Safety, efficacy, and long-term follow-up evaluation of perioperative epirubicin, Cisplatin, and capecitabine chemotherapy in esophageal resection for adenocarcinoma.

BACKGROUND: Perioperative epirubicin, cisplatin, and capecitabine (ECC) chemotherapy was evaluated in patients who underwent esophageal resection for adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). METHODS: A cohort of 93 consecutive patients was analyzed. The median follow-up period was 60 months. Source data verification of adverse events was performed by two independent observers. RESULTS: All three planned preoperative chemotherapy cycles were administered to 65 patients (69.9 %). Only 27 % of the patients completed both pre- and postoperative chemotherapy. The reasons for not receiving postoperative adjuvant chemotherapy could be separated in two main problems: toxicity of the preoperative chemotherapy and postoperative problems involving difficulty in recovery and postoperative complications. Finally, 25 patients (27 %), completed three preoperative and three postoperative cycles. Grades 3 and 4 nonhematologic adverse events of preoperative chemotherapy mainly consisted of thromboembolic events (16.2 %) and cardiac complications (7.5 %). A history of cardiac and vascular disease was independently associated with discontinuation of preoperative chemotherapy and the occurrence of grade 3 or higher adverse events. Surgery was performed for 94 % of all the patients who started with ECC chemotherapy. A radical resection (R0) was achieved in 93 % of the patients. A complete pathologic response was observed in 8 % of the patients. During a median follow-up period of 60 months, the median disease-free survival time was 28 months, and the median overall survival time was 36 months. The 3-year overall survival rate was 50 %, and the 5-year overall survival rate was 42 %. CONCLUSION: For patients with adenocarcinoma of the esophagus or GEJ, six cycles of ECC-based perioperative chemotherapy is associated with a relatively high number of adverse events. Although this toxicity did not affect the esophageal resectability rate, this regimen should be used with caution in this patient population.

Leflunomide as part of the treatment for multidrug-resistant cytomegalovirus disease after lung transplantation: case report and review of the literature.

Treatment of cytomegalovirus (CMV) disease in transplant patients is challenging and, with antiviral resistance to first-line drugs, it remains uncertain which treatment algorithm to follow. Some data suggest that leflunomide, a pyrimidine synthesis inhibitor, can be used to treat resistant CMV infections. We report a 57-year-old CMV immunoglobulin-G (IgG)-seronegative woman, who received a bilateral lung transplant (LuTx) from a CMV IgG-positive donor with CMV primary disease. The CMV strain was genotypically resistant to ganciclovir, foscarnet, and cidofovir. After starting leflunomide as add-on therapy to a multidrug anti-CMV regimen, viral load declined substantially in 2 months without adverse events. This experience is discussed against the background of existing literature on the use of leflunomide as an anti-CMV agent in LuTx recipients.

Histopathology in the isolated chicken eye test and comparison of different stainings of the cornea.

The isolated chicken eye (ICE) test, developed at our Institute, is accepted by the OECD for identification of severe eye irritants. The OECD ICE Guideline (No. 438) encourages preservation of the treated eyes for possible histopathology of the cornea, which is believed to strengthen evidence of absence or presence of irritation and to help clarify borderline effects by assessment of the corneal Depth-of-Injury. Histopathology of the cornea in addition to the normal slit-lamp microscope assessment of corneal effects has already been performed routinely in ICE tests at our Institute, using two standard stainings (H&E and PAS). In this study, three other stainings (AZAN, EVG and Trichrome), more specific for collagen-rich membranes such as basement- and Bowman's membranes were examined with corneas exposed to four model compounds ranging from non- to severely irritating (corrosive). PAS appeared to be the superior staining method. Surprisingly, the well-known eye corrosive sodium hydroxide (NaOH, solid) did not visibly compromise the integrity of Bowman's or the basement membrane. Based on our experience, histopathology of the treated cornea is confirmative in relation to the standard assessment of eye irritation by slit-lamp observation in the ICE and in certain cases can help to evaluate borderline effects. Besides establishing the depth of injury, additional investigation of corneal limbal stem cell damage after chemical exposure might be appropriate to determine reversibility or irreversibility of eye effects.

