Study on relationship between angiogenesis and micrometastases of peripheral blood in breast cancer

Purpose  To investigate the relationship between microvessel density, expression of vascular endothelial growth factor A (VEGF-A) and micrometastases in peripheral blood of patients with breast cancer. Method  Microvessel density (MVD) and expression of VEGF-A were detected by immunohistochemistry S-P. Nested RT-PCR was introduced to detect the expression of hMAM mRNA in peripheral blood of all cases. Result  Average MVD was 28.95 ± 6.95 microvessels/100× and positive rate of VEGF-A was 64.0% (32/50) in 50 cases with breast cancer. MVD count and expression of VEGF-A were related to tumor size, metastasis of axillary lymph nodes and clinical stages (P < 0.05), independent of age and histological classification (P > 0.05). The positive rate of hMAM mRNA in peripheral blood was 34.0% (17/50), which correlated with lymphatic metastasis and clinical stages (P < 0.05), independent of pathological category, menopause and hormone receptor (P > 0.05). MVD count and positive rate of VEGF-A in breast cancer with positive expression of hMAM mRNA was obviously higher than those without hMAM mRNA expression (χ ² = 5.766, P = 0.032; t = 5.37, P = 0.002). Conclusions  MVD count and positive expression of VEGF-A closely correlated to hMAM mRNA released from tumor cells in the circulation. hMAM mRNA is expected to become a valuable marker for further study on micrometastases of breast cancer.     

Clinical significance of cytokeratin positive cells in bone marrow of gastric cancer patients

Bone marrow (BM) is a prognostically relevant indicator organ of micrometastasis; however, the clinical importance of BM micrometastasis in gastric cancer patients is not yet known. In the present study, the BM of 267 consecutive patients with primary gastric cancer was examined for tumor cells using immunocytochemical techniques. Real-time quantitative RT-PCR was used to ensure that the tumor cells were detected properly. Among the 267 cases analyzed, 30 cases (11.2%) had cytokeratine-positive cells in the bone marrow. Positive findings were related to the tumor stage (P < 0.05) and to the prominent depth of invasion (P < 0.05). All patients with liver metastasis at operation had cytokeratine-positive cells in the BM. Recurrence of the disease was confirmed in 50 cases (18.7%); 4 of 30 (13.3%) in the cytokeratine-positive group and 46 of 237 (19.4%) in the cytokeratine-negative group. There were no significant differences in the 5-year survival rates between the cytokeratine-positive and cytokeratin-negative groups. Our study shows that BM micrometastasis increases according to tumor progression; however, only a subset of cancer cells may survive in the BM and finally evolve to a clinically apparent disease. Therefore it does not accurately predict the prognosis or recurrence of the disease.     

Increased soluble CD44 concentrations are associated with larger tumor size and lymph node metastasis in breast cancer patients

Purpose  CD44 is a cell surface glycoprotein involved in cell–cell and cell–substrate interactions, which may be shed or released into circulation by proteolytic enzymatic mechanisms. Alternative splicing of CD44 and aberrant levels of soluble CD44 variants in the serum of cancer patients have been correlated to tumor progression and metastasis in different tumors including breast cancer. In this study we evaluated the clinical value of CD44 serum levels (sCD44) in patients with primary breast cancer. Methods  Concentrations of soluble isoforms sCD44std, sCD44v5 and sCD44v6 were determined with a sensitive ELISA and normalized against the total protein concentration (TP). Pre-operative serum samples from 82 patients and 67 age-matched healthy blood donors were analyzed. The results were correlated to clinico-pathological parameters (tumor size, grading, lymph node metastasis, etc.). Results  In sera of breast cancer patients, we detected elevated concentrations of sCD44v6 (P = 0.0001) and total protein TP (P = 0.0001) in comparison to healthy controls, whereas overall sCD44 (sCD44std) and sCD44v5 did not differ. Patients with sCD44v6-concentrations above the 75%-percentile showed an increased T stage (2.9 cm vs. 1.8 cm) as well as a higher risk for lymph node metastasis (55% vs. 35%). In breast cancer patients with lymph node metastasis the median value of sCD44v6 was significantly higher (P = 0.025) in comparison to patients without lymph node metastasis and healthy controls. Conclusions  Our data suggest an upregulated expression of alternatively spliced soluble CD44 isoforms in breast cancer patients. The specific alterations of certain CD44 isoform concentrations (especially sCD44v6) may reflect disturbances of the nuclear splicing machinery in tumor cells. The clinical significance of our findings are underlined by the positive correlation of elevated sCD44v6 concentrations and lymph node metastases (r _s = 0.25).     

