The Distress Thermometer for screening for severe fatigue in newly diagnosed breast and colorectal cancer patients.

OBJECTIVE: Internationally, the Distress Thermometer and associated Problem List are increasingly used in oncology as screening tools for psychological distress. Cancer-related fatigue is common but often overlooked in clinical practice. We examined if severe fatigue in cancer patients can be identified with the fatigue item of the Problem List. METHODS: Newly diagnosed breast (N = 334) and colorectal (N = 179) cancer patients were screened for severe fatigue, which was defined as having a positive score on the fatigue item of the Problem List. The Fatigue Severity subscale of the Checklist Individual Strength was used as gold standard measure for severe fatigue. RESULTS: In total, 78% of breast cancer patients and 81% of colorectal cancer patients were correctly identified with the fatigue item. The sensitivity was 89% in breast cancer patients and 91% in colorectal cancer patients. The specificity was 75% in breast cancer patients and 77% in colorectal cancer patients. The positive predictive value was 53% in breast cancer patients and 64% in colorectal cancer patients, whereas the negative predictive value was 95% in both tumor types. CONCLUSIONS: The fatigue item of the Problem List performs satisfactorily as a quick screening tool for severe fatigue. However, a positive screen should be followed up with a more thorough assessment of fatigue, ie, a questionnaire with a validated cutoff point. Given time pressure of clinicians, this already implemented and brief screening tool may prevent severe fatigue from going undetected in clinical practice.

Management of the axilla after neoadjuvant chemotherapy for clinically node positive breast cancer: A nationwide survey study in The Netherlands.

BACKGROUND: Axillary pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is achieved in a substantial part of clinically node positive breast cancer patients. Treatment of the axilla after NAC varies widely, and new techniques to spare patients from an axillary lymph node dissection (ALND) are being introduced. METHODS: This Dutch nationwide survey regarding treatment of the initially clinically node positive axilla in patients receiving NAC was conducted amongst 148 surgical oncologists during November 2014-June 2015, to survey the diagnostic work-up, axillary mapping and willingness to omit ALND. RESULTS: Axillary ultrasound was considered a standard procedure in the diagnostic work-up by 99% of participants. The majority of 70% of participants stated that ALND could possibly be omitted in node positive patients with a favourable response to NAC. A positive correlation was observed between the total amount of patients treated, versus patients receiving NAC (P < 0.01). A total of 93 respondents performed axillary response evaluation after NAC, using imaging (72%), excision of localized lymph nodes (56%) or sentinel node biopsy (SNB; 45%). Decision-making in omitting ALND was influenced by the presence of N2-3 disease, patient age and type of breast surgery. Multivariable analysis showed that clinicians who administered NAC more often, were more likely to omit ALND (P < 0.01). DISCUSSION: The majority of surgeons are inclined to omit ALND in case of an axillary pCR. A large variety of techniques is being used to identify a pCR. The lack of consensus on this topic indicates the need for guidelines based on the best available evidence.

Adenovirus-mediated interleukin 3 beta gene transfer by isolated limb perfusion inhibits growth of limb sarcoma in rats.

Cytokine gene transfer using (multiple) intratumoral injections can induce tumor regression in several animal models, but this administration technique limits the use for human gene therapy. In the present studies we describe tumor growth inhibition of established limb sarcomas after a single isolated limb perfusion (ILP) with recombinant adenoviral vectors harboring the rat IL-3 beta gene (IG.Ad.CMV.rIL-3 beta). In contrast, a single intratumoral injection or intravenous administration did not affect tumor growth. Dose-finding studies demonstrated a dose-dependent response with a loss of antitumor effect below 1 x 10(9) IU of IG.Ad.CMV.rIL-3 beta. Perfusions with adenoviral vectors bearing a weaker promoter (MLP promoter) driving the rIL-3 beta gene did not result in antitumor responses, suggesting that the rIL-3 beta-mediated antitumor effect depends on the amount of rIL-3 beta protein expressed by the infected cells. Furthermore, it was shown by direct comparison that ILP with IG.Ad.CMV.rIL-3 beta in the ROS-1 osteosarcoma model is at least as efficient as the established therapy with the combination of TNF-alpha and melphalan. Treatment with IG.Ad.CMV.rIL-3 beta induced a transient dose-dependent leukocytosis accompanied by an increase in peripheral blood levels of histamine. Leukocyte infiltrations were also histopathologically demonstrated in tumors after perfusion. These results demonstrate that ILP with recombinant adenoviral vectors carrying the IL-3 beta transgene inhibits tumor growth in rats and suggest that cytokine gene therapy using this administration technique might be beneficial for clinical cancer treatment.

