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Highlights • Preoperative imaging is essential for minimal invasive parathyroidectomy. • Conventional imaging is often negative or inconclusive. • 18F-Fluorocholine PET–CT might be a solution. • We describe a patient with negative SPECT–CT and ultrasound. • Patient underwent successful surgery after positive PET–CT., Introduction Primary hyperparathyroidism is a common endocrine disorder for which the primary treatment is surgery. For minimal invasive parathyroidectomy adequate pre-operative imaging is essential. Conventional imaging is often inconclusive. There are reports that 18F-fluorocholine PET–CT might be a superior imaging modality, however evidence is still very scarce. This is the first report of a case with negative ultrasound and sestamibi SPECT–CT imaging that underwent successful minimal invasive surgery because of 18F-fluorocholine PET–CT. Presentation of case A 57 year-old man presented to us with complaints of fatigue. Laboratory results showed a biochemical primary hyperparathyroidism and an additional DEXA-scan revealed osteopenia of the lumbar spine. Conventional imaging consisting of neck ultrasound and Tc-99m-sestamibi SPECT–CT was however unable to localize the pathological gland. Subsequent 18F-fluorocholine PET–CT did clearly localize an adenoma dorsally of the left thyroid lobe which was removed at that exact location using minimal invasive parathyroidectomy. Histological examination confirmed the diagnosis adenoma and calcium levels remained normal at follow-up. Discussion There is clinical need for a superior imaging modality to detect pathological parathyroid glands to enable minimal invasive surgery. 18F-Fluorocholine is widely available. Conclusion 18F-Fluorocholine PET–CT is a promising new imaging modality for localizing parathyroid adenomas and enabling minimal invasive parathyroidectomy when conventional imaging fails to do. Clinicians should consider its use as a second line modality for optimal patient care.

High-resolution intravital microscopy through imaging windows has become an indispensable technique for the long-term visualization of dynamic processes in living animals. Easily accessible sites such as the skin, the breast and the skull can be imaged using various different imaging windows; however, long-term imaging studies on cellular processes in abdominal organs are more challenging. These processes include colonization of the liver by metastatic tumor cells and the development of an immune response in the spleen. We have recently developed an abdominal imaging window (AIW) that allows long-term imaging of the liver, the pancreas, the intestine, the kidney and the spleen. Here we describe the detailed protocol for the optimal surgical implantation of the AIW, which takes approximately 1 h, and subsequent multiphoton imaging, which takes up to 1 month.

Background Consensus molecular subtype 4 (CMS4) is a recently identified aggressive colon cancer subtype for which platelet-derived growth factor receptors (PDGFRs) and KIT are potential therapeutic targets. We aimed to develop a clinically applicable CMS4 reverse transcription polymerase chain reaction (RT-qPCR) test to select patients for PDGFR/KIT-targeted therapy. Methods We used logistic regression to develop a CMS4 prediction rule based on microarray expression values of PDGFRA , PDGFRB , PDGFC , and KIT (566 training and 1259 test samples, using the 273-gene random forest classifier as CMS4 reference standard). We next translated the prediction rule into a single-sample RT-qPCR test, which we independently validated in 29 fresh tumor samples. To study intratumor CMS4 heterogeneity, we used the RT-qPCR test to analyze five random regions of 20 colon tumors. Results The microarray-based prediction rule diagnosed CMS4-type tumors extremely well in both training and independent test samples (training: area under the curve [AUC] = 0.95, 95% confidence interval [CI] = 0.94 to 0.97; test: AUC = 0.95, 95% CI = 0.94 to 0.96), with excellent calibration and approximately 80% overall net benefit over a large threshold range. Translation into an RT-qPCR test did not affect discrimination (AUC = 0.97, 95% CI = 0.93 to 1.00, independent validation). RT-qPCR analysis of five random tumor regions revealed extensive intratumor CMS4 heterogeneity in nine out of 20 tumors. At least two regions likely have to be analyzed to identify patients that are predominantly CMS4 positive (>50% average CMS4 chance). Conclusion The CMS4 RT-qPCR test is a promising clinical tool for selecting individual patients for CMS4-subtype-targeted therapy.

Purpose Breast cancer in men is uncommon; it accounts for 1 % of all patients with primary breast cancer. Its treatment is mostly extrapolated from its female counterpart. Accurate predictions are essential for adjuvant systemic treatment decision-making and informing patients. Several predictive models are available for female breast cancer (FBC) including the Morphometric Prognostic Index (MPI), Nottingham Prognostic Index (NPI), Adjuvant! Online and Predict. The aim of this study was to examine and compare the prognostic performance of these models for male breast cancer (MBC). Methods The population of this study consists of 166 MBC patients. The prognostic scores of the patients are categorized by good, (moderate) and poor, defined by the test itself (MPI and NPI) or based on tertiles (Adjuvant! Online and Predict). Survival according to prognostic score was compared by Kaplan–Meier analysis and differences were tested by logRank. The prognostic performances were evaluated with C-statistics. Calibration was done with the aim to estimate to what extent the survival rates predicted by Predict were similar to the observed survival rates. Results All prediction models were capable of discriminating between good, moderate and poor survivors. P-values were highly significant. Comparison between the models using C-statistics (n = 88) showed equal performance of MPI (0.67), NPI (0.68), Adjuvant! Online (0.69) and Predict (0.69). Calibration of Predict showed overestimation for MBC patients. Conclusion In conclusion, MPI, NPI, Adjuvant! and Predict prognostic models, originally developed and validated for FBC patients, also perform quite well for MBC patients. Electronic supplementary material The online version of this article (doi:10.1007/s10549-016-3991-9) contains supplementary material, which is available to authorized users.