R0 Liver Resections for Primary Malignant Liver Tumors in the Noncirrhotic Liver: A Diagnosis-Related Analysis

Background Primary liver cancer constitutes an increasingly malignancy in the Western world and one of the leading causes of cancer-related deaths worldwide. The purpose of this study was to evaluate and compare long-term outcomes after R0 resections in noncirrhotic livers for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods Between April 1998 and May 2006 a total of 102 patients with either ICC (n = 41, group 1) or HCC (n = 61, group 2) in the absence of cirrhosis underwent curative liver resection in our department. Demographic characteristics, operative details, perioperative complications, pathologic findings, tumor recurrence and survival were analyzed. Results Gender (P = 0.007), extent of liver resection (P = 0.036), additional surgical procedures (P < 0.001) and operative morbidity (P = 0.018) differed among the two groups. Following resection, after a median follow-up of 28 months, the calculated 5-year survival was 44% and 40% for ICC and HCC, respectively (P = 0.38). The corresponding recurrence-free survival was 25% for both ICC and HCC (P = 0.66). UICC stage was found to predict overall and recurrence-free survival in both types of tumors. Multifocality in the case of ICC, and tumor differentiation and vascular invasion in the case of HCC, were predictive factors for overall and recurrence-free survival, respectively. In multivariable analyses, vascular invasion for HCC was predictive for overall and recurrence-free survival, whereas in the case of ICC significant differences were detected in the recurrence analysis for multifocality and UICC stage. Conclusions R0 resections for both ICC and HCC result to similar long-term outcomes, which are characterized by good overall and acceptable recurrence-free survival rates.     

Progesterone receptors A and B and estrogen receptor alpha expression in normal breast tissue and fibroadenomas

Fibroadenomas are the most common benign breast tumors, occurring mainly in young women. Their responses to the hormonal environment are similar to those of normal breast tissue, which suggests that steroid receptors may play a role in tumor development. We evaluated the gene and protein expression of progesterone receptors A and B (PRA and PRB) and the protein expression of estrogen receptor α (ER-α) in fibroadenoma samples, comparing with adjacent normal breast tissue, from 11 premenopausal women. Progesterone and estradiol levels were determined. No alterations in the PRs gene and protein expression and the ER-α protein expression were observed between the follicular and luteal phases, in normal breast versus fibroadenomas. Protein levels of PRA and PRB were higher in fibroadenomas compared to normal breast tissue (P = 0.038 and P = 0.031), while the PRs mRNA levels were similar in both tissues (P = 0.721 and P = 0.139). There were no differences in ER-α protein expression between normal breast tissue and fibroadenomas (P = 0.508). The PRA:PRB ratio was similar in the tissues, and also showed a strong correlation in both (r = 0.964, P = 0.0001). Our data suggest a role of PRs in the growth and development of fibroadenomas, although without alterations of the PRA:PRB ratio in these tumors. The absence of alterations in ER-α protein levels could be a characteristic behavior of fibroadenomas, unlike breast cancer.     

Early thoracentesis correlated with survival benefit in patients with spontaneous bacterial empyema

BackgroundSpontaneous bacterial empyema (SBEM) is a rare complication of hepatic hydrothorax characterized by hydrothorax infection in the absence of pneumonia.Aims and methodsWe conducted this study to compare clinical outcomes in SBEM patients who underwent early thoracentesis (ET) (≤ 24 h from presentation) versus those who underwent delayed thoracentesis (DT). All patients diagnosed with SBEM at Mayo Clinic Rochester, Minnesota from January 1st 1999 to December 31st 2020 were reviewed. Demographics, pleural fluid studies, laboratory results and clinical outcomes were analyzed.ResultsA total of 54 SBEM patients (27 ET and 27 DT) were identified with 38 (70.4%) of patients presenting with right-sided effusions. Both groups had similar baseline characteristics. The rate of ICU admission was significantly higher in the DT group (15 (55.6%) vs. 7 (25.9%) patients, P = 0.027). Patients with DT had similar rate of AKI (11 (40.7%) vs. 6 (22.2%) patients, P = 0.074). In-hospital mortality (11 (40.7%) vs. 2 (7.4%) patients, P = 0.004), 3-month mortality (16 (59.3%) vs. 2 (7.4%) patients, P < 0.001) and 1-year mortality rate (21 (77.8%) vs. 6 (22.2%) patients, P < 0.001) were higher in the DT group.ConclusionPatients with SBEM who underwent thoracentesis after 24 h from presentation (DT) had higher rates of mortality and ICU admission compared to patients who received early thoracentesis. Thoracentesis should be performed early in patients with suspected SBEM since it may improve survival.     

