Availability of immunocytochemistry using cocktail antibody targeting p63/cytokeratin14 for the differential diagnosis of fibroadenoma and ductal carcinoma in situ in fine needle aspiration cytology of the breast.

OBJECTIVE: The differential diagnosis of fibroadenoma (FA) and ductal carcinoma in situ (DCIS) has been problematic in fine needle aspiration biopsy (FNAC) because it has been difficult to differentiate between the "large epithelial clusters" associated with FA and those associated with DCIS. The purpose of this study was to prospectively validate the usefulness of immunocytochemical staining using cocktail antibody targeting p63/CK14 in the differential diagnosis of FA and DCIS. MATERIALS AND METHODS: Twenty patients diagnosed as having an uncertain malignant potential (indeterminate) for breast cancer on the basis of a FNAC finding were selected randomly: ten patients with FA and ten with DCIS. The cover glass on a specimen stained with the Papanicolaou stain on a glass slide was peeled off, and the specimen was restained by immunocytochemical staining of cocktail antibody targeting p63 and CK14. RESULTS: Six of the twenty patients were CK14-immunopositive: FA, 6; DCIS, 0. The remaining patients were CK14-immunonegative: FA, 4; DCIS, 10. The number of CK14-immunopositive DCIS patients was significantly different from that of FA patients (P=.0054). Eight out of the twenty patients were p63-immunopositive: FA, 8; DCIS, 0. The remaining patients were p63-immunonegative: FA, 2; DCIS, 10. The number of p63-immunopositive DCIS patients was significantly different from that of FA patients (P=.0004). CONCLUSIONS: Immunocytochemical staining using cocktail antibody targeting p63/CK14 was useful for the differential diagnosis of FA and DCIS in FNAC of the breast.

Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry.

BACKGROUND: We investigate rates of pathologic complete response (pCR) and tumor expression of ER, PgR, HER2 discordance after neoadjuvant chemotherapy using Japanese breast cancer registry data. PATIENTS AND METHODS: Records of more than 300,000 breast cancer cases treated at 800 hospitals from 2004 to 2013 were retrieved from the breast cancer registry. After data cleanup, we included 21,755 patients who received neoadjuvant chemotherapy and had no distant metastases. pCR was defined as no invasive tumor in the breast detected during surgery after neoadjuvant chemotherapy. HER2 overexpression was determined immunohistochemically and/or using fluorescence in situ hybridization. RESULTS: pCR was achieved in 5.7% of luminal tumors (n = 8730), 24.6% of HER2-positive tumors (n = 4403), and 18.9% of triple-negative tumors (n = 3660). Among HER2-positive tumors, pCR was achieved in 31.6% of ER-negative tumors (n = 2252), 17.0% of ER-positive ones (n = 2132), 31.4% of patients who received trastuzumab as neoadjuvant chemotherapy (n = 2437), and 16.2% of patients who did not receive trastuzumab (n = 1966). Of the 2811 patients who were HER2-positive before treatment, 601 (21.4%) had HER2-negative tumors after neoadjuvant chemotherapy, whereas 340 (3.4%) of the 9947 patients with HER2-negative tumors before treatment had HER2-positive tumors afterward. Of the 10,973 patients with ER-positive tumors before treatment, 499 (4.6%) had ER-negative tumors after neoadjuvant chemotherapy, whereas 519 (9.3%) of the 5607 patients who were ER-negative before treatment had ER-positive tumors afterward. CONCLUSION: We confirmed that loss of HER2-positive status can occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer. We also confirmed that in practice, differences in pCR rates between breast cancer subtypes are the same as in clinical trials. Our data strongly support the need for retest ER, PgR, HER2 of surgical sample after neoadjuvant therapy in order to accurately determine appropriate use of targeted therapy.

Molecular detection of lymph node metastasis in breast cancer patients treated with preoperative systemic chemotherapy: a prospective multicentre trial using the one-step nucleic acid amplification assay.