Contains fulltext : 172109.pdf (Publisher’s version ) (Open Access) PURPOSE: Traditionally, total thyroidectomy has been advocated for patients with tumors larger than 1 cm. However, according to the ATA and NCCN guidelines (2015, USA), patients with tumors up to 4 cm are now eligible for lobectomy. A rationale for adhering to total thyroidectomy might be the presence of contralateral carcinomas. The purpose of this study was to describe the characteristics of contralateral carcinomas in patients with differentiated thyroid cancer (DTC) larger than 1 cm. METHODS: A retrospective study was performed including patients from 17 centers in 5 countries. Adults diagnosed with DTC stage T1b-T3 N0-1a M0 who all underwent a total thyroidectomy were included. The primary endpoint was the presence of a contralateral carcinoma. RESULTS: A total of 1313 patients were included, of whom 426 (32 %) had a contralateral carcinoma. The contralateral carcinomas consisted of 288 (67 %) papillary thyroid carcinomas (PTC), 124 (30 %) follicular variant of a papillary thyroid carcinoma (FvPTC), 5 (1 %) follicular thyroid carcinomas (FTC), and 3 (1 %) Hurthle cell carcinomas (HTC). Ipsilateral multifocality was strongly associated with the presence of contralateral carcinomas (OR 2.62). Of all contralateral carcinomas, 82 % were

Background Robot-assisted laparoscopy has been introduced to overcome the limitations of conventional laparoscopy. This technique has potential advantages over laparoscopy, such as increased dexterity, three-dimensional view, and a magnified view of the operative field. Therefore, improved dexterity may make a robotic system particularly suited for liver resections, which require nonlinear manipulation, such as curved parenchymal transection, hilar dissection, and resection of posterosuperior segments. Methods Between August 2014 and March 2016, 16 patients underwent robot-assisted laparoscopic liver resection at University Medical Center Utrecht. Results Fifteen robot-assisted laparoscopic liver resections were performed in a minimally invasive manner. One procedure was converted. In eight patients, we performed a resection of a posterosuperior segment (segment 7 or 8). Median operating time was 146 (60-265) min, and median blood loss was 150 (5-600) mL. Four patients had a Clavien–Dindo grade III complication. Median length of stay was 4 (1-8) days. There was no mortality. Conclusions This prospective study reporting on our initial experience with robot-assisted laparoscopic liver resection demonstrates that this technique is easily adopted, safe, and feasible for minor hepatectomies in selected patients. Moreover, it shows that the robotic platform also enables fully laparoscopic resections of the posterior segments.

BACKGROUND: Omitting extensive lymph node dissection could reduce esophagectomy morbidity in patients without lymph node metastases. Sentinel node biopsy may identify abdominal or thoracic lymph node metastases, thereby differentiating treatment. Feasibility of this approach was investigated in Western European esophageal cancer patients with advanced disease, without lymph node metastases at diagnostic work-up. METHODS: The sentinel node biopsy was performed in eight esophageal cancer patients with cT1-3N0 disease. One day pre-operatively, Tc-99m-labeled nanocolloid was endoscopically injected around the tumor. Lymphoscintigraphy was performed 1 and 3 h after injection. All patients underwent robotic thoracolaparoscopic esophagectomy with two-field lymph node dissection. Intraoperatively, sentinel nodes were detected by gamma probe. The resection specimen was analyzed for remaining activity by scintigraphy and gamma probe. RESULTS: Visualization rates of lymphoscintigraphy 1 and 3 h after tracer injection were 88 and 100 %, respectively. Intraoperative identification rate was 38 %. Postoperative identification was possible in all patients using the gamma probe to analyze the resection specimen. In 5/8 patients, lymph node metastases were found at histopathology, none of which was detected by the sentinel node biopsy. No adverse events related to the sentinel node biopsy were observed. CONCLUSIONS: In our advanced esophageal cancer patients who underwent thoracolaparoscopic esophagectomy, the sentinel node biopsy did not predict lymph node status. Probably the real sentinel node could not be identified due to localization adjacent to the primary tumor or bypassing due to metastatic tumor involvement. Therefore, we consider the sentinel node biopsy not feasible in advanced esophageal cancer.

Background Robotic surgery has been introduced to overcome the limitations of conventional laparoscopy. A systematic review and meta-analysis were performed to assess the safety and feasibility for three subgroups of robot-assisted laparoscopic liver resection: (i) minor resections of easily accessible segments: 2/3, 4B, 5, 6, (ii) minor resections of difficult located segments: 1, 4A, 7, 8 and (iii) major resections: ≥ 4 segments. Methods A systematic search was performed in PubMed, EMBASE and Cochrane Library. Results Twelve observational, mostly retrospective studies reporting on 363 patients were included. Data were pooled and analyzed. For subgroup (i) (n = 81) the weighted mean operative time was 215 ± 65 min. One conversion (1%) to laparotomy was needed. Weighted mean operative time for subgroup (ii) (n = 17) was 220 ± 60 min. No conversions were needed. For subgroup (iii) (n = 99) the weighted mean operative time was 405 ± 100 min. In this subgroup 8 robotic procedures (8%) were converted to open surgery. Conclusion Data show that robot-assisted laparoscopic liver resection is feasible in minor resections of all segments and major resections. Larger, prospective studies are warranted to compare the possible advantages of robot-assisted surgery with conventional laparoscopy and open surgery.