Monitoring engraftment of transplanted hepatocytes in recipient liver with 5-bromo-2'-deoxyuridine.

For studies on the intrahepatic engraftment of transplanted hepatocytes, labeling of donor cells is necessary. Current labeling techniques enable only short-term monitoring of engraftment. In the present study, we describe the use of 5-bromo-2'-deoxyuridine (BrdU) for a more permanent hepatocyte labeling. BrdU is stably incorporated into replicating DNA; consequently, BrdU labeling was performed in regenerating livers. In 10 Lewis rats, a two-thirds partial hepatectomy was performed, followed by continuous, low-dose BrdU administration. This approach provided a fraction of 89+/-1.5% BrdU-labeled donor hepatocytes, without influencing the efficacy of the ensuing isolation of donor hepatocytes. Subsequently, +/-1 x 10(7) isolated hepatocytes were transplanted either intraportally or intrasplenically into syngeneic recipients, and the engraftment of transplanted cells was evaluated in liver lobes at successive time intervals after transplantation. BrdU-positive hepatocytes could be identified and quantitated in recipient livers up to 180 days after transplantation. Repetitive quantitative assessments over time revealed an initial, drastic loss of transplanted cells (<24 hr), followed by a stabilization at approximately 7% of the injected cells. Histological monitoring showed that during this period (<48 hr) the transplanted cells migrate from the portal venules to the liver parenchyma. In recipient livers a homogeneous lobe distribution of hepatocyte engraftment was found 30 days after both intraportal and intrasplenic transplantation. Moreover, no significant difference between the intrahepatic liver cell engraftment of the two transplantation routes was demonstrated. In conclusion, the BrdU-labeling technique of donor hepatocytes enables long-term histological monitoring and quantitative evaluation of the engraftment of transplanted liver cells in recipient livers.

Correction of an inborn error of metabolism by intraportal hepatocyte transplantation in a dog model.

The aims of this study were (1) to assess portal hemodynamics during intraportal hepatocyte transplantation (HTX) in dogs, (2) to evaluate a new method for the detection of transplanted hepatocytes using 5-bromo-2'-deoxyuridine (BrdU) incorporation, and (3) to determine the metabolic effects of HTX on an inborn error of the purine metabolism in dalmatian dogs. HTX was performed by intraportal infusion of freshly isolated allogeneic beagle hepatocytes. Portal flow and pressure were monitored continuously during HTX. For the detection experiments, beagles received hepatocytes that had been exposed to BrdU during regeneration of the donor liver, induced by partial hepatectomy. For metabolic studies, dalmatian dogs were used as recipients. Repetitive HTX was performed. As judged by the portal hemodynamics, the number of hepatocytes that could be infused safely varied from 5 x 1O(8) to 8 x 1O(8) in beagles, to 1 x 10(9) in dalmatians. Transaminase levels showed a 5- to 6-fold increase (P=0.05) after HTX, but normalized within 3 weeks. BrdU-positive cells were identified in the recipient livers 2 weeks after HTX and 5-10% of the total amount of transplanted hepatocytes was retrieved. A significant (P=0.05) decrease in serum uric acid was demonstrated after repeated HTX in dalmatians. In conclusion, (1) intraportal HTX is feasible, but portal hypertension limits the maximum amount of hepatocytes that can be infused in one HTX; (2) BrdU labeling is an attractive method for the detection of transplanted hepatocytes in the recipient liver; and (3) after two consecutive hepatocyte transplantations, a temporary correction of the purine metabolism was accomplished in the dalmatian dog.