A polymorphism in the promoter region of Ku70/XRCC6, associated with breast cancer risk and oestrogen exposure

Purpose  Polymorphisms in double strand break repair genes could be involved in genetic breast cancer predisposition as enhanced chromosomal radiosensitivity is a hallmark for breast cancer. Previously, the c.-1310 C>G SNP, located in the Ku70 promoter, showed a significant odds ratio (OR) of 1.85 (P = 0.048) in sporadic, but not familial breast cancer patients, indicating that other factors besides genetic aptitude influence this association. As breast epithelium is exposed to endogenous oxidative stress through oestrogen exposure, the influence of hormone exposure was further examined. Methods and results  A significant OR (1.69, P = 0.017) was found for an enlarged patient population through PCR-RFLP assays in a case–control study in a Belgian population. After dividing the patient population according to oestrogen exposure, high and significant ORs were seen for patients with a longer oestrogen exposure (late age at menopause: OR = 1.96, P = 0.029). Conclusion  These results show that the variant allele of c.-1310 C>G, located in the Ku70 promoter, is a risk allele for breast cancer. Furthermore, the association of the c.-1310 C>G SNP with breast cancer risk was stronger in women with a long oestrogen exposure.     

Expression of anion exchanger 1 is associated with tumor progress in human gastric cancer

Purpose  Anion exchanger 1 (AE1) is a transmembrane glycoprotein which is abundantly expressed in erythrocyte plasma membrane and mediates the electroneutral exchange of Cl⁻ and HCO₃ ⁻. We previously reported that the AE1 protein was unexpectedly expressed in the gastric and colonic cancer and take part in the carcinogenesis of the cancer cells. The aim of the present study is to determine the potential clinical implications of AE1 expression in gastric carcinoma. Methods  Immunohistochemistry assay was used to determine the expression of AE1 protein. The expression of AE1 in normal and malignant tissues from 286 patients with early and advanced gastric carcinoma was examined. The correlations of AE1 expression with clinicopathological parameters, including age, tumor size, location and subtypes, expression frequency, survival period and lymph metastasis were assessed by Chi-squared test and t test analysis. Results  AE1 immunoreactivity was negative in normal gastric tissue. Positive immunostaining of AE1 was detected in gastric carcinoma regardless of the location. AE1 was most frequently expressed in the gastric antrum carcinoma compared with gastric body cancer (P = 0.034). Expression of AE1 was significantly associated with bigger tumor size, deeper invasion, shorter survival period, and non-lymph metastasis. In para-cancer tissues of intestinal-type gastric cancer, the expression frequency of AE1 was higher than that in diffuse-type (P = 0.011). Conclusion  The results showed a strong association of AE1 expression with the onset and progression of the gastric cancer and that may be helpful for improving the tumor classification and the treatment of cancer. W.-Q. Xu and L.-J. Song have been equally contributed to this work.     

HER2 overexpression and activation, and tamoxifen efficacy in receptor-positive early breast cancer