Since the 1950s, preoperative medical preparation has been widely applied in patients with pheochromocytoma to improve intraoperative hemodynamic instability and postoperative complications. However, advancements in preoperative imaging, laparoscopic surgical techniques, and anesthesia have considerably improved management in patients with pheochromocytoma. In consequence, there is no validated consensus on current predictive factors for postoperative morbidity. The aim of this study was to determine perioperative factors which are predictive for postoperative morbidity in patients undergoing laparoscopic adrenalectomy for pheochromocytoma. It is a retrospective analysis of prospectively maintained databases in five medical centers from 2002 to 2013. Inclusion criteria were consecutive patients who underwent non-converted laparoscopic unilateral total adrenalectomy for pheochromocytoma. Two-hundred and twenty-five patients were included. All-cause and cardiovascular postoperative morbidity rates were 16 % (n = 36) and 4.8 % (n = 11), respectively. Preinduction blood pressure normalization after preoperative medical preparation had no impact on postoperative morbidity. However, past medical history of coronary artery disease (OR [CI95 %] = 3.39; [1.317–8.727]) and incidence of intraoperative hemodynamic instability episodes (both SBP ≥ 160 mmHg and MAP

Multiple endocrine neoplasia type 1 is an autosomal dominantly inherited syndrome. MEN1 is characterized by the occurrence of tumors of the parathyroid glands, the pancreatic islets, the anterior pituitary gland, and the adrenal glands, as well as neuroendocrine tumors in the thymus, lungs, and stomach, often at a young age. Nonendocrine manifestations of MEN1 include angiofibromas, collagenomas, lipomas, leiomyomas, and meningiomas. The prevalence of MEN1 is two to three per 100,000, and is equal among males and females. MEN1 and multiple endocrine neoplasia type 2 (MEN2) are two distinct syndromes. In MEN2, patients frequently develop medullary thyroid carcinoma and adrenal medullary tumors (pheochromocytoma).

Epithelial cyst in an intrapancreatic accessory spleen (ECIPAS) is exceedingly rare with only 57 cases reported since the first publication in 1980. Comprehensive clinical and diagnostic features remain to be clarified. We present a case of ECIPAS in a 21-year-old Philippine woman who was admitted with right upper quadrant abdominal pain. A cystic lesion in the pancreatic tail was discovered and evaluated by computed tomography and magnetic resonance images. Based on clinical and radiological features a solid pseudopapillary neoplasm was suspected. The patient underwent robot-assisted spleen preserving distal pancreatectomy. Pathological evaluation revealed a 26 mm intrapancreatic accessory spleen with a 16 mm cyst, lined by multilayered epithelium in the tail of the pancreas. The postoperative course was uneventful. Differentiating ECIPAS from (pre)malignant cystic pancreatic neoplasms based on clinical and radiological features remains difficult. When typical radiological signs can be combined with scintigraphy using Technetium-99m labelled colloid or Technetium-99m labelled erythrocytes, which can identify the solid component of the lesion as splenic tissue, it should be possible to make the right diagnosis noninvasively. When pancreatectomy is inevitable due to symptoms or patient preference, minimally invasive laparoscopic or robot-assisted spleen preserving distal pancreatectomy should be considered.

OBJECTIVE: Evaluation of the feasibility and safety of radiocolloid as a tracer for sentinel lymph node (SLN) mapping in colon cancer. METHODS: A feasibility study was conducted in consecutive colon cancer patients who were surgically treated at our institute. During preoperative colonoscopy, radiocolloid was injected around the tumour, followed by scintigraphic imaging to identify SLNs. SLNs were identified intraoperatively by a gamma probe and postoperatively by additional ex-vivo scintigraphy of the resection specimen. All retrieved SLNs were examined by histopathological ultrastaging. Standard oncologic laparoscopic resections with lymphadenectomy were performed following the identification of SLNs in all patients. RESULTS: Fourteen patients were included. At least one SLN was identified in 86% of patients. In one patient (7%) SLNs could be detected intraoperatively. In 83% of patients, the SLNs accurately reflected the tumour status of the remaining lymph nodes. Aberrant lymphatic drainage was preoperatively identified in one patient (7%), but this could not be confirmed intraoperatively. Sensitivity was 67% and the false-negative rate was 33%. Seventeen per cent of patients were upstaged because of SLN micrometastases. CONCLUSION: SLN mapping in colon cancer using radiocolloid as a single tracer is feasible and safe. However, it was difficult to identify SLNs intraoperatively because of high radioactivity at the injection site. Furthermore, the protocol is labour intensive, especially because of the additional colonoscopic tracer injection. Sensitivity is not better than when blue dye is used, and aberrant lymphatic drainage patterns are scarce. Therefore, this technique is not preferred for SLN mapping in colon cancer.

The aim of this study was to compare the outcome of the hemorrhoidal artery ligation procedure for hemorrhoidal disease with and without use of the provided Doppler transducer.Hemorrhoidal artery ligation, known as HAL (hemorrhoidal artery ligation) or THD (transanal hemorrhoidal dearterialization) procedure, is a common treatment modality for hemorrhoidal disease in which a Doppler transducer is used to locate the supplying arteries that are subsequently ligated. It has been suggested that the use of the Doppler transducer does not contribute to the beneficial effect of these ligation procedures.The authors conducted a single-blinded randomized clinical trial and assigned a total of 82 patients with grade II and III hemorrhoidal disease to undergo either a HAL/THD procedure without use of the Doppler transducer (non-Doppler group, 40 patients) or a conventional HAL/THD procedure (Doppler group, 42 patients). Primary endpoint was improvement of self-reported clinical parameters after both 6 weeks and 6 months. This study is registered at trialregister.nl and carries the ID number: NTR2139.After 6 weeks and 6 months in both the non-Doppler and the Doppler group, significant improvement was observed with regard to blood loss, pain, prolapse, and problems with defecation (P0.05). The improvement of symptoms between both groups did not differ significantly (P0.05), except for prolapse, which improved more in the non-Doppler group (P = 0.047). There were more complications and unscheduled postoperative events in the Doppler group (P0.0005). After 6 months, 31% of the patients in the non-Doppler group and 21% in the Doppler group reported completely complaint free (P = 0.313).The authors' findings confirm that the hemorrhoidal artery ligation procedure significantly reduces signs and symptoms of hemorrhoidal disease. The authors' data also show that the Doppler transducer does not contribute to this beneficial effect.