Robot-assisted thoracoscopic oesophagectomy for cancer.

BACKGROUND: Thoracoscopic oesophagectomy was introduced to reduce the morbidity of transthoracic oesophagectomy. The aim was to assess the short- and mid-term results of robot-assisted thoracoscopic oesophagectomy for oesophageal cancer. METHODS: Between October 2003 and May 2007, 47 patients with resectable oesophageal cancer underwent robot-assisted thoracoscopic oesophagectomy. Clinical data were collected prospectively. RESULTS: Conversion to thoracotomy was necessary in seven patients. Median operating time was 450 min and median blood loss 625 ml. Median postoperative ventilation time was 1 day, intensive care stay 3 days and hospital stay 18 days. Twenty-one of 47 patients had pulmonary complications. Three patients died in hospital. A median of 29 (range 8-68) lymph nodes was dissected and R0 resection was achieved in 36 patients. Twenty-three patients had stage IVa disease. After a median follow-up of 35 months, median disease-free survival was 15 (95 per cent confidence interval 12 to 18) months. CONCLUSION: Robot-assisted thoracoscopic oesophagectomy was oncologically acceptable. Operating time, blood loss and pulmonary complications might decrease with further experience.

High prevalence of esophageal involvement in lichen planus: a study using magnification chromoendoscopy.

BACKGROUND AND STUDY AIMS: The first cases of squamous cell carcinoma in esophageal lichen planus were recently described. We performed a study to establish the prevalence of endoscopic and histopathologic abnormalities consistent with lichen planus and (pre-) malignancy in a cohort of patients with lichen planus. PATIENTS AND METHODS: A total of 24 patients with lichen planus were prospectively studied using high-magnification chromoendoscopy. Focal esophageal abnormalities were mapped, classified, and biopsied. Biopsies were also taken from normal-appearing esophageal mucosa at three levels (proximal, middle, and distal). The presence of a lymphohistiocytic interface inflammatory infiltrate and Civatte bodies (i. e. apoptotic basal keratinocytes) at histopathologic examination was considered diagnostic for esophageal lichen planus. Symptoms were assessed using validated questionnaires. RESULTS: A total of 38 focal abnormalities were biopsied. These consisted of: layers of mucosa peeling off, hyperemic lesions, papular lesions, submucosal plaques/papules, a flat polypoid lesion, and segments of cylindrical epithelium. No endoscopic signs of dysplasia were present. Esophagitis consistent with gastroesophageal reflux disease was noted in 12 / 24 patients. Histopathology showed chronic inflammation of the esophageal mucosa in the majority (18 / 24) of patients. In 50 % (12 / 24), the diagnosis of esophageal lichen planus was made. Dysplasia was not present. There were no differences in symptoms between patients with and without esophageal lichen planus. CONCLUSIONS: At screening endoscopy a high prevalence (50 %) of esophageal lichen planus was found in patients with orocutaneous lichen planus. No dysplasia was found.

T cells in cardiac allograft vasculopathy are skewed to memory Th-1 cells in the presence of a distinct Th-2 population.

Cardiac allograft vasculopathy (CAV) in heart transplantation (HTx) patients remains the major complication for long-term survival, due to concentric neointima hyperplasia induced by infiltrating mononuclear cells (MNC). Previously, we showed that activated memory T-helper-1 (Th-1) cells are the major component of infiltrating MNC in coronary arteries with CAV. In this study, a more detailed characterization of the MNC in human coronary arteries with CAV (n = 5) was performed and compared to coronary arteries without CAV (n = 5), by investigating MNC markers (CD1a, DRC-1, CD3, CD20, CD27, CD28, CD56, CD68, CD69, FOXP3 and HLA-DR), cytokines (IL-1A, 2, 4, 10, 12B, IFN-gamma, and TGF-beta1), and chemokine receptors (CCR3, CCR4, CCR5, CCR7, CCR8, CXCR3 and CX3CR1) by immunohistochemical double-labeling and quantitative PCR on mRNA isolated from laser microdissected layers of coronary arteries. T cells in the neointima and adventitia of CAV were skewed toward an activated memory Th-1 phenotype, but in the presence of a distinct Th-2 population. FOXP3 positive T cells were not detected and production of most cytokines was low or absent, except for IFN-gamma, and TGF-beta. This typical composition of T-helper cells and especially production of IFN-gamma and TGF-beta may play an important role in the proliferative CAV reaction.