Objectives  Tamoxifen is a partial ER antagonist that is highly effective in the treatment of receptor positive breast cancer. It significantly reduces recurrence and improves survival in both pre- and postmenopausal women. Unfortunately, many ER+ positive tumors progress despite tamoxifen treatment and until now, no possibility exists to prospectively identify tamoxifen-resistant tumors. It has been suggested that that in HER2 over-expressing tumors, cross-talk via activated HER2 receptors is a key mechanisms by which tumors become tamoxifen-resistant. Methods  We have therefore used immunohistochemistry to analyze the expression of HER2 and activated ptyr-1248 HER2 in 408 women of ER+, early breast cancer who had received at least 2 years of adjuvant tamoxifen. We then analyzed possible associations between HER2 and pHER2 expression, and prognostic parameters, and evaluated the effect of HER2 expression and survival. Results  With HER2 being positive in 12 of 208 (2.9%) of ER+ positive tumors, HER2 overexpression was found to be considerably less common in ER+ tumors than what has been thought previously. The majority of HER2 overexpressing tumors, however, also expressed the activated receptor form (r = 0.664; P < 0.0001). Both HER2 and pHER2 are moderately correlated with Grading (r = 0.138; P = 0.0052 and r = 0.118; P = 0.0241, respectively) and nodal involvement (r = 0.163; P = 0.0018 and r = 0.134; P = 0.016, respectively), but neither HER2 nor its activated form are significant predictors of RFS, DFS, or OS. Conclusions  Taken together, we have demonstrated that in ER+ breast cancer, the HER2 receptor is commonly activated, but its low prevalence in ER+ tumors does not render it a useful prognostic parameter in tamoxifen-treated patients.     

Characterization of bone marrow mesenchymal stromal cells in aplastic anaemia

In aplastic anaemia (AA), haemopoietic activity is significantly reduced and generally attributed to failure of haemopoietic stem cells (HSC) within the bone marrow (BM). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the BM microenvironment, including mesenchymal stromal cells (MSC). MSC involvement in the functional restriction of HSC in AA is largely unknown and therefore, the physical and functional properties of AA MSC were studied in vitro. MSC were characterized by their phenotype and ability to form adherent stromal layers. The functional properties of AA MSC were assessed through proliferative, clonogenic and cross‐over culture assays. Results indicate that although AA MSC presented typical morphology and distinctive mesenchymal markers, stromal formation was reduced, with 50% of BM samples failing to produce adherent layers. Furthermore, their proliferative and clonogenic capacity was markedly decreased (P = 0·03 and P = 0·04 respectively) and the ability to sustain haemopoiesis was significantly reduced, as assessed by total cell proliferation (P = 0·032 and P = 0·019 at Week 5 and 6, respectively) and clonogenic potential of HSC (P = 0·02 at Week 6). It was concluded that the biological characteristics of AA MSC are different from those of control MSC and their in vitro haemopoiesis‐supporting ability is significantly reduced.     

Clinical features associated with a favorable outcome following neoadjuvant chemotherapy in women with localized breast cancer aged 35 years or younger

Background  There is scarce data on the outcome of young patients aged 35 years and younger, who have been treated with neoadjuvant chemotherapy. The aim of this study is to evaluate the impact of body mass index (BMI) and various prognostic factors on pathologic response and survival in young patients with localized breast cancer. Patients and methods  This is a retrospective evaluation on the outcome of 110 patients who were younger than 35 years at diagnosis and treated with neoadjuvant chemotherapy (CT). Patients were grouped in quartiles of BMI calculated prior to initiation of chemotherapy. Logistic regression analysis was performed to investigate the associations between prognostic variables including BMI and treatment outcome. The impact of prognostic factors on survival was analyzed by Kaplan-Maier and Cox regression tests. Results  Body mass index was not correlated with pathologic complete response (pCR) (n = 13, 11.7%) or survival. Cox regression analysis revealed nodal pCR following neoadjuvant chemotherapy (HR 2.45, P = 0.048) and stage at diagnosis (HR1.99, P = 0.027) as significant independent prognostic factors for DFS, while recurrence was independently associated with shorter OS (HR 169, P = 0.029). Conclusion  Body mass index was not correlated with pCR or prognosis in young women with early breast cancer. Pathologic CR was shown to have a significant influence on DFS. Total axillary clearance may be used a surrogate variable in determining prognosis in young patients treated with neoadjuvant chemotherapy.     

Biological profile of oestrogen receptor positive primary breast cancers in the elderly and response to primary endocrine therapy