In patients with unresectable colorectal liver metastases (CRLM), radiofrequency ablation (RFA) might be a good alternative, whenever possible. In contrast to systemic therapy, the aim of RFA is to achieve complete local tumor control in an attempt to provide long-term survival. In this article we discuss the available evidence regarding the treatment of patients with unresectable CRLM, focusing on RFA in conjunction with modern systemic therapies. We observed that the available evidence in the existing literature is limited, and often consists of level 2 and 3 evidence, thereby hampering any firm conclusions. Nonetheless, RFA seems superior to chemotherapy alone in patients with liver-only disease amenable for RFA. However, the combination of RFA and chemotherapy has been demonstrated to be feasible and safe, lending support to the concept of RFA followed by chemotherapy, in order to reduce local recurrence rates and prolong survival.

Homeostasis of the continuously self-renewing intestinal tract involves cell proliferation, migration, differentiation along the crypt-villus-axis and shedding of cells into the gut lumen. CD95-ligand (FAS-ligand, CD95L) is a cytokine that is known for its capacity to induce apoptosis by binding its cognate receptor, CD95 (Fas). More recently, it was discovered that CD95L can also induce other cellular responses, such as proliferation, differentiation and cell migration. CD95L is highly expressed in Paneth cells of the small intestine which are in close contact with intestinal stem cells. This suggests a potential role for CD95L in controlling stem cell function and, possibly, intestinal homeostasis. We analyzed the intestines of mice deficient for functional CD95L (gld) for potential alterations in the diversity of stem-cell-lineages and parameters of intestinal homeostasis. Stem cell diversity was assessed by analyzing methylation patterns of the non-transcribed mMYOD gene. Proliferation was analyzed by BrdU labeling and differentiation was assessed by immunohistochemistry. Of all parameters analyzed, only epithelial cell proliferation was significantly reduced in the small intestines of gld-mice, but not in their colons which lack CD95L expression. We conclude that CD95L has a proliferation-stimulating role during normal turnover of the small intestine, but has a marginal effect on overall intestinal homeostasis.

The optimal surgical approach for patients with primary hyperparathyroidism (pHPT) and multiple endocrine neoplasia 1 (MEN1) is controversial. We sought to determine the optimal type of surgery for pHPT in MEN1. We collected data on clinical presentation, surgery, and follow-up for MEN1 patients with pHPT at the University Medical Center Utrecht and affiliated hospitals between 1967 and 2008. Furthermore, we performed a systematic review of the literature and meta-analysis. Surgical procedures were classified into less than subtotal (

Nasal colonization by Staphylococcus aureus is an important risk factor for the development of a nosocomial infection. Acquisition of nasal colonization by S. aureus increases mortality in hospitalized patients, but little is known about the transmission dynamics of S. aureus. To study S. aureus transmission, colonization and colonization persistence, we developed a murine transmission model. In 20 cages, 2 out of 10 mice were nasally inoculated (at 5×10(8) c.f.u. per mouse) with either meticillin-susceptible S. aureus (MSSA) (10 cages) or meticillin-resistant S. aureus (MRSA) (10 cages). On days 5, 15, 25 and 40, all mice in a cage were swabbed or sacrificed and nasal colonization and c.f.u. were determined in all 10 mice by nasal dissection or by nasal swab. Spread and subsequent stable colonization by both MSSA and MRSA from colonized to uncolonized mice within a cage was seen. At day 5, an increased number of colonized mice were observed in the MSSA group compared to the MRSA group (P = 0.003). On day 40, the mean number of c.f.u. per mouse was higher for MRSA than for MSSA (P = 0.06). Faecal-oral transmission was shown to be a possibly important transmission route in this model. These results suggest a more rapid spread of MSSA compared to MRSA. However, MRSA shows a more stable nasal colonization after a longer period of time.

Objective To determine the best surgical strategy for patients with multiple endocrine neoplasia type 2A (MEN 2A) who have primary hyperparathyroidism (PHPT). Methods We performed a systematic literature review and conducted a retrospective cohort study that included patients with PHPT identified from the MEN 2A database at the University Medical Center of Utrecht, Utrecht, the Netherlands, between 1979 and 2009. Results The review describes the course of worldwide parathyroid surgical management in MEN 2A PHPT over the past 75 years, which has evolved from aggressive parathyroid resections to minimally invasive parathyroidectomy (MIP). The study cohort included 20 patients. Primary surgery for parathyroid disease in patients with MEN 2A (n = 16) included MIP (n = 6), conventional neck exploration with resection of enlarged parathyroid gland(s) (n = 4), and resection of 1 or more enlarged gland(s) during total thyroidectomy (n = 6). Thirteen patients were initially cured after the primary operation. Five patients experi enced persistent or recurrent PHPT. After MIP, 1 patient had persistent PHPT, but no patient developed recurrent PHPT during 5 years of follow-up. Five patients had hypoparathyroidism after subtotal or total parathyroidectomy with autotransplantation, but only 1 patient had transient hypoparathyroidism after MIP. One patient had transient recurrent laryngeal nerve injury after MIP. Conclusions Surgery for PHPT in patients with MEN 2A has evolved from aggressive conventional exploration of all 4 glands to focused MIP, which appears to be a feasible approach. MIP has low rates of persistent and recurrent PHPT, and the complications are minimal. (Endocr Pract. 2011;17:7-15)

PURPOSE: To evaluate the incremental value of arterial and equilibrium phase compared to hepatic venous phase multidetector row CT (MDCT) in the preoperative staging of colorectal liver metastases (CLM) and to determine the influence of the reference standard. MATERIALS AND METHODS: Fifty-three consecutive CLM patients underwent 16 detector row CT in hepatic arterial, venous, and equilibrium phase before surgery between March 2003 and January 2007. Detected lesions were characterized by three independent radiologists. The reference standard consisted of intraoperative palpation and ultrasound of the liver, and histopathological examination of the resected specimen. Additionally, data of follow-up CT was added. Statistical analysis was performed on a per-lesion basis. RESULTS: According to the reference standard 251 lesions were present, of which 203 (81%) were malignant (mean size: 29.4 ± 22.5 mm), and 41 (16%) were benign (mean size: 8.3 ± 7.7 mm). Sensitivity rates for CLM were comparable between triphasic and hepatic venous phase CT (P>0.05). Sensitivity for the detection of CLM lowered from 60-77% to 52-68% when follow-up CT was added to the reference standard. CONCLUSION: Arterial and equilibrium phase CT have no incremental value compared to hepatic venous phase MDCT in the detection of CLM. Sensitivity rates are, however, influenced by the type of reference standard used.

