Excellent prognosis of node negative patients after sentinel node procedure in colon carcinoma: a 5-year follow-up study.

AIM: Investigate the prognostic impact and clinical relevance of the sentinel node (SN)-procedure in colon carcinoma. PATIENTS AND METHODS: Between May 2002 and January 2004, the SN-procedure was performed in 55 patients that underwent elective resection for clinically non-advanced colon carcinoma. A control group of 110 patients was identified from a cohort between January 2000 and April 2002. All lymph nodes were analysed by conventional haematoxylin-eosin staining. All negative SNs underwent in-depth analysis using immunohistochemical-staining and automated microscopy with the Ariol-system. Patients with positive lymph nodes were offered adjuvant chemotherapy. All patients were routinely monitored at 6-month intervals and follow-up was more than 5 years. RESULTS: The SN was successfully identified in 98% of the patients, with 94% sensitivity. In-depth analysis with immunohistochemistry and automated microscopy (Ariol-system) upstaged 3 and 4 patients respectively. When only node-negative patients were analysed, overall 5-year-survival was significantly better in the SN group (91% vs. 76%, p = 0.04). Cancer-specific-mortality was even 0% (vs. 8%, p = 0.08). Disease-free-survival was significantly improved to 96% (vs. 77%, p < 0.01). CONCLUSIONS: This study describes the prognostic impact of the SN-procedure in colon carcinoma after 5-year-follow-up. Only one patient had recurrent disease after a negative SN procedure (disease-free-survival 96%). These results indicate that the SN-procedure is of prognostic relevance and might be useful to select patients for adjuvant chemotherapy. Patients that are lymph node negative after an SN-procedure have an excellent prognosis and do not need adjuvant treatment.

[Mazabraud syndrome--benign intramuscular myxoma with fibrous skeletal dysplasia]. / Het syndroom van Mazabraud. Benigne intramusculaire myxomen met fibreuze skeletdysplasie.

A 51-year-old woman presented with a soft-tissue swelling of the thigh. A MRI scan of the thigh showed an intramuscular lesion and bone-marrow abnormalities in the femur. A bone scintigraphy and PET/CT-scan showed multiple hotspots in the skeleton. The soft-tissue swelling was excised. Although we initially suspected a malignancy of the thigh with diffuse skeletal metastases, this proved to be a benign myxoma which, together with the skeletal abnormalities, corresponded with a diagnosis of Mazabraud syndrome. This is a rare benign disorder in which intramuscular myxomas are associated with fibrous dysplasia of the skeleton. In the case of asymptomatic fibrous dysplasia a conservative approach is sufficient. In the case of fibrous dysplasia associated with pain, or imminent fracture, a prophylactic surgical intervention is indicated. To avoid anxiety, unnecessary diagnostic procedures and surgery Mazabraud syndrome should be always be considered in the case of an intramuscular tumour associated with concurrent skeletal abnormalities.

Disorder in the serotonergic system due to tryptophan hydroxylation impairment: a cause of hypothalamic syndrome?

BACKGROUND: The hypothalamus regulates basic homeostasis such as appetite, circadian rhythm, autonomic and pituitary functions. Dysregulation in these functions results in the hypothalamic syndrome, a rare disorder of various origins. Since serotonin (5-HT) modulates most of the above-mentioned homeostasis, a defect in the serotonergic system can possibly participate in this syndrome. METHODS: We describe a girl suffering from hypothalamic syndrome with a decreased concentration of 5-hydroxytryptophan (5-HTP) and a normal level of tryptophan in the cerebrospinal fluid (CSF) suggesting a functional defect in tryptophan hydroxylase (TPH). TPH is a rate-limiting enzyme in the synthesis of the neurotransmitter 5-HT. RESULTS: Therapeutic intervention with 5-HTP, carbidopa and a specific serotonin reuptake inhibitor significantly improved her clinical symptoms and caused biochemical normalisation of neurotransmitters. CONCLUSION: The girl described had the typical symptoms of a hypothalamic disorder and a defective serotonergic metabolism, a relationship which has not been reported before. Therapeutic interventions to restore 5-HT metabolism resulted in clinical improvement. We suggest that investigation of 5-HT metabolism in CSF of patients with this rare disorder is included in the aetiological work-up.

[Interval appendectomy as indicated rather than as routine therapy: fewer operations and shorter hospital stays]. / Appendectomie à froid op indicatie in plaats van als routine-ingreep: minder operaties en minder opnamedagen.