Aromatase inhibitors have been shown to be superior to Tamoxifen in several settings. It is unclear whether this superiority extends to their use as primary endocrine therapy in elderly patients with early operable primary breast cancer. Biological characteristics of the tumours may aid in selecting the most suitable agent.Primary endocrine therapy with Anastrozole in 64 women >70 years with oestrogen receptor α-positive (ERα+) breast cancer was compared to that in 84 treated with Tamoxifen during the same period. Biomarkers were assessed by immunohistochemistry on diagnostic core biopsies.There was no significant difference between the two groups (Anastrozole vs Tamoxifen) in terms of clinical benefit rates at 6 months (97% vs 100%) or median progression free survival (16.5 vs 22.5 months). There were no withdrawals due to adverse events from Anastrozole, compared to four with Tamoxifen. 46%, 99%, 8% and 5% of all patients were positive for progesterone receptor, ERβ2, HER2 and EGFR, respectively, and 64% of patients had a moderate Ki-67 index. Positive HER2 status (18 vs 21 months, p = 0.003) and moderate Ki-67 index (17.5 vs 23 months, p = 0.042) were associated with significantly shorter progression free survival.Results thus far show that primary endocrine therapy with Anastrozole in elderly patients with early operable ERα+ breast cancer is similar to Tamoxifen in terms of efficacy, but appears to be associated with less adverse events leading to withdrawals. In this population, ERα+ breast cancer also appears to have a less aggressive biological profile favouring better hormone sensitivity.     

Intrahepatic cholangiocarcinoma: report of 272 patients compared with 5,829 patients with hepatocellular carcinoma

Purpose  To clarify clinicopathologic differences between patients with intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), and identify potential factors influencing survival after hepatectomy for ICC. Methods  Comparison of clinicopathologic data was made between patients who underwent hepatectomy for ICC (n = 272) and HCC (n = 5,829) during the same period. Twenty-five clinicopathologic variables were selected for univariate and multivariate analyses to evaluate their influence on prognosis of ICC. Results  Compared with patients with HCC, ICC patients were more common in females and more elderly, had a lower proportion of asymptomatic tumors, lower serum alpha-fetoprotein, higher serum carcinoembryonic antigen, carbohydrate antigen 19–9 and alkaline phosphatase levels; lower incidence of hepatitis history, associated cirrhosis and serum hepatitis B surface antigen; lower proportion of small tumors, well-encapsulated tumors and tumor emboli in the portal vein; higher proportion of single tumor, perihila lymph node involvement and poor differentiation; and less frequency of limited resection (all, P < 0.0001). Distant metastasis was less frequent in patients with ICC (P = 0.027). A total of 5-years overall and disease-free survival (in brackets) after resection was 26.4% (13.1%) and 44.5% (33.1%) (P < 0.0001, P < 0.0001) for patients with ICC and HCC, respectively. Factors influencing survival after resection of ICC can be divided mainly into two categories: early detection of asymptomatic ICC (P < 0.0001) and curative resection (P = 0.002). Conclusion  ICC Patients have distinct clinicopathologic features as compared with HCC patients. Surgery remains the only effective treatment for ICC. Early detection of asymptomatic ICC and curative resection were the key to achieve optimal survival.     

The effect of tamoxifen and medroxyprogesterone on giant cell formation by monocytes from patients with breast cancer

Summary Incubation of peripheral blood monocytes from patients with breast cancer under agarose for 6 days at 37 °C in a 5% CO₂ atmosphere resulted in giant cell formation. This phenomenon appeared to be mediated by retroviruses present in these cells. In this study giant cell formation was investigated in patients with primary stage I and II breast cancer before and 3 months after mastectomy with axillary lymph node clearance. Mastectomy had no significant inhibitory effect on giant cell formation. In vitro incubation of monocytes from patients with breast cancer in the presence of tamoxifen (Nolvadex) resulted in significant inhibition of giant cell formation (P<0.000003; paired Student'st-test). In vitro addition of medroxyprogesterone (Farlutal) to monocytes from patients with breast cancer also resulted in significant inhibition of giant cell formation (P<0.003: paired Student'st-test). Furthermore, incubation of monocytes from patients treated by mastectomy followed by 3 months treatment with adjuvant tamoxifen, resulted in a significant reduction (P<0.00007; paired Student'st-test) in the number of giant cells compared to the same samples tested before the commencement of the treatment. Giant cell formation may be used as a simple test to predicte the response of patients with breast cancer to either tamoxifen or medroxyprogesterone.This paper was presented in part to the (1) Association of Surgeons of Great Britain and Ireland: London, U.K., April 1986. (2) British Association of Surgical Oncology, American Society of Surgical Oncology, London, England, April 1987; (3) XXII Congress of the European Society for Surgical Research, Arhus, Denmark, May 1987; (4) European Organisation for Research on treatment of Cancer, London, England, June 1987     