BACKGROUND & AIMS: Stem cells of normal tissues have resistance mechanisms that allow them to survive genotoxic insults. The stem cell-like cells of tumors are defined by their tumor-initiating capacity and may have retained these resistance mechanisms, making them resistant to chemotherapy. We studied the relationship between resistance to the topoisomerase I inhibitor irinotecan and tumor-initiating potential in human colonosphere cultures and in mice with colorectal xenograft tumors. METHODS: Colonosphere cultures were established from human colorectal tumor specimens obtained from patients who underwent colon or liver resection for primary or metastatic adenocarcinoma. Stem cell and differentiation markers were analyzed by immunoblotting and fluorescence-activated cell sorting. Clone- and tumor-initiating capacities were assessed by single-cell cloning and in immune-deficient mice. Sensitivity to irinotecan was assessed in vitro and in tumor-bearing mice. The relationship between drug resistance and tumor-initiating capacity was tested by fluorescence-activated cell sorting of colonosphere cells, based on expression of ABCB1 and aldehyde dehydrogenase (ALDH) activity. RESULTS: Colonosphere cultures had a high capacity to initiate tumors in mice and were resistant to irinotecan. Inhibition of the drug-efflux pump ABCB1 by PSC-833 allowed irinotecan to eradicate tumor-initiating cells. However, ABCB1 was expressed only by a subpopulation of differentiated tumor cells that did not form clones or tumors. Conversely, tumor-initiating cells were ABCB1-negative and were identified by high ALDH activity. Tumorigenic ALDHhigh/ABCB1negative cells generated nontumorigenic ALDHlow/ABCB1positive daughter cells in vitro and in tumor xenografts. PSC-833 increased the antitumor efficacy of irinotecan in mice. CONCLUSIONS: The resistance of colorectal tumors to irinotecan requires the cooperative action of tumor-initiating ALDHhigh/ABCB1negative cells and their differentiated, drug-expelling, ALDHlow/ABCB1positive daughter cells. [KEYWORDS: Adenocarcinoma/ drug therapy/metabolism/secondary, Aldehyde Dehydrogenase/metabolism, Animals, Antineoplastic Agents, Phytogenic/metabolism/ pharmacology, Blotting, Western, Camptothecin/ analogs & derivatives/metabolism/pharmacology, Cell Differentiation/ drug effects, Colonic Neoplasms/ drug therapy/metabolism/pathology, Cyclosporins/pharmacology, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm/drug effects, Flow Cytometry/methods, Humans, Liver Neoplasms/ drug therapy/m

Previously, when a conventional neck exploration (CNE) without preceding diagnostic imaging was the surgical treatment for patients with primary hyperparathyroidism (pHPT) solitary adenomas were observed in 69–88% of patients. The advent of minimally invasive parathyroidectomy (MIP), aiming at a preoperatively identified parathyroid abnormality may be associated with a different incidence of solitary and multiglandular parathyroid disease. In a cohort of 467 patients with sporadic pHPT who preferentially underwent MIP in four hospitals in the same geographical region, the incidence of solitary adenomas, multiple adenomas, and multiglandular hyperplasia (MGD) was evaluated. A total of 367 patients were scheduled for MIP; 100 patients underwent a planned CNE. The overall surgical success rate of the first operation was 93%, and the cumulative success rate, including a second operative procedure, was 99%. Normocalcemia resulted from removing 1 abnormal PG in 426 patients (91%) and more than one abnormal gland in 35 patients (8%). A parathyroid carcinoma was diagnosed in four of the 426 patients with a single abnormal gland. Four gland hyperplasia was observed in 1 patient. In hospitals where diagnostic workup usually consisted of ultrasound (US) and computed tomography (CT) the incidence of solitary adenomas was 88%, compared with 96% in hospitals where MIBI, US, and CT were used preoperatively (P = 0.007). A higher frequency of solitary adenomas was observed than historically reported. The extent of the preoperative workup influences the number of observed solitary adenomas.

The goal of our study was to evaluate, and identify factors associated with, the adequacy rate of fine-needle aspiration (FNA) cytology of thyroid tumors to improve the quality of the procedure. We reviewed 1,611 cytological pathology reports of thyroid tumors of 871 patients between January 1998 and August 2008. The overall cytological adequacy rate was 53.9%. The freehand technique had significantly higher adequacy rates than the ultrasound (US)-guided technique (P < 0.001) regardless of size, tumor type, multinodularity, or location. Aspiration, performing specialist (endocrinologist versus radiologist), and size were the factors associated with adequacy rates. US-guided FNA is recommended in previous articles, but results in our clinic were in favor of freehand FNA. US guidance is a way to improve adequacy rates, but we would like to stress the importance of other factors like operator experience, education, and quality control in one's own institution before implementing techniques. Diagn. Cytopathol. 2012;40:E21–E26. © 2010 Wiley Periodicals, Inc.