BACKGROUND: For patients with breast cancer treated with preoperative chemotherapy, residual tumour burden in lymph nodes is the strongest prognostic factor. However, conventional pathological examination has limitations that hinder the accurate and reproducible measurement. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method for detecting nodal metastasis. In this prospective multicentre trial, we assessed the performance of the OSNA assay in detecting nodal metastasis after chemotherapy. METHODS: In total, 302 lymph nodes from 80 breast cancer patients who underwent axillary dissection after chemotherapy were analysed. Each node was cut into two or four slices. One piece or alternate pieces were evaluated by pathology, and the other(s) were examined using the OSNA assay. The results of the two methods were compared. Stromal fibrosis, histiocytic aggregates, and degenerated cancer cells were regarded as chemotherapy-induced histological changes. RESULTS: The overall accuracy, sensitivity, and specificity of the OSNA assay compared with the reference pathology were 91.1%, 88.3%, and 91.7%, respectively. Of the 302 lymph nodes, 66 (21.9%) exhibited chemotherapy-induced histology. For these nodes, the accuracy, sensitivity, and specificity were 90.9%, 88.9%, and 93.3%, respectively. CONCLUSION: The OSNA assay can detect the residual tumour burden as accurately as conventional pathology, although chemotherapy-induced histological changes are present.

Effective treatment of young patients with pediatric-onset, long-standing lupus nephritis with tacrolimus given as a single daily dose: an open-label pilot study.

The objective of the current work is to report the preliminary experience with tacrolimus (TL) administered as a single-dose daily for maintenance therapy of young patients with pediatric-onset, long-standing systemic lupus erythematosus (SLE). Six consecutive patients with long-standing SLE were recruited for a 6-month open-label trial of single-dose-daily administration of tacrolimus (3 mg/day) without dose up of concomitantly administered prednisolone (PDN). TL treatment was started at the time of the most recent flares. Data on the clinical and serologic lupus activity were collected prospectively. The baseline characteristics of the patients were: mean age, 20 years; urinary protein/creatinine ratio, 1.22 +/- 1.94; serum C3 level, 70.8 +/- 21.2 (normal, 79-152 mg/dL); serum complement hemolytic activity (CH50), 22.2 +/- 10.3 (normal, 23-46 U/mL); serum anti-dsDNA antibody titer, 60.4 +/- 71.7 IU/mL (normal, < 12.0 IU/mL); serum creatinine, 0.55 +/- 0.11 mg/dL; European Consensus Lupus Activity Measurement (ECLAM) index, 5.2 +/- 2.6. Despite the gradual tapering of the PDN dose, marked improvement as compared with the baseline values was observed in the ECLAM index examined at one and three months and serological parameters examined at three months after the start of treatment. After a 6-months' therapy, complete response was achieved in all of the patients (serum CH50 value, 27.7 +/- 8.3 U/mL; serum anti-dsDNA antibody titer, 28.4 +/- 27.9 U/mL and the ECLAM index, 1.2 +/- 1.2 (P < 0.05), respectively), except in one patient who showed WHO class V lupus nephritis. No serious adverse effects were observed. These data suggest that TL, even when administered as a single-daily dose, is effective and safe for selected young patients with pediatric-onset, long-standing SLE. However, further studies on a larger number of patients are needed to confirm these results.

C1-C2 point monitoring of low-dose cyclosporin a given as a single daily dose in children with steroid-dependent relapsing nephrotic syndrome.

