blue nevus with satellitosis. Periappendageal and perivascular concentrations of the nevus cells were observed in the main papule as well as in the satellite lesions. These findings suggest that blue nevus cells could infiltrate along the perivascular area in the dermis and form multiple satellite lesions. Blue nevus should be considered as a differential diagnosis when a locally disseminating malignant melanoma is suspected.

N -Methyl- N -nitrosourea-induced Renal Tumors in Rats: Immunohistochemical Comparison to Human Wilms Tumors.

N-Methyl-N-nitrosourea (MNU)-induced renal tumors in rats and Wilms tumors in humans were compared. Renal mesenchymal tumors (RMTs) and nephroblastomas (blastemal and epithelial components) in female Lewis rats treated with a single intraperitoneal injection of 50 mg/kg MNU at birth and Wilms tumors (blastemal, epithelial and mesenchymal components) in humans were analyzed for the expression of pancytokeratin (CK), vimentin, p63, α-smooth muscle actin (SMA), desmin, S-100, CD57, CD117/c-kit, Wilms tumor 1 protein (WT1) and ß-catenin. The mesenchymal components of rat RMTs and human Wilms tumors expressed vimentin, SMA and ß-catenin. The blastemal components of rat nephroblastomas and human Wilms tumors expressed vimentin, CD117/c-kit and ß-catenin. The epithelial components of rat nephroblastomas and human Wilms tumors expressed vimentin and ß-catenin. WT1 was expressed in different cellular components of rat tumors as compared with human Wilms tumors; the expression was seen in mesenchymal tumors and blastemal components of nephroblastomas in rats and epithelial components in human Wilms tumors. CK, p63 and CD57 were not expressed in rat RMTs or nephroblastomas, while CK and WT1 were expressed in epithelial components and CD57 was expressed in blastemal and epithelial components of human Wilms tumors. Rat and human tumors were universally negative for the expression of desmin and S-100. The immunohistochemical characteristics of rat renal tumors and human Wilms tumors may provide valuable information on the differences in renal oncogenesis and biology between the two species.

Pulmonary and Meningeal Cryptococcosis after Corticosteroid Therapy for Autoimmune Hepatitis: Coexistence of Cryptococci within Pulmonary Cancer Nodule.

A case of autoimmune hepatitis complicated with pulmonary and meningeal cryptococcosis during long-term treatment with corticosteroid is reported. An 84-year-old woman who received long-term corticosteroid therapy (40 mg/day prednisolone for two years) for autoimmune hepatitis developed a headache, slight fever, and anorexia and was diagnosed with cryptococcal meningitis two months prior to hospital admission. Due to deterioration of her condition, the patient was transferred to our university hospital. After admission, a pulmonary nodule 1 cm in diameter was noticed in the patient's right lower lobe. Cryptococcal meningitis was diagnosed as positive for cryptococcal antigen from both serum and cerebrospinal fluid (CSF) as well as the growth of Cryptococcus neoformans (C. neoformans) in fungal culture. A combination therapy of amphotericin B and flucytosine was started, and the corticosteroid therapy was gradually reduced and finally discontinued. In addition to continuous cryptococcal infection, complications of Pseudomonas aeruginosa and methicillin-resistance Staphylococcus aureus infection caused death after a 2-month hospitalization. Autopsy disclosed encapsulated yeast in the lungs and subarachnoid space characteristic of Cryptococcus. The pulmonary nodule was found to be squamous cell carcinoma coexisting with C. neoformans within and around the cancer cell nests.

Histopathological and immunohistochemical characterization of spontaneously occurring uterine deciduomas in young adult rats.