The effect of azygos vein preservation on mediastinal lymph node harvesting in thoracic esophagolymphadenectomy.

The standard surgical procedure for esophageal cancer is transthoracic esophagectomy with en bloc resection of the azygos vein, thoracic duct and mediastinal lymph nodes. To reduce morbidity of esophago-lymphadenectomy, minimally invasive techniques are increasingly being applied. In (robot-assisted) thoracoscopic esophagolymphadenectomy, the azygos vein is generally left in place, as the scopic ligation of the numerous intercostal veins is technically difficult and time-consuming. This could affect the extent of mediastinal lymph node dissection. Therefore, in this study, the effect of azygos vein preservation during thoracic esophagectomy on mediastinal lymph node harvesting was assessed. In 15 human cadavers, a right-sided thoracotomy was performed, followed by esophagectomy with mediastinal lymph node dissection after ligation of the azygos arch (representing the situation in robot-assisted thoracoscopic esophagolymphadenectomy). Subsequently, the remaining azygos vein with surrounding tissue was resected. The number of lymph nodes in both specimens was determined. A mean of 17.3 (95% Poisson CI 15.3-19.6) lymph nodes was dissected en bloc with the esophagus, and 0.67 (95% Poisson CI 0.32-1.23) around the separately resected azygos vein. The additional azygos vein resection did not add to the number of lymph nodes dissected in 60% (9/15) of cadavers. In conclusion, the extent of mediastinal lymph node dissection was not substantially affected by leaving the azygos vein in situ . Time-sparing azygos vein preservation in (robot-assisted) thoracoscopic esophagolymphadenectomy may therefore be considered justified.

High frequency of early colorectal cancer in inflammatory bowel disease.

BACKGROUND AND AIMS: To detect precancerous dysplasia or asymptomatic cancer, patients suffering from inflammatory bowel disease often undergo colonoscopic surveillance based on American or British guidelines. It is recommended that surveillance is initiated after 8-10 years of extensive colitis, or after 15-20 years for left-sided disease. These starting points, however, are not based on solid scientific evidence. Our aim was to assess the time interval between onset of inflammatory bowel disease (IBD) and colorectal carcinoma (CRC), and subsequently evaluate how many patients developed cancer before their surveillance was recommended to commence. METHODS: A nationwide automated pathology database (PALGA) was consulted to identify patients with IBD-associated colorectal carcinoma in seven university medical centres in The Netherlands between January 1990 and June 2006. Data were collected retrospectively from patient charts. Time intervals between onset of disease and cancer diagnosis were calculated in months. RESULTS: 149 patients were identified with confirmed diagnoses of IBD and CRC (ulcerative colitis n = 89/Crohn's disease n = 59/indeterminate colitis n = 1). Taking date of diagnosis as the entry point, 22% of patients developed cancer before the 8 or 15 year starting points of surveillance, and 28% if surveillance was commenced 10 or 20 years after diagnosis for extensive or left-sided disease, respectively. Using onset of symptoms to calculate the time interval, 17-22% of patients would present with cancer prior to the surveillance starting points. CONCLUSIONS: These results show that the diagnosis of colorectal cancer is delayed or missed in a substantial number of patients (17-28%) when conducting surveillance strictly according to formal guidelines.

Robot-assisted thoracoscopic esophagectomy for a giant upper esophageal leiomyoma.