AIM: It has been reported that the pharmacokinetics of cyclosporin A (CsA) in children is different from that in adults. It appears that, in general, pediatric patients metabolize CsA more rapidly than adult patients, necessitating the use of higher dose of the drug in pediatric transplant recipients. In this context, we speculated that single-dose daily administration of low-dose CsA may be associated with a higher peak blood level without associated trough blood level elevation, and thereby yield better results and allow safer use of the drug than the conventional twice daily administration dosing used for the treatment of childhood idiopathic nephrotic syndrome (INS). METHODS: A total of 10 children with steroid-dependent relapsing INS (9 with biopsy-proven minimal-change disease) who showed steroid toxicity were enrolled in the study. The initial daily dose of CsA (Neoral) used was around 2.0 mg/kg, given as a single daily dose before breakfast. The dose was subsequently adjusted to achieve a C1-C2 point blood level between 600 - 800 ng/ml. The dose of the concomitantly administered prednisolone was tapered following the commencement of CsA. RESULTS: The mean daily CsA dosage, the mean C1-C2 point blood level and the mean trough blood level in the subjects were 2.2 +/- 0.8 mg/kg, 754.0 +/- 71.9 ng/ml and 42.7 +/- 29.2 ng/ml, respectively. At the latest observation, after a mean duration of 17 months (6 - 24 months) of CsA therapy, the minimum dose of prednisolone required for maintenance of clinical remission and the calculated relapse rate were significantly decreased as compared to the respective pretreatment values (0.52 +/- 0.46 mg/kg on alternate days, vs. 0.97 +/- 0.63 mg/kg on alternate days, and 0.28 +/- 0.32 times per six months, vs. 1.06 +/- 0.41 times per six months, respectively, p = 0.005). No significant change was observed in the mean estimated GFR value as compared to the pretreatment value (183.1 +/- 35.4 ml/min/1.73 m2vs. 185.4 +/- 39.3 ml/min/1.73 m2). No evidence of CsA nephrotoxicity was observed in a repeat renal biopsy performed around 12 months after the commencement of CsA therapy in two patients. CONCLUSIONS: Despite the limitations of the study, our results suggest that administration of low-dose CsA as a single daily dose with C1-C2 point blood level monitoring might be an equally effective and safe and, therefore, more cost-beneficial, protocol for the treatment of steroid-dependent cases of relapsing INS, as conventional twice-daily administration of CsA with trough blood level monitoring. Further studies to confirm the long-term efficacy and safety of this CsA treatment protocol in larger numbers of patients are, however, needed.

Implication of the peak serum level of mizoribine for control of the serum anti-dsDNA antibody titer in patients with lupus nephritis.

AIM: Mizoribine (MZR) is a novel selective inhibitor of inosine monophosphatase dehydrogenase that was developed in Japan. We previously reported the efficacy and safety of oral MZR pulse therapy, which is associated with elevated peak serum MZR levels, in selected patients with lupus nephritis. However, only limited information is available as yet on the optimal peak serum level of MZR that would yield an enhanced clinical efficacy without serious toxicity in patients with lupus nephritis. METHODS: A total of 11 patients with clinically stable lupus nephritis treated with oral MZR pulse therapy combined with low-dose prednisolone were enrolled in the cross-sectional study. The peak serum concentrations of MZR (as determined by HPLC) and the serum anti-dsDNA antibody titers (as determined by ELISA) were examined in the patients in order to evaluate the correlation between these two parameters. The correlation between the dose of MZR (mg/kg) administered orally as a single daily dose and the peak serum level of the drug was also examined. In two of the patients, serial measurements of the changes in the peak serum levels of MZR and anti-dsDNA titers could be conducted over 10 months. RESULTS: A significant inverse correlation (r = -0.596, p = 0.0116) was observed between the peak serum levels of MZR and the serum anti-dsDNA antibody titers in the study participants, while the dose of prednisolone remained unchanged. The peak level of MZR in the serum was significantly correlated with the single dose of MZR (r = 0.509, p = 0.0371). In the two patients in whom serial measurements were conducted, the first patient who showed a peak serum MZR level of less than 2.5-3.0 microg/ml eventually developed an increase of the serum anti-dsDNA titer with hypocomplementemia and proteinuria. On the other hand, in the second patient who showed a peak serum MZR level in excess of 4.0 microg/ml, persistently low serum anti-dsDNA titers with normocomplementemia were observed. CONCLUSION: Although this study is only a preliminary study conducted on a small sample, we speculate from the results that a peak serum level of MZR of at least more than 2.5-3.0 mirog/ml is necessary to achieve satisfactory clinical efficacy of the drug for the treatment of lupus nephritis. Further study is needed to confirm these preliminary findings.

Mizoribine for the treatment of lupus nephritis in children and adolescents.