RETRACTED ARTICLE: Overexpression of Cks1 is associated with poor survival by inhibiting apoptosis in breast cancer

Purpose  The present study was undertaken to examine the amplification and expression status of Cks1 in breast cancer and its significance. Methods  The amplification and expression status of Cks1 gene was examined by FISH, real-time PCR and immunohistochemistry, respectively. RNA interference was used to detect the effects of Cks1 on migration, invasion, cell cycle progress and apoptosis of breast cancer cells. Results   Cks1 gene amplification was highly correlated with protein overexpression. Overexpression of Cks1 was strongly associated with lymph node metastasis and poor prognosis (P = 0.000, 95% CI (0.00–0.02); P = 0.008, 95% CI (0.001–0.05), respectively). Knockdown of Cks1 expression by RNA interference inhibited the cell cycle progress, migration and invasion ability of breast cancer cells. Moreover, overexpression of Cks1 inhibited apoptosis of breast cancer cells through MEK-Erk pathway. Conclusion  Cks1 may be considered as potential novel prognostic markers and targets for the future development of specific therapeutic interventions in breast cancer. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Effect of TNF‐inhibitor therapy on spinal structural progression in ankylosing spondylitis patients: A systematic review and meta‐analysis

To review the effect of tumor necrosis factor‐alpha inhibitor (TNFi) therapies on radiographic progression in ankylosing spondylitis (AS) patients as evaluated by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Pubmed, MEDLINE, EMBASE, and the Cochrane Library databases were searched from inception to August 2019. All comparative and non‐comparative studies that evaluated the clinical effectiveness of TNFi on radiographic progression as assessed by mSASSS change at a minimum follow‐up of 1 year were included. The Newcastle–Ottawa Scale and Cochrane Collaboration Risk of Bias Tool were utilized to assess the methodological quality. Pooled analysis was performed for continuous and binomial variables where appropriate. Inter‐rater reliability of mSASSS status and change scores were assessed with intra‐class coefficients (ICC). Twenty‐one studies were identified with a total of 4460 patients (mean age: 40.4 years [range 25.3‐50 years]; 76% male; mean baseline mSASSS: 12.7 units [range 5.5‐19.8 units]). All studies (3 randomized and 18 observational studies) were considered to have moderate‐to‐high methodological quality. The inter‐rater reliability of mSASSS status and change scores from 14 of the 21 studies were excellent (ICC ranges, 0.91‐0.99) and moderate‐to‐excellent (ICC ranges, 0.58‐0.90), respectively. From the 21 studies, 11/21 (50%) demonstrated a delayed effect in mSASSS in AS patient administered TNFi. When stratifying these studies into those with ≤4 years of follow‐up and >4 years follow‐up, 3/11 (27%) and 8/10 (80%) studies respectively indicated a delayed effect of mSASSS with TNFi in AS patients. Pooling for meta‐analysis from 3 studies (1159 patients) with study durations ranging 4‐8 years, indicated that TNFi‐treated patients had reduced odds of structural progression (odds ratio 0.81; 95% CI 0.68‐0.96; P = .01; I² = 0%). Mean rate of mSASSS change from 16 studies ranged from ?0.15 to 7.3 mSASSS units for all AS patients. Meta‐analysis indicated a numerical, but statistically non‐significant, reduction in the rate of mSASSS change with TNFi treatment (7 studies [1438 patients]; mean difference, ?0.24; 95% CI, ?0.49‐0.01; P = .06; I² = 0%). This systematic review and meta‐analysis indicated that >4 years of TNFi usage was associated with delayed structural progression by mSASSS. The narrative analysis of the data from 21 studies further confirmed that studies with >4 years of follow‐up had delayed structural progression with TNFi use in AS patients. The systematic review also confirmed that mSASSS has good‐to‐excellent inter‐rater reliability in AS.     