This is the first report of a thoracoscopic esophagectomy for a giant leiomyoma of the upper esophagus aided by a robotic system. A 37-year-old man presented with progressive dysphagia and nocturnal aspiration. Endoscopic ultrasound and CT scan of the chest revealed an upper esophageal tumor of 9 x 4 cm arising from the muscularis mucosae. A fine needle aspiration showed clustering of mesenchymal cells, confirming the diagnosis of a stromal cell tumor. A mesenchymal malignancy was suspected because the tumor was located in the upper esophagus and was arising from the muscularis mucosae, both uncommon for a leiomyoma. Moreover, tumor size, an indicator of potential malignancy if >3 cm, was 9 cm. Therefore, an esophagectomy was performed thoracoscopically with the formation of a gastric conduit via laparotomy and a hand-sewn end-to-side cervical anastomosis. The thoracoscopic phase was performed with support of the da Vincitrade mark robotic system, which allowed for an excellent 3-dimensional view and a precise dissection of the esophagus along the vital mediastinal structures. The duration of the thoracoscopic part was 115 min and that of the total procedure was 270 min. Blood loss during the thoracoscopic phase was 50 mL; total blood loss was 200 mL. The patient was ventilated for 1 day; his total intensive care stay was 2 days. He left the hospital in good condition on the 11th postoperative day. Histopathological examination combined with immunohistochemistry revealed a leiomyoma of 9.0 x 5.0 x 2.5 cm. After 3 years of follow-up, the patient is in good health.

Hormone replacement therapy, mammography screening and changing age-specific incidence rates of breast cancer: an ecological study comparing two European populations.

BACKGROUND: In 2003, for the first time, US breast cancer incidence rates have fallen. Experts argue whether this is due to the reduced uptake of screening mammography or to lower use of Hormone Replacement Therapy (HRT). This study aims to disentangle the respective impact of screening and HRT on age-incidence rates and histology of breast cancer, by comparing two populations with comparably high levels of screening mammography, but with different prevalence of HRT. METHODS: We included all invasive breast cancers recorded at the Geneva cancer registry (n = 4,909) and the Netherlands Cancer Registry (n = 152,428) between 1989-2003. We compared age-specific incidence rates and trends in histological subtyping between the two populations. RESULTS: Between 1989-1991, incidence rates increased with age in both populations. In 2001-2003, women aged 60-64 years showed highest incidence rates in Geneva, while in the Netherlands incidence rates continued to increase with age. The annual increase in ductal cancer incidence was similar in the Netherlands (2.3%) and Geneva (2.5%), but the annual increase in lobular cancer was sharper in Geneva (10%) than in the Netherlands (5%). CONCLUSION: The sharp differences in age distribution and histological subtyping of breast cancer between two European populations are not attributable to screening, since both populations have a high uptake of mammography screening. Since the prevalence of HRT use is very high in Geneva and rather low in the Netherlands, HRT may explain these discrepancies. However, other etiological factors and differences in histological assessment may also have played a role.

Vascular occlusion as a late complication of the Angio-Seal closure device. A review of literature.

Although early vascular complications of the Angio-Seal closure device have been well described, little is known about late vascular complications due to this device. The aim of this paper is to discuss late femoral stenosis associated with the use of the Angio-Seal closure device. A literature search was performed using Medline', Embase' and The Cochrane Library' to identify relevant articles published up to the first of May 2007. Late occlusion was defined as an occlusion after approximately one week after Angio-Seal deployment. All together, eleven relevant papers were available. The reported prevalence of late vascular stenosis associated with Angio-Seal use varies between 1/961 and 4/175. Claudication was the most frequently reported complaint. In most cases, late stenosis due to the use of the Angio-Seal required surgery. Vascular obstruction due to the device has been reported up to 6 months after placement. In conclusion, vascular stenosis due to the use an Angio-Seal closure device is a complication that not only occurs in the first few days after placement, but also in the following months. In every patient developing complaints of arterial insufficiency after using an Angio-Seal, local arterial stenosis due to the device should be considered in the differential diagnosis. It therefore is important to register the use of the device in the patient chart.

Regional differences in expression of TPH-1, SERT, 5-HT(3) and 5-HT(4) receptors in the human stomach and duodenum.