AIM: The optimal treatment for lupus nephritis in the pubertal age group is still unclear. We therefore retrospectively evaluated the efficacy and safety of mizoribine (MZR), a novel selective inhibitor of inosine monophosphatase dehydrogenase, developed in Japan for the treatment of lupus nephritis in pubertal patients, because MZR has been reported to have relatively less clinically toxicity than conventionally used drugs. METHODS: Over the past 12 years, we have treated 20 children with newly diagnosed, biopsy-proven lupus nephritis at our hospital. Of these, 10 patients who received a 2-year course of MZR in combination with prednisolone (PSL) as initial maintenance therapy and who could be observed for at least two years after the commencement of the MZR treatment, were enrolled in this study. MZR was given orally at the dose of 4 - 5 mg/kg per day in two divided doses. Changes in the clinical parameters, such as the urinary protein excretion, serum anti-dsDNA antibody titer, serum hemolytic complement activity (CH50) and serum creatinine, and in the frequency of disease flares defined as persistent worsening of those clinical parameters, were examined pre- and posttreatment for comparison, and the steroid-sparing effect of MZR was analyzed. RESULTS: As induction therapy, all the patients had received high-dose oral PSL or intravenous methylprednisolone pulse therapy. Five female patients who were diagnosed to have proliferative lupus nephritis (WHO class III or IV) were scheduled to receive an 8-week course of oral cyclophosphamide (CPA) combined with high-dose steroids prior to the commencement of MZR, but CPA needed to be discontinued in four of these patients because of clinical drug toxicity. The clinical parameters showed significant improvement after the 2-year treatment with MZR combined with PSL, as compared to the pretreatment values (mean urinary protein excretion: 1.6+/-1.9 g/day vs.0.1 +/-0.1 g/day, serum CH50 value: 12.6+/-5.4 U/ml vs. 34.5+/-7.7 U/ml, serum anti-dsDNA antibody titer: 141.8+/-128.2 IU/ml vs. 18.5+/-17.7 IU/ml, respectively (p <0.01)). The serum creatinine remained normal. Although the daily dose of the concomitantly administered PSL to maintain clinical remission could be decreased significantly in all the study participants (39.5+/-1.6 mg/day vs. 6.8+/-5.1 mg/day, p < 0.01), two patients developed flares while on treatment, which were successfully treated by transiently increasing the dose of PSL. The MZR therapy could be completed in all of the patients without significant clinical toxicity being reported. At their most recent follow-up (mean 4.3 years), none of the 10 patients had renal insufficiency, and complete remission without any need for further medication had been achieved in two patients. CONCLUSION: Although this case series is without controls, maintenance therapy with MZR administered in combination with PSL may be beneficial and clinically less toxic in at least a proportion of pubertal patients with lupus nephritis.

Mizoribine oral pulse therapy for patients with disease flare of lupus nephritis.

AIM: Mizoribine (MZR) is a newly developed immunosuppressive agent in Japan. To relieve disease flare of lupus nephritis, a prospective pilot study of oral MZR pulse therapy (a phase II trial) is conducted as an alternative therapy to dose up of corticosteroids. METHODS: Six Japanese patients with biopsy-proven lupus nephritis who experienced disease flare were prospectively evaluated. MZR at a dose of 5 - 10 mg/kg per day (up to 500 mg) in 1 or 2 divided daily doses was orally administered twice a week for 3 months. At the time of disease flare, 4 patients had refused to take dose up of corticosteroids, and the other 2 had complained of opportunistic infection. RESULTS: At presentation, urine protein excretion, serum hemolytic complement activity (CH50) and serum anti-dsDNA antibody were 1.9 +/- 0.6 g/day, 15.7 +/- 5.8 U/ml (normal 23 - 46 U/ml) and 164.8 +/- 184.0 IU/ml (normal < 12.0 IU/ml), respectively. Urine protein excretion and serum anti-dsDNA antibody decreased significantly following MZR oral pulse therapy (0.2 +/- 0.1 g/day and 29.7 +/- 23.4 IU/ml (p < 0.05), respectively), and serum CH50 recovered to normal (35.1 +/- 10.4 U/ml, p < 0.05). Moreover, a significant histologic improvement was observed in a patient who received repeat renal biopsies at pre- and post-treatment. Reported peak serum MZR levels enough to inhibit human mixed-lymphocyte reaction (3.0 - 6.0 microg/ml) were achieved in all patients. No serious adverse effects were observed. CONCLUSION: Although we had no control subjects in this series, MZR oral pulse therapy may be of benefit to a proportion of patients with disease flare of lupus nephritis as an alternative therapy to dose up of corticosteroids.

Quantitative evaluation of metastases in axillary lymph nodes of breast cancer.