Follow-up diagnostic radioiodine whole-body scintigraphy (DxWBS) is still advised for high-risk patients with differentiated thyroid cancer. The aim of this study was to evaluate the additional value of DxWBS to stimulated thyroglobulin measurement in high-risk patients. Methods: The results of DxWBS and thyroglobulin measurements performed 6–12 mo after surgery and radioiodine thyroid remnant ablation in patients with differentiated thyroid cancer were retrospectively evaluated for 112 patients with high-risk features for recurrence (R3/T4 and N1). Results: One patient had an undetectable thyroglobulin level, with DxWBS results suggestive of cervical recurrence. DxWBS was found to be false-positive. Of the patients with detectable thyroglobulin levels, the DxWBS results were negative in 65 and positive in only 8. The 6 patients positive for thyroglobulin antibody had negative DxWBS results. The remaining patients had an undetectable thyroglobulin level and negative DxWBS results. Conclusion: Because undetectable stimulated thyroglobulin levels have a negative predictive value of 100%, DxWBS offers no information additional to recombinant human thyroid-stimulating hormone–stimulated thyroglobulin measurements in patients with high-risk differentiated thyroid cancer.

Background & Aims Recently, we have shown that micro-metastases, in the hypoxic transition zone surrounding lesions generated by radiofrequency ablation (RFA), display strongly accelerated outgrowth. CD95 is best known for its ability to induce apoptosis but can also promote tumorigenesis in apoptosis-resistant tumor cells. Therefore, we tested whether CD95 signaling plays a role in accelerated outgrowth of colorectal liver metastases following RFA. Methods Hypoxia-induced invasion was assessed in three-dimensional EGFP-expressing C26 tumor cell cultures by confocal microscopy. CD95 localization was tested by immunofluorescence. Invasion and outgrowth of liver metastases following RFA were analyzed by post-mortem confocal microscopy and by morphometric assessment of tumor load. Neutralization of CD95L was performed by using antibody MFL4. CD95 was suppressed by lentiviral RNA interference. The role of host CD95L was assessed using gld mice. Results Micro-metastases in the hypoxic transition zone following RFA displayed a highly invasive phenotype and increased expression of CD95 and CD95L. Hypoxia-induced tumor cell invasion in vitro increased the expression of CD95 and CD95L and induced translocation of CD95 to the invasive front. In vitro invasion, metastasis invasion, and accelerated tumor growth in the transition zone were strongly suppressed by neutralizing CD95L or by suppressing tumor cell CD95. In contrast, metastasis invasion and outgrowth were unaffected in gld mice. Conclusions Hypoxia causes autocrine activation of CD95 on colorectal tumor cells, thereby promoting local invasion and accelerated metastasis outgrowth in the hypoxic transition zone following RFA. Further pre-clinical work is needed to assess the role of CD95L neutralization, either alone or in combination with chemotherapy, in limiting aggressive recurrence of liver metastases following RFA.

Background The aim of this study was to evaluate the need of axillary staging in breast cancer patients showing exclusive lymphatic drainage to the internal mammary chain (IMC). Methods A total of 2203 patients treated for breast carcinoma in three participating hospitals between July 2001 and July 2008 were analyzed. Only patients showing drainage to the IMC on preoperative lymphoscintigraphy were included. The number of harvested IMC sentinel lymph nodes (SLNs), axillary SLNs, and metastases were recorded. Finally, the follow-up of this group of patients was analyzed. Results In 25/426 patients, drainage was exclusively to the IMC. Exploration of the axilla resulted in the harvesting of blue SLNs in 9 patients (36%) and the retrieval of an enlarged lymph node in 1 patient. In 4 of the remaining 15 patients, an axillary lymph node dissection (ALND) was done. Lymph node metastases were found in 3 patients who had blue axillary SLNs and in 1 patient who underwent ALND. In the 11 patients who had no blue SLNs and no ALND, no axillary recurrences were observed during follow-up (median = 26 months). Conclusions Proper staging of the axilla remains crucial in patients showing exclusive drainage to the IMC. When no axillary node can be retrieved, ALND remains subject to discussion.

Objectives Radiologic surveillance after resection of pancreatic ductal adenocarcinoma (PDAC) can provide information on the extent and location of disease recurrence. This systematic review and meta-analysis aims to give an overview of the literature on the diagnostic performance of different imaging modalities for the detection of recurrent disease after surgery for PDAC. Methods A systematic search was performed in PubMed, EMBASE and Cochrane Library up to 20 December 2017. All studies reporting on the diagnostic value of imaging modalities for the detection of local and/or distant disease recurrence during follow-up after resection of PDAC were eligible. Both histologic confirmation of recurrent PDAC and clinical confirmation by disease progression on follow-up imaging were considered as suitable reference standard. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used for critical appraisal of methodological quality. Diagnostic accuracy data were extracted or calculated and presented in forest plots. A bivariate random-effects model was used to calculate pooled estimates of sensitivity and specificity. Results A total of seven retrospective studies with 333 relevant patients were ultimately eligible for data extraction. Overall, the methodological quality of the included studies was acceptable. All seven articles described test results of contrast-enhanced CT, whilst five and three articles reported outcomes on diagnostic accuracy of FDG PET-CT and FDG PET-CT combined with contrast-enhanced CT, respectively. For CT, pooled estimates for sensitivity were 0.70 (95% CI 0.61–0.78) and for specificity 0.80 (95% CI 0.69–0.88). For FDG PET-CT, pooled estimates for sensitivity and specificity were 0.88 (95% CI 0.81–0.93) and 0.89 (95% CI 0.80–0.94), respectively. For FDG PET-CT in combination with contrast-enhanced CT, pooled estimates for sensitivity were 0.95 (95% CI 0.88–0.98) and for specificity 0.81 (95% CI 0.63–0.92). Conclusions According to the current literature, post-operative CT has a moderate diagnostic accuracy in the detection of recurrent disease. FDG PET-CT imaging could be of additional value when disease recurrence is suspected despite negative or equivocal CT findings. Nevertheless, evidence supporting radiologic surveillance after resection of PDAC is limited. Future prospective studies are needed to optimize surveillance strategies after resection of pancreatic cancer.