Chronic mesenteric vascular syndrome. Results of reconstructive surgery.

Since 1961, 14 patients at the University Hospital of Leiden, the Netherlands, have undergone reconstructive surgery for treatment of chronic mesenteric vascular syndrome. Of the 42 mesenteric arteries, 31 were severely obstructed (mean, 2.2 stenotic arteries per patient). A total of 23 mesenteric arteries were repaired. Long-term follow-up data were available for all 13 surviving patients (mean follow-up, 11.8 years). Symptoms were relieved immediately after surgery, and relief was maintained during follow-up. Digital subtraction angiography at long-term follow-up evaluation was performed in eight patients (13 reconstructions) with these results: 11 (85%) of the 13 reconstructions were patent and severe stenoses were found in eight (33%) of the 24 mesenteric arteries (mean, 1.0 stenotic artery per patient). We conclude that reconstructive surgery for patients with chronic mesenteric vascular syndrome promptly relieves symptoms, provides excellent patency, and has long-lasting beneficial results.

Assessment of resectability of carcinoma of the pancreatic head by ultrasonography and computed tomography. A retrospective analysis.

In order to establish the reliability of the assessment of tumour stage and hence of resectability of carcinoma of the pancreatic head by ultrasonography (US) and computed tomography (CT) a retrospective analysis was performed on 41 patients. Both direct imaging techniques were very accurate in detecting non-resectable disease, 100 and 85% respectively, but were much less accurate in predicting resectable cancer, 18 and 15% respectively. False-resectable results were established in 58% of US examinations and 42% of CT examinations. As demonstrated in this study, predicting resectability of carcinoma of the pancreatic head with US and CT is an inadequate method of assessing tumour stage and should be complemented by other techniques to ensure a reliable result.

A prospective validation study of sentinel lymph node biopsy in multicentric breast cancer: SMMaC trial.

BACKGROUND: Multicentric breast cancer is often considered a contra-indication for sentinel lymph node (SLN) biopsy due to concerns with sensitivity and false negative rate. To assess SLN feasibility and accuracy in multicentric breast cancer, the multi-institutional SMMaC trial was conducted. METHODS: In this study 30 patients with multicentric breast cancer and a clinically negative axilla were prospectively included. Periareolar injection of radioisotope and blue dye was administered. In all patients SLN biopsy was validated by back-up completion axillary lymph node dissection. RESULTS: the SLN was successfully identified in 30 of 30 patients (identification rate 100%). The incidence of axillary metastases was 66.7% (20/30). The false negative rate was 0% (0/20) and the sensitivity was 100% (20/20). The negative predictive value was 100% (10/10). CONCLUSION: SLN biopsy in multicentric breast cancer seems feasible and accurate and should therefore be considered in patients with multicentric breast cancer and clinically negative axilla.

Discordance between number of scintigraphic and perioperatively identified sentinel lymph nodes and axillary tumour recurrence.