We have established a highly sensitive and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method to detect axillary lymph node metastases of breast cancer. Amplifying cytokeratin 19 (CK19) mRNA transcripts using real-time TaqMan PCR made it possible to quantify axillary metastatic burden. Metastases in 358 axillary lymph nodes obtained from 23 breast cancers of 22 patients were investigated by conventional haematoxylin and eosin (H&E) staining, immunohistochemical staining and quantitative RT-PCR assay. The detection rates of axillary lymph node metastasis using H&E staining, immunohistochemistry and RT-PCR assay were 4.5, 5.9 and 13.1%, respectively. RT-PCR assay was the most sensitive of these three methods for detecting lymph node metastases. Cytokeratin 19 mRNA expression values of both histologically and immunohistochemically positive lymph nodes were significantly higher than the values for lymph nodes judged to be negative by both histological and immunohistochemical methods (P<0.0001), and those of histologically negative, but immunohistochemically positive lymph nodes were significantly higher than the values for lymph nodes judged to be negative by both histological and immunohistochemical methods (P<0.0001). Furthermore, metastatic rates of sentinel nodes were higher than the rates of nonsentinel lymph nodes as measured by all three methods. These results indicate that quantitative RT-PCR assay is a sensitive and reliable method for detecting lymph node metastasis. Furthermore, quantification of metastases in sentinel lymph nodes by quantitative RT-PCR assay may be useful to assess the entire axillary burden of breast cancer patients.

Intraoperative lymphatic mapping and sentinel lymph node biopsy in patients with papillary carcinoma of the thyroid gland.

We examined the feasibility of sentinel lymph node biopsy for thyroid cancer. Thirty-eight patients with papillary thyroid carcinoma underwent intraoperative lymphatic mapping and sentinel lymph node biopsy. At surgery, we exposed the thyroid gland and used a tuberculin syringe to inject 0.2 ml of 1% patent blue dye directly into the thyroid mass. The lymphatics and the lymph node dyed with blue dyes, was excised as a sentinel lymph node. Modified radical neck dissection was performed following sentinel lymph node biopsy and the diagnostic ability of sentinel lymph node biopsy was examined. A sentinel lymph node was identified successfully in 27 (71%) of 38 patients. Sentinel lymph node biopsy removed one to three lymph nodes (median, two nodes). Eighteen patients had paratracheal sentinel lymph nodes, five patients had jugular sentinel lymph nodes, and four patients had both. Histological nodal metastasis was recognized in 16 of 27 cases. The positive rate of cancer metastases in sentinel lymph nodes was 58%, which was significantly higher than 11% in non-sentinel lymph nodes. Diagnostic ability of sentinel lymph node biopsy showed that accuracy was 89%, sensitivity was 84%, and specificity was 100%. Our preliminary study indicated that sentinel lymph node biopsy was available on detection of non-palpable nodal metastasis in the patients with thyroid cancer; however, further experience and refinement are needed.

Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1.

BACKGROUND & AIMS: Angiogenesis, formation of new capillary blood vessels, is crucial for gastroduodenal ulcer healing because it enables delivery of oxygen and nutrients to the healing site. Because angiogenesis is stimulated by vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1), we studied whether local gene therapy with nonviral DNA encoding VEGF and/or Ang1 into the ulcer base could accelerate ulcer healing through enhanced angiogenesis. METHODS: Gastric ulcers were induced in rats by acetic acid applied to the serosal surface of the stomach, and the site around the ulcer was injected with nonviral plasmid-encoding full-length complementary DNA (cDNA) of human recombinant (rh) VEGF165, rhAng1, or their combination. For some studies, neutralizing anti-VEGF antibody was administered. RESULTS: Single local injection of plasmids encoding VEGF165 and Ang1 significantly increased neovascularization and accelerated ulcer healing. A neutralizing anti-VEGF antibody significantly reduced the acceleration of ulcer healing resulting from the treatment. Coinjection of both plasmids encoding rhVEGF165 and rhAng1 resulted in formation of more mature vessels and to more complete restoration of gastric glandular structures within the ulcer scar. However, this did not result in further reduction of ulcer size. CONCLUSIONS: VEGF and Ang1 gene therapy, with limited duration of target gene expression, significantly accelerates gastric ulcer healing. Coinjection of both plasmids leads to more complete structural restoration. Inhibition of accelerated healing by a neutralizing anti-VEGF antibody indicates an essential role for VEGF and enhanced angiogenesis in ulcer healing.