Uterine deciduomas were found in two female virgin rats, a 15-week-old Lewis rat and a 7-week-old Sprague-Dawley rat. The firm white nodules were located at the base of unilateral uterine horns and were approximately 6 mm and 4 mm in diameter. Histopathologically, the nodules were composed of three areas, each with a distinct type of proliferating cells: large epithelioid decidual cells with round nuclei, prominent nucleoli and abundant eosinophilic cytoplasm (antimesometrial region); compact spindle-shaped cells with oval nuclei and vacuolar cytoplasm (transitional region); and pleomorphic and spiny cells with round to oval nuclei and compact eosinophilic cytoplasm (mesometrial region). These cells proliferated in sheet-like arrangements and transformed into the other types of cells located in surrounding regions. Immunohistochemically, proliferating cells in all regions were strongly positive for proliferating cell nuclear antigen. The proliferating cells were positive for vimentin, and large decidual cells were positive for common acute lymphoblastic leukemia antigen 10, a marker of uterine interstitial cells. Large decidual cells were positive for α-smooth muscle actin and desmin, suggesting differentiation into muscular cells. Progesterone receptor was expressed in all cell types; however, estrogen receptor α was not expressed in the antimesometrial region. These extremely rare tumor-like nodules represent nonneoplastic lesions referred as decidual reactions of endometrial interstitial cells, and their biological behavior is that of a space-occupying benign tumor in young rats. Our cases might provide information as a historical control in toxicity and pharmacological studies in rats.

Arachidonic acid supplementation does not affect N-methyl-N-nitrosourea-induced renal preneoplastic lesions in young Lewis rats.

Arachidonic acid (AA) is naturally found in human breast milk. AA, together with docosahexaenoic acid, is commonly added as a functional food ingredient to commercial infant formula worldwide, in accordance with the international standards of Codex Alimentarius. However, few studies of the possible renal carcinogenic effects of AA supplementation during neonatal life have been performed. The effect of dietary AA supplementation in dams during gestation and lactation was investigated on N-methyl-N-nitrosourea (MNU)-induced preneoplastic lesions in the kidneys of young Lewis rats. Dams were fed a 2.0% AA diet or a basal diet (<0.01% AA). At birth (postnatal day 0), male and female pups received a single intraperitoneal injection of 35 mg/kg MNU or vehicle. Renal morphology was examined after 7, 14, 21, 28 and 60 days. Histopathologically, renal preneoplastic lesions, such as nephroblastomatosis and mesenchymal cell proliferation, were found on day 60 in both the MNU-treated groups. There was no significant difference in lesion incidence of 38% in the basal diet group and 31% in the AA diet group. In conclusion, an AA-rich diet for dams during gestation and lactation does not modify MNU-induced renal preneoplastic lesions in their offspring.

Promoting effect of arachidonic acid supplementation on N-methyl-N-nitrosourea-induced pancreatic acinar cell hyperplasia in young Lewis rats.

Arachidonic acid (AA) is naturally found in human breast milk. AA, together with docosahexaenoic acid, is commonly added as a functional food ingredient to commercial infant formula worldwide, in accordance with the international standard of Codex Alimentarius. However, few studies have been performed that are concerned with the possible carcinogenic effects of AA supplementation during neonatal life. The effect of dietary AA supplementation in dams, during gestation and lactation, was investigated in N-methyl-N-nitrosourea (MNU)-induced preneoplastic lesions in the exocrine pancreas of young Lewis rats. Dams were fed either an AA (2.0% AA) or a basal (<0.01% AA) diet. On postnatal day 0 (at birth), male and female pups received a single intraperitoneal injection of either 35 mg/kg MNU or vehicle. The morphology and proliferating activity of the exocrine pancreas were examined by proliferative cell nuclear antigen immunohistochemistry 7, 14, 21, 28 and/or 60 days post-MNU. Histopathologically, acinar cell hyperplasia (ACH) occurred in the MNU-treated groups 60 days after MNU injection, irrespecitive of whether the rats had been fed an AA diet. Morphometrically, the number and area of ACH per 1 mm(2) in MNU-treated rats increased significantly in the AA diet-fed rats, compared with basal diet-fed rats. The number of proliferative cell nuclear antigen-positive acinar cells in both the normal and hyperplastic areas of MNU-treated rats increased significantly in the AA diet-fed rats. In conclusion, providing dams with an AA-rich diet during gestation and lactation promotes MNU-induced pancreatic ACH in young Lewis rats.