BACKGROUND: In breast cancer, sentinel node biopsy is considered the standard method to assess the lymph node status of the axilla. Preoperative identification of sentinel lymph nodes (SLN) is performed by injecting a radioactive tracer, followed by lymphoscintigraphy. In some patients there is a discrepancy between the number of lymphoscintigraphically identified sentinel nodes and the number of nodes found during surgery. We hypothesized that the inability to find peroperatively all the lymphoscintigraphically identified sentinel nodes, might lead to an increase in axillary recurrence because of positive SLNs not being removed. METHODS: Patients who underwent sentinel node biopsy between January 2000 and July 2010 were identified from a prospectively collected database. The number of lymphoscintigraphically and peroperatively identified sentinel nodes were reviewed and compared. Axillary recurrences were scored. RESULTS: 1368 patients underwent a SLN biopsy. Median follow up was 58.5 months (range 12-157). Patient and tumour characteristics showed no significant differences. In 139 patients (10.2%) the number of radioactive nodes found during surgery was less than preoperative scanning (group 1) and in 89.8% (N = 1229) there were equal or more peroperative nodes identified than seen lymphoscintigraphically (group 2). In group 1, 0/139 patients (0%) developed an axillary recurrence and in the second group this was 25/1229 (2.0%) respectively. No significant difference between groups regarding axillary recurrence, sentinel node status and distant metastasis was found. CONCLUSION: Axillary recurrence rate is not influenced by the inability to remove all sentinel nodes during surgery that have been identified preoperatively by scintigraphy.

Evaluation of the benefit of routine intraoperative frozen section analysis of sentinel lymph nodes in breast cancer.

Aims. Intraoperative analysis of the sentinel lymph node (SLN) by frozen section (FS) allows for immediate axillary lymph node dissection (ALND) in case of metastatic disease in patients with breast cancer. The aim of this study is to evaluate the benefit of intraoperative FS, with regard to false negative rate (FNR) and influence on operation time. Materials and Methods. Intraoperative analysis of the SLN by FS was performed on 628 patients between January 2005 and October 2009. Patients were retrospectively studied. Results. FS accurately predicted axillary status in 525 patients (83.6%). There were 78 true positive findings (12.4%), of which there are 66 macrometastases (84.6%), 2 false positive findings (0.3%), and 101 false negative findings (16.1%), of which there are 65 micrometastases and isolated tumour cells (64.4%) resulting in an FNR of 56.4%. Additional operation time of a secondary ALND after wide local excision and SLNB is 17 minutes, in case of ablative surgery 35 minutes. The SLN was negative in 449 patients (71.5%), making their scheduled operation time unnecessary. Conclusions. FS was associated with a high false negative rate (FNR) in our population, and the use of telepathology caused an increase in this rate. Only 12.4% of the patients benefited from intraoperative FS, as secondary ALND could be avoided, so FS may be indicated for a selected group of patients.

Assessment of the Memorial Sloan-Kettering Cancer Center nomogram to predict sentinel lymph node metastases in a Dutch breast cancer population.

AIM: Sentinel lymph node (SLN) biopsy is an accepted alternative to axillary lymph node dissection to assess the axillary tumour status in breast cancer patients. Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram to predict the likelihood of SLN metastases in breast cancer patients. Nomogram performance was tested on a Dutch population. METHODS: Data of 770 breast cancer patients who underwent successful SLN biopsy were collected. SLN metastases were present in 222 patients. A receiver operating characteristic (ROC) curve was drawn and the area under the curve was calculated to assess the discriminative ability of the MSKCC nomogram. A calibration plot was drawn to compare actual versus nomogram-predicted probabilities. RESULTS: The area under the ROC curve for the predictive nomogram was 0.67 (95% confidence interval 0.63-0.72) as compared to 0.75 in the original population. The nomogram was well-calibrated in the Dutch population. CONCLUSIONS: In a Dutch population, the MSKCC nomogram estimated risk of sentinel node metastases in breast cancer patients well (i.e. calibration) with reasonable discrimination (area under ROC curve). Nomogram performance on core needle biopsy data has to be evaluated prospectively.

Human T47D-ERß breast cancer cells with tetracycline-dependent ERß expression reflect ERα/ERß ratios in rat and human breast tissue.