Defective mitogen-activated protein kinase (ERK2) signaling in gastric mucosa of portal hypertensive rats: potential therapeutic implications.

Portal hypertensive (PHT) gastropathy is a frequent, serious complication of liver cirrhosis. PHT gastric mucosa has numerous abnormalities such as reduced mucosal potential differences, reduced surface oxygenation, and increased susceptibility to injury caused by alcohol, aspirin, and other noxious factors. Because such mucosal injury is initially mediated by oxygen free radicals, and because mitogen-activated protein (MAP) kinase (ERK2) protects against cellular stress and induces cell proliferation, we postulated that oxidative stress-induced ERK2 activation is defective in PHT gastric mucosa. Here we show that in PHT gastric mucosa, ERK2 activation by oxidative stress is impaired. This impairment is mediated by overexpression of MAP kinase phosphatase-1 (MKP-1), which results from the underlying and continual oxidative state associated with portal hypertension, and is ameliorated by inhibiting MKP-1. Furthermore, we found that supplementing vitamin E, a free radical scavenger, reduces the oxidative state in PHT gastric mucosa, normalizes MKP-1 expression, and thereby reverses impairment of oxidative stress-induced ERK2 activation. Finally, we show that orally administered vitamin E completely reverses the increased susceptibility of PHT gastric mucosa to alcohol injury. Our findings point to a new molecular and mechanistic basis for PHT gastropathy and provide a new therapeutic modality for protection of PHT gastric mucosa.

A comparison of an open and laparoscopic appendectomy for patients with liver cirrhosis.

Liver cirrhosis is a critical factor contributing to morbidity and mortality in abdominal surgery, because patients with cirrhosis have a particularly high risk of developing bleeding, infection, and ascites. Laparoscopic appendectomy (LA) recently has gained a lot of attention around the world; however, comparisons between the benefits of LA and those of conventional open appendectomy (OA) for patients with liver cirrhosis have yet to be sufficiently compiled. In the present retrospective study, 40 patients with liver cirrhosis who were diagnosed with acute appendicitis before surgery underwent an appendectomy (OA in 25 patients and LA in 15 patients). This study focused on the operative time, amount of postoperative pain, use of analgesics, the restart of a normal diet, number of complications, length of hospital stay, and cost-effectiveness of the procedure in such patients. The amount of postoperative pain and the length of hospital stay were significantly smaller in the LA group. The mean values of the serum C-reactive protein on postoperative days 1, 3, and 7 were significantly less in the LA group. The number of wound infections and wound bleeding was also less in the LA group. The difference in the total cost of hospitalization was not significant. The cost of the operation was greater in the LA group than in the OA group, whereas the hospitalization cost in the LA group was less than that in the OA group. The results of this study suggest that LA may be superior to OA for the treatment of postoperative pain and postoperative complications for patients with liver cirrhosis. Long-term follow-up studies are still necessary, however, to determine any possible decrease in the number of late complications.

Immunohistochemical localization of vascular endothelial growth factor in the rat portal hypertensive gastropathy.

BACKGROUND AND AIMS: Portal hypertensive gastropathy (PHG) is now recognized to be a distinct entity. Recently, angiogenesis has been noticed as a key factor in clarifying the pathophysiology of various diseases. Angiogenesis in the PHT of explored gastric mucosa has yet to be explored. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. The aim of the present study was thus to investigate whether the hypoxic state exists in PHG, and whether VEGF appears more strongly in PHG than in normal gastric mucosa and, if so, what exactly is the role of the hypoxic state and VEGF in PHG. METHODS: At 1, 3, 7 and 14 days after either a portal ligation or sham operation, the portal venous pressure, the gastric mucosal blood flow volume and the blood gas were measured and, the expression of VEGF and antiproliferating cell nuclear antigen (PCNA) in gastric mucosal specimens was immunohistochemically assessed. RESULTS: The portal pressure (PP) and the gastric mucosal blood flow (GMBF) in the PHT rats were significantly greater than in the control (CTR). Both the SaO2 and PaO2 of the arterial blood gas were lower in the PHT rats than in the control rats. The percentage of VEGF expression in the PHG was found to be higher than that in the control gastric mucosa. The percentage of PCNA expression in the PHG was higher than that in the control gastric mucosa. CONCLUSION: The levels of SaO2 and PaO2 were lower in the PHT rats. There is a possibility that a kind of portal hypertensive gastric change may trigger an enhanced histochemical expression of VEGF. The increased activity of VEGF may have a possibility of the hypoxic gastric mucosal state caused by the presence of active congestion. This damaged mucosal state 'PHG' may thus facilitate the fragility in PHG and such lesions may be slow and insidious, which may therefore lead to sudden and severe anemia, thus causing massive and sometimes fatal hemorrhaging.