OBJECTIVE: To determine whether performing interval appendectomy only as indicated reduces the number of interval appendectomies, morbidity and duration of hospital stay compared with the conventional approach of routine interval appendectomy. DESIGN: Prospective and comparison with a historical control group. METHODS: In the period May 2000-December 2002 46 patients were prospectively followed after conservative treatment for an appendiceal mass or abscess. Interval appendectomy was performed only as indicated. Study endpoints were the number of patients who were symptom-free at the last outpatient visit and the number ofinterval appendectomies or emergency appendectomies performed for symptoms or acute appendicitis, respectively. Morbidity and duration of hospital stay were compared with a consecutive historical group of patients who had undergone routine interval appendectomy in the period 1994-April 2000. RESULTS: Appendectomy was avoided in 29 of the 46 patients. The median total admission time was 9 days versus 12 days for patients who had undergone routine interval appendectomy. Three patients in each group had complications. CONCLUSION: By performing interval appendectomy only as indicated for persistent pain in the lower right abdomen or emergency appendectomy for acute appendicitis, the number of appendectomies was reduced by 63% and the duration of hospital stay was reduced by 4 days.

Sentinel node detection after preoperative short-course radiotherapy in rectal carcinoma is not reliable.

BACKGROUND: Sentinel node (SN) detection may be used in patients with colonic carcinoma. However, its use in patients with rectal carcinoma may be unreliable. To address this, SN detection was evaluated in patients with rectal carcinoma after short-course preoperative radiotherapy. METHODS: Patent Blue V (1-2 ml) was injected peritumorally and submucosally directly after total mesorectal excision (TME) in 34 patients. The first one to four blue lymph nodes were categorized as SNs. All lymph nodes (non-SNs and SNs) were examined by conventional haematoxylin and eosin stained sections. If the SN was negative for metastasis, additional sections were immunostained with anticytokeratin CK7/8. In addition, SN detection was performed in 57 patients with colonic carcinoma. RESULTS: A SN was identified in 26 of 34 patients with rectal carcinoma. In three the SN was the only positive lymph node. There were six false-negative SNs (sensitivity 40 per cent) and two patients were upstaged. By contrast, SN detection was possible in 56 of 57 patient with colonic carcinoma with a sensitivity of 90 per cent, and four patients were upstaged. CONCLUSION: The SN procedure for rectal carcinoma is not reliable in combination with TME and preoperative short-course radiotherapy.

Lymphatic staging in colorectal cancer: pathologic, molecular, and sentinel node techniques.

PURPOSE: Accurate staging in colorectal cancer is important to predict prognosis and identify patients who could benefit from adjuvant therapy. Patients with lymphatic metastasis, Stage III/Dukes C, are generally treated with adjuvant chemotherapy. Still, patients without lymphatic metastasis do have relapse as high as 27 percent in five years in Dukes B2. It is hypothesized that these patients have occult (micro)metastasis in their lymph nodes. If these (micro)metastasis can be identified, these patients might benefit from adjuvant therapy. We reviewed the literature on procedures to improve lymph node staging. METHODS: An extensive literature search was performed in PubMed (www.pubmed.com). Using the reference lists, more articles were found. RESULTS: We found 30 articles about sentinel node in colorectal cancer describing original series. Some groups reported several studies including the same patients. We reported their largest studies. For all other techniques, we only included key articles. CONCLUSIONS: Many techniques to improve staging have been described. The finding of occult (micro)metastasis is of prognostic significance in most studies. The sentinel node technique has been recently described for use in colorectal cancer. Although it seems clear that this technique has prognostic potential, it is not yet been shown in a follow-up study. Furthermore, the finding of occult (micro)metastasis in any technique used has not been shown to be clinically significant. Whether to treat patients with adjuvant therapy if occult (micro)metastasis are found needs to be proven in future studies.

Successful sentinel node identification in colon carcinoma using Patent Blue V.

AIM: The aim of this study was to evaluate the use of Patent Blue V for identification of the sentinel node in patients with colon carcinoma. METHOD: From May 2002, 35 patients operated for colon carcinoma underwent lymphatic mapping using Patent Blue V as marker. Either directly after resection of the colon or during operation 2 ml of Patent Blue V was injected peritumourally, and the first 1 to 4 blue nodes were marked as sentinel nodes. Pathological evaluation was done on a single HE-stained section of all lymph nodes. Only if all sentinel nodes were negative for metastases, serial sectioning and additional immunohistochemical staining against keratine CK 7/8 was performed to reveal micrometastasis in the sentinel nodes. RESULTS: In 33/35 of patients at least one sentinel node was identified. In 10/33 the sentinel node was positive for metastases, and in 5/10 this was the only node containing metastases. One patient had a false negative sentinel node (accuracy 97%, sensitivity 91%). CONCLUSION: Using Patent Blue V, it is possible to identify the sentinel node in most patients with colon cancer. The results are comparable with other sentinel node studies using Lymphazurin.

Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial.