T47D-ERß breast cancer cells with tetracycline-dependent ERß expression and constant ERα expression can be used to investigate effects of varying ERα/ERß ratios on estrogen-induced cellular responses. This study defines conditions at which ERα/ERß ratios in T47D-ERß cells best mimic ERα/ERß ratios in breast and other estrogen-sensitive tissues in vivo in rat as well as in human. Protein and mRNA levels of ERα and ERß were analyzed in T47D-ERß cells exposed to a range of tetracycline concentrations and compared to ERα and ERß levels found in breast, prostate, and uterus from rat and human origin. The ERα/ERß ratio in T47D-ERß cells exposed to >150ng/ml tetracycline is comparable to the ratio found in rat mammary gland and in human breast tissue. The ERα/ERß ratio of other estrogen-sensitive rat and human tissues can also be mimicked in T47D-ERß cells. The ERα/ERß ratio found in MCF-7 and native T47D breast cancer cell lines did not reflect ratios in analyzed rat and human tissues, which further supports the use of T47D-ERß cells as model for estrogen-responsive tissues. Using 17ß-estradiol and the T47D-ERß cells under the conditions defined to mimic various tissues it could be demonstrated how these different tissues vary in their proliferative response.

A flexor tendon rupture in the palm of the hand.

Traumatic, subcutaneous ruptures of flexor tendons in the hand are infrequent findings in clinical practice. They usually occur at the bony insertion or at the musculotendinous junction. Intratendinous ruptures are reported almost only in association with underlying pathologic conditions. We report a case of subcutaneous rupture through the healthy substance of the profundus flexor tendon of the small finger in the palm of the hand, which was associated with a complete tendinous fusion between the deep flexor of the ring and small finger up to the lumbrical insertion.

Factors leading to local recurrence or death after surgical resection of phyllodes tumours of the breast.

BACKGROUND: Local recurrence and death from metastases are occasional, but consistent, themes in reports of patients with phyllodes tumours. Factors that might contribute to these outcomes were sought. METHODS: Data from 38 patients with a phyllodes breast tumour were reviewed retrospectively, reclassifying the pathological material using the Pietruszka and Barnes criteria. RESULTS: At a median of 12 months, nine patients had developed a local recurrence and four had died from metastases. Following local excision in 24 patients (for diagnosis in 13, for 'fibroadenoma' in nine and for phyllodes tumour in two patients), 13 had no further surgery and five had local recurrence (three of eight benign tumours, two of two malignant tumours). Wide local excision or mastectomy in 18 patients was followed by four recurrences (one of eight borderline tumours, three of ten malignant tumours). All patients with recurrence had margin involvement on histological examination, but not all patients with margin involvement developed recurrence. Lack of statistical correlation between local recurrence and age, delay, size, grade or type of surgery was confounded by selection bias for more extensive surgery for malignant tumours. Death correlated with size (P = 0.05) and grade (P = 0.03) of tumour. CONCLUSION: Inadequate preoperative diagnosis ('fibroadenoma' or failure of triple assessment) frequently led to local excision with positive margins. Without revision this often resulted in local recurrence. Local recurrence of any grade was usually followed by further recurrence. Death was related to tumour size and histological grade, confirming these as prognostic factors.

Acute mesenteric embolism: an appeal for a pro-active diagnostic approach.

Acute mesenteric ischaemia can be caused by arterial embolism. The initial aspecific symptoms mostly lead to late recognition of acute mesenteric ischaemia which leads to intestinal infarction. Intestinal infarction with signs of peritonitis has a very high mortality. Since 1982, a pro-active approach is followed in our department. After thorough exclusion of other causes, patients with serious acute abdominal complaints undergo an emergency angiography and/or emergency laparotomy. After confirmation of the diagnosis, primary vascular reconstructive surgery is performed if possible. We have treated eight patients with acute mesenteric embolism according to this policy. Per- and post-operatively, three patients died of extensive intestinal infarction. The five surviving patients were on a normal diet and had normal bowel functions at the time of discharge from the hospital. This limited experience shows that a pro-active approach in patients with acute mesenteric embolism can result in survival and preservation of a normally functioning alimentary tract.