The therapeutic strategies in performing emergency surgery for gastroduodenal ulcer perforation in 130 patients over 70 years of age.

BACKGROUND/AIMS: Gastroduodenal ulcer is a very common illness in Japan. As the number of elderly persons in Japan increases the same as in Europe and America, the number of such patients requiring a gastroduodenal emergency operation has also increased. Regarding the complications of peptic ulcer, a perforation remains the most important fatal complication. The aim of this study is to investigate the operative risk factors and the long-term recurrence rates and to define the optimal surgical procedures in emergency situations in elderly patients. METHODOLOGY: From April 1988 through March 1997, 130 patients over 70 years of age with a perforated gastroduodenal ulcer (a duodenal ulcer perforation in 50 patients and a gastric ulcer perforation in 80 patients) were operated on in an emergency situation in our clinic. We investigated the following items; medical illness, preoperative risk factor, optimal surgical procedure, postoperative organ failure and the cumulative recurrence-free rates after surgical treatment. RESULTS: A significant correlation with mortality was observed in patients with established comorbidity in the following organs: lung (P = 0.03), heart (P = 0.02), kidney (P = 0.04), and diabetes (P = 0.03). The highest postoperative mortality rate was recorded in patients who underwent a simple closure of a duodenal ulcer perforation (4 patients; 26.7%), while the lowest postoperative mortality rate was recorded in patients who underwent a simple closure and vagotomy of a duodenal ulcer perforation (3 patients; 12.5%). In gastric ulcers, the mortality rate in patients with a gastrectomy was significantly higher than in patients with a simple closure. The practical application of the three risk factors (preoperative shock, delay to surgery over 24 hours, and medical illness) was shown by the progressive rise in the mortality rate with the increasing number of risk factors. Based on the 5 postoperative years after treating a perforated duodenal ulcer, the cumulative recurrence rate after a simple closure (63.6%) was significantly higher than that after a simple closure and vagotomy (38.1%) (n = 0.02) or after gastrectomy (0%) (P < 0.001). At 5 years postoperatively, the cumulative recurrence rate after a simple closure (41.2%) was significantly higher than that after a gastrectomy (15.9%) (P < 0.01). CONCLUSIONS: In conclusion, in an emergency situation, elderly patients are in a highly unfavorable prognostic condition due to their advanced age, and comorbidity, which thus leads to poorer results, not only worldwide, but also in Japan. Based on our findings, in duodenal ulcer cases, a simple closure and vagotomy is recommended because of its low mortality and minimal stress, except for cases with a giant perforation measuring over 20 mm in diameter at the perforation hole or with severe duodenal stenosis. In stomach ulcer cases, a gastrectomy may be recommended because of its low recurrence rate.

Prognosis of node-positive breast cancer patients who underwent parasternal lymph node biopsy during surgery followed by doxorubicin- or mitoxantrone-containing adjuvant chemotherapy.

The authors examined the survival rates of 60 patients with breast cancer who underwent parasternal lymph node biopsy during surgery with axillary lymph node dissection and had histologically confirmed axillary node metastasis followed by adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy to ascertain whether administration of anthracycline or its analogue improved the prognosis of both axillary and parasternal node-positive patients. The overall survival rate (OS) for the parasternal node-positive patients (n=13, 21.7%) was 30.6%, and relapse-free survival rate (RFS) fell to 0% at the 104-month follow-up. Although the survival rate for all axillary node-positive patients was similar to those in previous reports, the OS and RFS for both axillary and parasternal node-positive patients were significantly worse than that for axillary node-positive and parasternal node-negative patients, despite treatment with adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy. Other intensive adjuvant treatment strategies are needed to reduce distant metastases for high-risk breast cancer patients having both axillary and parasternal nodes positive.