AIMS: Gastric cancer in Western countries is often diagnosed in an advanced stage and prognosis is poor. We performed a randomised trial with pre-operative FAMTX vs. surgery alone in order to evaluate the effect of pre-operative chemotherapy on resectability and survival. METHODS: Patients with proven adenocarcinoma of the stomach were randomised to receive four courses of chemotherapy using 5-Fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery alone. RESULTS: Fifty-nine patients were randomised; 29 patients were allocated to the FAMTX regimen prior to surgery and 30 patients had surgery alone. Resectability rates were equal for both groups. Complete or partial response was registered in 32% of the FAMTX group. With a median follow-up of 83 months the median survival since randomisation is 18 months in the FAMTX group vs. 30 months in the surgery alone group (p=0.17). CONCLUSIONS: This trial could not show a beneficial effect of pre-operative FAMTX. Until large randomised studies prove otherwise, adequate surgery without delay is the best treatment for operable gastric cancer.

[Diagnostic image (158). A woman with a painful cord below and a dimple in the breast. Mondor's disease]. / Diagnose in beeld (158). Een vrouw met een pijnlijke streng onder en een intrekking van de borst. Ziekte van Mondor.

A 35-year-old woman had a palpable painful cord under the left breast with dimpling in the breast, due to Mondor's disease.

Application of nonperiodic phase structures in optical systems.

Wide, nonperiodic stepped phase structures are studied to correct various parameter-dependent wave-front aberrations in optical systems. The wide nature of these phase structures makes them easy to manufacture with sufficient compensation of the wave-front aberrations. Wave-front aberration correction for both continuous and discrete parameter variations are studied. An analytical method is derived for the discrete parameter variations to find the optimal phase structure. Both theoretical and experimental results show that these nonperiodic phase structures can be used to make (1) lenses athermal (defocus and spherical aberration compensated), (2) lenses achromatic, (3) lenses with a large field of view, (4) lenses with a reduced field curvature, and (5) digital versatile disk objective lenses for optical recording that are compatible with compact disk readout.

Long-chain fatty acid-induced changes in gene expression in neonatal cardiac myocytes.

Long-chain fatty acids are the most important substrates for the heart. In addition, they have been shown to affect signalling pathways and gene expression. To explore the effects of long-chain fatty acids on cardiac gene expression, neonatal rat ventricular myocytes were cultured for 48 h with either glucose (10 mm), fatty acids (palmitic and oleic acid, 0.25 mm each), or a combination of both as exogenous substrates. Exposure to fatty acids (both in the absence or presence of glucose) neither affected cellular morphology and protein content nor induced alterations in the expression of phenotypic marker genes like atrial natriuretic factor and the Ca-ATPase SERCA2. However, incubation with fatty acids (with or without glucose) resulted in up to 4-fold increases of the mRNA levels of fatty acid translocase (FAT/CD36), heart-type fatty acid-binding protein, acyl-CoA synthetase, and long-chain acyl-CoA dehydrogenase. In contrast, the expression of genes coding for proteins involved in glucose uptake and metabolism, i.e., glucose transporter GLUT4, hexokinase II, and glyceraldehyde 3-phosphate dehydrogenase, remained constant or even declined under these conditions. These changes corresponded with a 60% increase in cardiomyocyte fatty acid oxidation capacity. Interestingly, the peroxisome proliferator-activated receptor-alpha (PPARalpha)-ligand Wy 14,643, but not the PPARgamma-ligand ciglitazone, also resulted in increased mRNA levels of genes involved in fatty acid metabolism. In conclusion, fatty acids specifically and co-ordinately up-regulate transcription of genes coding for proteins involved in cardiac fatty acid transport and metabolism, most likely through activation of PPARalpha.

Molecular and functional characterization of mouse signaling lymphocytic activation molecule (SLAM): differential expression and responsiveness in Th1 and Th2 cells.

Optimal T cell activation and expansion require engagement of the TCR plus costimulatory signals delivered through accessory molecules. SLAM (signaling lymphocytic activation molecule), a 70-kDa costimulatory molecule belonging to the Ig superfamily, was defined as a human cell surface molecule that mediated CD28-independent proliferation of human T cells and IFN-gamma production by human Th1 and Th2 clones. In this study, we describe the cloning of mouse SLAM and the production of mAb against it which reveal its expression on primary mouse T and B cells. Mouse SLAM is expressed on highly polarized Th1 and Th2 populations, and is maintained on Th1, but not on Th2 clones. Anti-mouse SLAM mAb augmented IFN-gamma production by Th1 cells and Th1 clones stimulated through the TCR, but did not induce IFN-gamma production by Th2 cells, nor their production of IL-4 or their proliferation. Mouse SLAM is a 75-kDa glycoprotein that upon tyrosine phosphorylation associates with the src homology 2-domain-containing protein tyrosine phosphatase SHP-2, but not SHP-1. Mouse SLAM also associates with the recently described human SLAM-associated protein. These studies may provide new insights into the regulation of Th1 responses.