The high rate of interval malignancies urges for new screening methods for women at high risk for breast cancer. Nipple aspiration provides direct access to the breast tissue and its DNA, and therefore is a likely candidate, but clinical applications have been limited by the failure to obtain nipple aspiration fluid from most women. We performed oxytocin-assisted nipple aspiration in 90 women at increased risk for breast cancer based on family history or genetic test results (n = 63) and/or previous breast cancer (n = 34). Nipple fluid was obtained from 81/90 women (90%) and bilaterally in 77%. Mean discomfort rating was 0.6 (on a 0-10 scale), which was significantly lower than for mammography or MRI. These findings suggest that a new tool for biomarker detection in oxytocin-assisted nipple fluid of women at high risk for breast cancer is at hand.

Overwhelming clinical evidence supports the use of minimally invasive liver surgery (MILS), at least in case of minor hepatectomy, given its benefits in perioperative outcome measures and postoperative recovery (1,2). Conceptually, these findings make sense in resections where the volume of the liver remnant is large enough to not expect significant post-hepatectomy liver insufficiency and reconvalescence is mostly dependent on the surgical incision.

6 Background: The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) may reduce perioperative complications and improve functional recovery. Methods: In this randomized controlled trial, 112 patients with resectable intrathoracic esophageal cancer were randomly assigned to RAMIE or OTE. The composite primary endpoint was the occurrence of overall postoperative complications (modified Clavien–Dindo classification (MCDC) grade 2-5). Results: Postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) (RR 0.74 (0.57-0.96; P = 0.02). RAMIE resulted in a less median blood loss (400ml versus 568ml, P < 0.001), a lower percentage of surgery-related complications (RR 0.74 (0.57-0.96; P = 0.02), pulmonary complications (RR 0.54 (0.34-0.85; P = 0.005) and cardiac complications (RR 0.47 (0.27-0.83; P = 0.006)) and lower mean postoperative pain (visual analogue scale, 1.86 versus 2.62; p < 0.000) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group (RR 1.48 (1.03–2.13; P = 0.038)) with better quality of life score at discharge (mean difference quality of life score 13.4 (2.0-24.7, p = 0.02) and 6 weeks post-discharge (mean difference 11.1 quality of life score (1.0-21.1; p = 0.03)). Mean costs for RAMIE were €34.892 and mean costs for OTE were €39.463 (p = 0.07). Oncological outcomes at short term (radicality, number of lymph nodes) and long term (overall and disease-free survival) were equal at a medium follow up of 38 months. Conclusions: RAMIE resulted in a lower percentage of overall, surgery-related and (cardio)pulmonary complications with lower postoperative pain, better quality of life and a better short term postoperative functional recovery compared to OTE. Oncological outcomes were equal. This randomized controlled trial provides evidence for the use of RAMIE to improve postoperative outcome in patients with resectable esophageal cancer. Clinical trial information: NCT01544790.

Background Surgery for pancreatic cancer yields significant morbidity and mortality risks and survival is limited. Therefore, the influence of complications on quality of life (QoL) after pancreatic surgery is important. This study compares QoL in patients with and without severe complications after surgery for pancreatic (pre-)malignancy. Methods This prospective cohort study scored complications after pancreatic surgery according to the Clavien–Dindo system and the definitions of the International Study Group of Pancreatic Surgery. QoL was measured by the RAND36 questionnaire, the European Organization for Research and Treatment of Cancer core questionnaire (QLQ-C30) and the pancreas specific QLQ-PAN26. QoL in patients with severe complications was compared with QoL in patients with no or mild complications over a period of 12 months. Analysis was performed with linear mixed models for repeated measurements. Results Between March 2012 and July 2016, 137 patients were included. Sixty-eight patients (50%) had at least 1 severe complication. There were no statistically significant and clinically relevant differences between both groups in QoL up to 12 months after surgery. Conclusion In this study, no differences in QoL between patients with and without severe postoperative complications were encountered during the first 12 months after surgery for pancreatic (pre-)malignancy. Trial registration http://www.clinicaltrials.gov Identifier: NCT02175992 .

Contains fulltext : 88633.pdf (Publisher’s version ) (Closed access) BACKGROUND Multiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients. METHODS In a nationwide case-control study, all patients who underwent total thyroidectomy in the Netherlands under the age of 20 years were classified into standard (1), high (2), or very high risk (3) for MTC based on RET-mutation type. Disease-free patients were compared with those with recurrent disease. RESULTS A total of 93 patients were included in the study. Sixty-six percent had MTC on histology, the youngest being 1 year old. Codon 634 was most affected. Sixteen (18%) patients had persistent or recurrent disease, one of whom died. Significantly associated determinants of outcome in univariate analysis were higher age at surgery, no age-appropriate prophylactic surgery according to risk level, elevated preoperative calcitonin levels, affected codon, and the presence of lymph node metastases at surgery. On multivariate analysis only age of surgery was the single independent factor associated with persistent disease. CONCLUSIONS Prophylactic thyroidectomy beyond the recommended age is associated with persistent/recurrent disease. In addition, codon 634 mutation is associated with a high risk of recurrence requiring early surgery for all these patients. 01 april 2010

Background Parathyroid carcinoma is a rare entity that has diverse presentation and diverse treatments. This case-series highlights the atypical and diverse presentation of parathyroid carcinoma and stresses the importance of the diagnostic approach and intraoperative strategy. Methods We report three patients with parathyroid cancer. Results In one patient, a parathyroid lesion was found to be a parathyroid carcinoma intraoperatively, resulting in a change of operative strategy. In another, parathyroid carcinoma was suspected preoperatively and was treated accordingly. A third patient presented with an already a metastasized parathyroid carcinoma. Conclusion The diagnostic approach and intraoperative strategy are instrumental to determining the best treatment and yielding the best outcome.