Surgical treatment of intestinal artery aneurysms.

Intestinal artery aneurysms are usually asymptomatic. However, occasionally they occur as a vascular emergency and when rupture occurs, mortality rates of up to 75% have been reported. Therefore, elective surgery of asymptomatic intestinal artery aneurysms seems indicated provided that the procedure is safe with a low morbidity and mortality. We have reviewed the results of surgical treatment of eight patients with intestinal artery aneurysm who were operated on electively and seven who had emergency procedures over a 20 year period. Mortality was high when rupture had occurred, despite acute surgical intervention. After elective procedures however mortality and morbidity were substantially lower. Elective surgical intervention should therefore be performed as soon as an intestinal artery aneurysm is diagnosed.

Coeliac artery compression syndrome: the effect of decompression.

The effects of operation to decompress the coeliac artery were evaluated in 11 consecutive patients with coeliac artery compression syndrome. Immediately after the operation all patients were free of symptoms. Three months later three of the 11 had recurrent abdominal pain. Long-term follow-up between 15 and 23 years, obtained by questionnaire, was available for eight patients. All eight had return of symptoms similar to those before surgery. These unsatisfactory results suggest that operation should not be undertaken in patients with vague upper abdominal complaints and compression of the coeliac artery by the median arcuate ligament, who do not otherwise have pathological conditions which might explain their symptoms.

Fournier's gangrene: the need for early recognition and radical surgical débridement.

Fournier's gangrene, a specific form of necrotizing fasciitis, predominantly affects the male genitals, perineum and perianal region. Most frequently Fournier's gangrene is caused by the synergistic action of aerobic and anaerobic microorganisms and leads to early septicaemia with a high mortality. The case histories of three patients with Fournier's gangrene are presented to illustrate the importance of early recognition and radical surgical débridement as essential objectives for therapeutic success. In the first patient, who died of Fournier's gangrene after a vasectomy, appropriate therapy was significantly delayed due to late recognition of the condition. The second patient presented with a rapidly progressive fasciitis secondary to a perianal abscess; immediate excision of all necrotic tissue was successfully performed. The third patient developed gangrene from an urogenital infectious focus, which was primarily treated by insufficient incisional and drainage therapy. Only after radical débridement his general condition rapidly improved.

Isolated-organ perfusion for local gene delivery: efficient adenovirus-mediated gene transfer into the liver.

Targeted gene delivery is essential for gene therapy involving in vivo gene transfer. In the present study we analyzed the efficiency and tissue-specificity of gene transfer into the liver with recombinant adenoviruses. Adenovirus vectors carrying the E. coli lacZ gene (Ad.RSV.beta-gal) and the firefly luciferase gene (AdCMV-luc) as reporters were administered to the liver of adult Wistar rats, either via infusion into the portal vein (intraportal infusion; IPI) or via perfusion of the vascularity isolated liver (isolated liver perfusion; ILP). Ex vivo liver perfusion experiments with Ad.RSV. beta-gal were used to optimize the conditions for hepatic gene transfer. Ex vivo perfusion of rat livers with 2 x 10(9) plaque forming units (p.f.u) Ad RSV.beta-gal was sufficient to infect about 20% of the liver parenchymal cells. Perfusion with chelating agents (1 mM EGTA, or 2 mM EDTA) prior to the administration of the vector increased the efficiency to at least 40%. Similar efficiencies were obtained in experiments with liver lobes of Rhesus monkeys. In vivo administration of AdCMV-luc via ILP resulted in a significantly more efficient (P = 0.028) and also more reproducible gene transfer when compared to IPI. Although detectable in both groups, extrahepatic luciferase expression was considerably reduced in the ILP group. Our data demonstrate that IPL can be used for efficient and reproducible liver-specific gene delivery. Therefore, we think that the perfusion of vascularly isolated organs is useful as a modality for the tissue-specific administration of recombinant adenovirus vectors.