The aim of this study was to increase the understanding of the role of serotonergic signalling in normal gastroduodenal function at a molecular level. Mucosal biopsy specimens were collected from the fundus, antrum and duodenum of 11 healthy subjects. Serotonin (5-HT)-positive cells were counted and the mRNA levels of tryptophan hydroxylase (TPH), serotonin transporter (SERT), 5-HT(4) receptor and 5-HT(3) receptor subunits were quantified by real-time reverse transcription polymerase chain reaction. The number of 5-HT-positive cells was larger in the duodenum compared with the stomach (P < 0.001). Serotonin transport protein expression was 19-fold higher in the duodenum compared with the antrum and 457-fold higher compared with the fundus (P < 0.001). Tryptophan hydroxylase-1 expression was lower in the duodenum compared with the antrum and fundus (regional differences -2.3 and -3.6, respectively). The 5-HT(4) receptor and the 5-HT(3C) and 5-HT(3E) receptor subunits were more abundantly expressed in duodenum compared with the stomach (P < 0.001). The larger number of 5-HT-positive cells, the higher expression of 5-HT(3) and 5-HT(4) receptors, and in particularly the higher uptake capacity of 5-HT in the duodenum, point out to a more prominent role of serotonergic signalling at the mucosal level in the duodenum compared with the stomach.

Targeting difficult accessible breast lesions: MRI-guided needle localization using a freehand technique in a 3.0 T closed bore magnet.

PURPOSE: To report the accuracy of magnetic resonance imaging (MRI)-guided needle localization for diagnosis of MRI detected suspicious breast lesions located in difficult accessible regions of the breast, using the freehand method in a 3.0 T closed bore magnet. MATERIALS AND METHODS: In five patients with five MRI-only breast lesions underwent MRI-guided needle localization for histopathologic evaluation of the lesions. All interventional procedures were performed in a 3.0 T MRI system with the patient in prone position and by using a dedicated phased array breast coil. MRI-guided needle localizations were performed by using a freehand technique. In our study, the high-resolution scan allowed preprocedural localization of all lesions without use of contrast enhancement. In all cases contrast-enhanced MRI was performed after insertion of the wire to confirm the tip of the wire in direct contact with the enhancing lesion. RESULTS: Needle localizations were performed in five patients. Histopathologic evaluation of tissue after surgery excision biopsy revealed one lymph node, three invasive ductal carcinoma and one ductal carcinoma in situ. Lesion size varied from 6 to 30 mm. Mean duration time was 25 min. No complications occurred during the intervention method. In the patient with the benign lesion control MRI of the breast after 6 months confirmed lesion removal. CONCLUSIONS: MRI-guided needle localization by using a freehand technique in a 3.0 T closed bore magnet is a safe and accurate method for diagnosis of difficult accessible breast lesions only visible on MRI.

[British and American screening guidelines inadequate for prevention of colorectal carcinoma in patients with inflammatory bowel disease]. / Preventie van colorectaal carcinoom bij inflammatoir darmlijden onvoldoende met de Britse en Amerikaanse opsporingsrichtlijnen.

OBJECTIVE: To determine how many cases of inflammatory bowel disease (IBD)-related colorectal cancer (CRC) occur before recommended colonoscopy screening commences. DESIGN: Descriptive. METHOD: A nationwide automated histological and cytopathological archive (PALGA) was used to identify patients with IBD and CRC in the period January 1990-June 2006 at the University Medical Center Utrecht, The Netherlands. The interval between the diagnosis of IBD or IBD-related symptoms and the diagnosis of CRC was calculated. The observed interval was compared with the recommended starting point for surveillance according to the British Society of Gastroenterology (BSG) and the American Gastroenterological Association (AGA), i.e. after 8-10 years for pancolitis or after 15-20 years for left-sided colitis. RESULTS: 33 colorectal cancers were found in 29 patients with IBD. The median age at the time of diagnosis was 29 years (range: 11-82) for IBD and 47 years (range: 23-82) for CRC. 7 of the 29 patients (24%) developed CRC before the minimum recommended time to initiate screening (8 years for pancolitis, 15 years for left-sided colitis), and 9 patients (31%) developed CRC within the maximum recommended time to initiate screening (10 years for pancolitis, 20 years for left-sided colitis). If the onset of IBD-related symptoms was considered the starting point of the disease (rather than the diagnosis of IBD), 17-24% of patients developed a CRC before surveillance would have commenced. CONCLUSION: These results suggest that, by following the British and American guidelines for screening for IBD-related CRC, a substantial portion of cases (17-31%) would not be diagnosed in a timely manner.