Chemotherapy for operable gastric cancer: results of the Dutch randomised FAMTX trial. The Dutch Gastric Cancer Group (DGCG).

The aim of this trial was to investigate whether pre-operative chemotherapy leads to a 15% higher curative resectability rate in patients with operable gastric cancer. In this randomised trial, patients were allocated to receive either four courses of chemotherapy using 5-fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery only. Patients younger than 75 years of age with a good physical and mental condition and a histologically proven adenocarcinoma of the stomach without clinical or radiographic (computed tomography scan) evidence of distant metastases were eligible for this trial. Early gastric cancer or cardia carcinoma were excluded. The response to chemotherapy was evaluated after two and four courses. In case of progressive disease (PD) after two courses, patients were operated upon as soon as possible. Otherwise complete response (CR) partial response (PR) or stable disease (SD), two more courses were scheduled. The standard surgical procedure was a limited lymphadenectomy (D1) with staging biopsy of the para-aortic lymph nodes. Between September 1993 and February 1996, 56 eligible and evaluable patients were entered: 27 were randomised to receive FAMTX before surgery and 29 to undergo surgery only. In the FAMTX + surgery treatment group, 15/27 (56%) had curative resections versus 18/29 (62%) in the surgery only arm. There was no difference in the frequency of TNM stages I + II in both treatment arms: 15/27 versus 15/29. Due to PD and/or toxicity, 12 patients (44%) could not complete the planned four courses of FAMTX. Response evaluation after chemotherapy was possible in 25 patients: 2 CR, 6 PR, 8 SD and 9 PD. The difference in curative resectability rate was 6.5% (95% confidence interval -32 to +19%) in favour of surgery only. Downstaging for stages I + II did not occur. PD was more often the reason for not completing the planned four courses than toxicity. More active regimens than FAMTX are required for future randomised trials.

Altered signaling lymphocytic activation molecule (SLAM) expression in HIV infection and redirection of HIV-specific responses via SLAM triggering.

Signaling lymphocytic activation molecule (SLAM) is a transmembrane lymphocytic receptor which gets rapidly upregulated following cell activation. SLAM engagement augments T cell expansion and interferon-gamma (IFN-gamma) production independently of CD28. SLAM signaling is regulated by the SLAM-associated protein. We evaluated the expression and function of SLAM on CD4(+) and CD8(+) lymphocytes in HIV-infected individuals with either recently acquired infection (Group A) or asymptomatic HIV infection (Group B) and in healthy controls (HC). Soluble antigen (HIV env peptides and tetanus toxoid)- and mitogen-stimulated proliferation and IFN-gamma and IL-10 production upon SLAM costimulation were also measured. Results showed that: (1) SLAM-expressing CD4(+) and CD8(+) lymphocytes diminish in group A patients compared to both group B patients and HC; (2) SLAM expression on CD4(+) lymphocytes is preferentially associated with the lack of CD7 on cell surface (CD4(+)CD7(-) produce IL-10 but not IFN-gamma); (3) SLAM engagement increases HIV env peptide-stimulated, but neither tetanus toxoid- nor PHA-stimulated proliferation of peripheral blood mononuclear cells (PBMC) in patients but not in HC; and (4) SLAM engagement augments IFN-gamma and reduces IL-10 production by env peptide-stimulated PBMC of HIV-infected individuals. These results demonstrate that early HIV infection results in an altered SLAM expression which correlates with a time-limited impairment of cell-mediated immunity. Furthermore, they show that triggering via SLAM potentiates HIV-specific proliferative responses with simultaneous downregulation of IL-10 and redirection of the response to TH0/TH1.

Receptors and cytokines involved in allergic TH2 cell responses.

Cytokines produced by allergen-specific TH2 cells play a central role in the induction and maintenance of allergic responses. Therefore antagonizing TH2 differentiation and TH2 effector functions will provide an effective way to intervene in allergic diseases. This article discusses that antagonizing the effects of IL-4 and IL-13 by IL-4Ralpha antagonists inhibits human TH2 development and IgE synthesis. In addition, it is shown that the activation of allergen-specific TH2 cells with an agonistic anti-CDw150 mAb redirects the cytokine production profile of these TH2 cells to a TH0 phenotype.

Liver rupture postpartum associated with preeclampsia and HELLP syndrome.

Liver rupture is a rare perinatal complication with high maternal mortality. In a multiparous woman with preeclampsia and Hemolysis, Elevated Liver enzymes, and Low Platelet count (HELLP) syndrome, liver rupture was suspected 10 h after a cesarean section. Laparotomy revealed liver rupture which was treated by perihepatic packing. Eventually, the mother was discharged with her baby 88 days after admission. Clinical symptoms, maternal hemodynamics by Swan-Ganz monitoring, and laboratory findings were not predictive until the emergency situation and the consecutive complications required multidisciplinary management.