Restoration of gut motility in Kit-deficient mice by bone marrow transplantation

Purpose  Interstitial cells of Cajal (ICC) play important roles in autonomic gut motility as electrical pacemakers and mediators of neural regulation of smooth muscle functions. Insufficiency of ICC has been reported in a wide range of gut dysmotilities. Thus, restoration of ICC may be a therapeutic modality in these diseases. Here we provide evidence that transplanted bone marrow (BM) cells can restore gut dysmotility in part via transdifferentiation to ICC. Methods  Bone marrow cells obtained from Kit insufficient W/W ^v mice or syngeneic GFP-transgenic mice with wild-type Kit were transferred to W/W ^v recipients. Whole gut transit time and gastric emptying were examined 5 and 6 weeks after BM transplantation, respectively, and ICCs were identified in whole mounts, frozen sections and transmission electron immunomicroscopy of the gut smooth muscle layers using specific antibodies. Results  Transplantation of wild-type BM into W/W ^v mice significantly improved whole gut transit time and gastric emptying. Fluorescent immunohistochemistry revealed GFP⁺Kit⁺ cells in the myenteric plexus, deep muscular plexus, and submucosal plexus smooth muscle layers of the stomach, small intestine, and colon, respectively. In the whole mounts, GFP⁺Kit⁺ cells were bipolar and spindle shaped, and transmission electron immunomicroscopy showed GFP⁺ cells rich in mitochondria and endoplasmic reticulum between gut smooth muscle layers, suggesting the presence of GFP⁺ cells with morphological characteristics of ICC. Conclusions  These results suggest that BM contains cells that may incorporate into ICC networks and improve dysmotility in W/W ^v mice. Thus, BM transplantation may become to a new therapeutic modality for gut dysmotilities due to ICC insufficiency.     

Comparative assessment of urinary oxidative indices in breast and colorectal cancer patients

Purpose  This study aimed to use non-invasive methods to assess and compare the levels of oxidative indices and non-enzymatic antioxidants in breast and colorectal cancer (CRC) patients. Various studies have reported on lipid peroxidation, hydrogen peroxide (H₂O₂) and ferric-reducing antioxidant power (FRAP) levels in the serum of cancer patients but this is the first report that highlights the significance of urinary-advanced oxidative protein product (AOPP) in cancer patients. Methods  The levels of advanced oxidative protein product (AOPP), hydrogen peroxide (H₂O₂), malondialdehyde (MDA) which is a marker for lipid peroxidation and ferric-reducing antioxidant power (FRAP) were measured in urine samples of breast (n = 101) and colorectal cancer (n = 49) patients attending the Oncology Clinic, University Malaya Medical Centre, Kuala Lumpur and were compared with 95 age-matched healthy individuals. Results  AOPP, H₂O₂ and MDA levels in the urine were significantly higher in the CRC patients compared to the control subjects and breast cancer patients. In breast cancer patients, only AOPP level was elevated. FRAP level did not differ between breast and colorectal cancer patients but the levels were significantly lower compared to control subjects. Conclusion  Urinary oxidative indices such as AOPP, H₂O₂, and MDA as well as FRAP could serve as useful non-invasive oxidative stress markers in colorectal cancer but only AOPP serves as a useful urinary oxidative biomarker in breast cancer.     

Circulating plasma cells in newly diagnosed symptomatic multiple myeloma as a possible prognostic marker for patients with standard‐risk cytogenetics

Detection of circulating plasma cells (PCs) in multiple myeloma (MM) patients is a well‐known prognostic factor. We evaluated circulating PCs by flow cytometry (FC) in 104 patients with active MM at diagnosis by gating on CD38⁺ CD45^‐cells and examined their relationship with cytogenetic risk. Patients had an average follow‐up of 36 months. By using a receiver operating characteristics analysis, we estimated the optimal cut‐off of circulating PCs for defining poor prognosis to be 41. Patients with high‐risk cytogenetics (n = 24) had poor prognosis, independently of circulating PC levels [PC < 41 vs. PC ≥ 41: overall survival (OS) = 0% vs. OS = 17%, P = not significant (n.s.); progression‐free survival (PFS) = 0% vs. 17%, P = n.s.]. Patients with standard‐risk cytogenetics (n = 65) showed a better prognosis when associated with a lower number of circulating PCs (PC < 41 vs. PC ≥ 41: OS = 62% vs. 24%, P = 0·008; PFS = 48% vs. 21%, P = 0·001). Multivariate analysis on the subgroup with standard‐risk cytogenetics confirmed that the co‐presence of circulating PCs ≥ 41, older age, Durie‐Salmon stage >I and lack of maintenance adversely affected PFS, while OS was adversely affected only by lactate dehydrogenase, older age and lack of maintenance. Our results indicate that the quantification of circulating PCs by a simple two‐colour FC analysis can provide useful prognostic information in newly diagnosed MM patients with standard‐risk cytogenetics.