The ileo neo rectal anastomosis (INRA) in patients with familial adenomatous polyposis: clinical results at two years.

BACKGROUND: Ileo neo rectal anastomosis (INRA) is a promising alternative for patients with familial adenomatous polyposis (FAP) to restorative proctocolectomy with its morbidity and unpredictable functional outcome to colectomy with ileo rectal anastomosis (IRA) with the continuing risk of rectal cancer. The aims of the present study were to evaluate the function of the neorectum, to assess the morbidity and complications of the operation and to determine the incidence of neorectal polyps. METHODS: Data of all patients having INRA, including bowel function and complications, were prospectively recorded. The reservoir capacity was determined repeatedly by physiologic tests. The anal sphincter complex was assessed by manometry and ultrasound examination. Evaluation of the neorectal mucosa was performed by endoscopy. RESULTS: Six patients underwent the INRA procedure for FAP. Median defaecation frequency two years postoperatively was 5.5/24 h (range 4-7) including 1/night (range 0-2). Endoscopic examination showed normal mucosa and no evidence of polyp formation in all patients. CONCLUSION: INRA affords a good functional reservoir and is accompanied by few reservoir-related complications. At a minimum follow up period of two years, no growth of polyps in the neorectum occurred.

Ileo-neorectal anastomosis: medium- and long-term follow-up of 37 patients.

BACKGROUND: Ileo-neorectal anastomosis (INRA), an alternative restorative procedure, was developed to reduce the pouch-related complication rate with an (at least) equal functional result. METHODS: For this surgical outcome, data of all INRA patients, including bowel function and complications, were prospectively recorded. The reservoir capacity was determined repeatedly by physiologic tests. The anal sphincter complex was assessed by manometry and ultrasound examination. Evaluation of the neorectal mucosa was performed by endoscopy. RESULTS: An INRA procedure was carried out in 39/53 selected patients (47 ulcerative colitis and 6 familial adenomatous polyposis). Fourteen UC cases were converted to ileal pouch anal anastomosis or proctectomy only, because of impossibility to completely remove the rectal mucosa or short of length of the rectal stump. The median operation time for INRA was 323 min (range 240-518), with 1,400 ml blood loss (400-4,500). The reservoirs were permanently defunctioned in 2 patients--one because of reclassification into Crohn's disease, and one with pouchitis refractory to medical treatment. In 18 out of 37 cases, web-like stenoses occurred at the mucosa-anal level, which were treated by single (9) or repeated (5) dilatation or surgical stenoplasty (2). No pouch-related complications like pelvic sepsis, fistula or sexual dysfunction occurred. Thirteen patients had episodes of 'pouchitis', successfully treated with antibiotics, and 7 other cases, with functioning reservoirs, also had proximal 'non-specific' (i.e. no histological criteria of Crohn's disease found) small bowel inflammation. The median bowel frequency decreased from 15x/24 h initially to 7x/24 h at 2 years. Continence was perfect in 24/37 cases. Twelve out of 37 cases had occasional nocturnal soiling and passive nocturnal fecal incontinence was reported by 2/37 patients. The neorectal compliance volume recovered from 12.5 ml kPa after subtotal colectomy and 11 ml/kPa at 6 months after INRA to a neorectal compliance of 24 ml/kPa at 2 years' follow-up (p < 0.002; Wilcoxon signed rank test). CONCLUSION: The INRA procedure shows a low complication rate and reasonable functional results, there was however a considerable conversion rate in these first 53 cases and a high incidence of reclassification to CD.