In patients with esophageal cancer, radical surgical resection of the esophagus and surrounding lymph nodes is the only curative treatment option. Nevertheless, no standard surgical procedure exists. The aims of the present study were to gain insight into the frequencies of the various surgical techniques in esophageal cancer surgery as applied by surgeons throughout the world and to identify intercontinental differences regarding surgical techniques. Surgeons with particular interest in esophageal surgery, including members of the International Society for Diseases of the Esophagus, the European Society of Esophagology Group d'Etude Européen des Maladies de l'Oesophage and the OESO, were invited to participate in an online questionnaire. Questions were asked regarding approach to esophagectomy, extent of lymphadenectomy (LND), type of reconstruction, and anastomotic techniques. Subanalyses were performed for the surgeons' case volume per year, years of experience in esophageal cancer surgery, and continent. Of 567 invited surgeons, 269 participated, resulting in an overall response rate of 47%. The responders currently performing esophagectomies (n= 250; 44%), represented 41 countries across the six continents. Fifty-two percent of responders favor open transthoracic esophagectomy (TTE) over transhiatal esophagectomy (THE) or minimally invasive esophagectomy (MIE). THE is preferred by 26%, whereas MIE is favored by 14%. Eight percent have no preference for one approach to esophagectomy over the other. The extent of LND is most frequently the 2-field, routinely performed by 73% of surgeons. The continuity of the digestive tract is most frequently restored with a gastric conduit (85%). In open TTE, the anastomosis is routinely created in the neck by 56% of responders and in the chest by 40%. Cervical anastomoses are routinely fashioned by means of a handsewn technique by 65% of responders, while 35% favor the stapled technique. The cervical incision is predominantly performed vertically on the left side of the neck (routinely by 66%). A horizontal neck incision is routinely carried out by 19% of responders and a vertical right-sided incision by 11%. Significant differences in surgical techniques could be detected between low- and high-volume surgeons, between surgeons withor=10 versusor=21 years of experience, and between surgeons from different continents. In conclusion, currently the most commonly applied surgical procedure is the open right-sided transthoracic approach with a two-field lymphadenectomy, using a gastric tube anastomosed at the left side of the neck by means of a handsewn, end-to-side technique. The results of this survey provide baseline data for future research and for the development of international guidelines.

The sentinel lymph node (SLN) procedure in rectal cancer was studied according to the following parameters: identification rate, accuracy, sensitivity, false-negative rate, and upstaging percentages. The analyzed studies reported a large variation of nodal identification rates with overall high false-negative rates (ie, the percentage of rectal cancer patients in whom the SLN did not correctly represent the tumor status of the lymph node basin). These results are likely due to the anatomic localization of the rectum and disturbed lymphatic drainage after preoperative radiotherapy with or without concurrent chemotherapy. Therefore, the SLN procedure does not appear to be technically feasible in rectal cancer, and full lymphatic staging (as part of total mesorectal excision) should remain the standard for patient care.

A retrospective cost-effectiveness analysis was carried out, comparing retroperitoneal endoscopic and conventional adrenalectomy, which is based on a large group of patients, restricted in tumor size for the purpose of ensuring comparability.Between 1990 and 2004, 61 patients underwent either an endoscopic or open adrenalectomy for tumors smaller than 6 cm. A short-term, base cost-effectiveness analysis was performed to evaluate costs per day prevented, and a sensitivity analysis was calculated.Average recovery time, postoperative stay, and resumption to oral intake were significantly shorter in the endoscopic group, whereas operative time was longer. No major complications occurred in either group. In 3 endoscopic procedures conversion was indicated. The base cost-effectiveness ratio was 15.41 per day postoperative stay prevented by the endoscopic approach. The number needed to treat with endoscopic adrenalectomy to prevent 1 week of postoperative stay is 2.Retroperitoneal endoscopic adrenalectomy may be considered a cost-effective procedure, compared to the conventional open adrenalectomy.

Background Substantial recurrence rates following partial liver resection for colorectal liver metastases (CRM) imply that small metastases remain undetected using intraoperative ultrasound (IOUS). The aim of this study was to evaluate the additional value of contrast enhanced IOUS (CE-IOUS) when compared to preoperative contrast enhanced computed tomography (CE-CT) and IOUS in liver surgery for CRM. Methods After obtaining informed consent, 39 consecutive patients with CRM were included prospectively for evaluation. The study population consisted of 26 male and 13 female patients with a median (range) age of 62 (49–83) years. A lesion-per-lesion analysis was performed with histopathological examination as the reference standard after resection and follow-up for unresected lesions. The added value of CE-IOUS in correctly diagnosing malignant lesions was statistically evaluated, using receiver operating characteristic curves. Results A total of 234 lesions were identified, 137 of which were malignant, according to the reference standard. The addition of CE-IOUS did not improve the diagnostic accuracy when compared to the combination of CE-CT and IOUS (P = 0.617). In one of two patients with newly detected lesions on CE-IOUS the extent of resection changed. Conclusions The addition of CE-IOUS to preoperative CE-CT and IOUS does not improve the ability to characterize already detected lesions. In a small number of patients it appears to facilitate the detection of new metastatic lesions with implications on surgical strategy.

Background: Loss of epithelial morphology and the acquisition of mesenchymal characteristics may contribute to metastasis formation during colorectal tumorigenesis. The Wnt, Notch and TGFβ signaling pathways control tissue homeostasis and tumor development in the gut. The relationship between the activity of these pathways and the expression of epithelial and mesenchymal markers was investigated in a series of primary colorectal tumors and their corresponding metastases.Methods: Tissue samples of primary colorectal tumors, normal colonic mucosa, and regional and systemic metastases were processed for immunohistochemistry in a tissue microarray format. The expression of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin) markers was related to markers of Wnt (β-catenin), Notch (HES1) and TGFβ (phospho-SMAD2) signalling. In addition, the KRAS mutation status was assessed.Results: When compared to normal mucosa, primary colorectal tumors showed a marked increase in the levels of cytoplasmic vimentin and nuclear β-catenin, phospho-SMAD2 and HES1. Increased vimentin expression correlated with the presence of oncogenic KRAS and with nuclear β-catenin. The corresponding liver, lymph node, brain and lung metastases did not express vimentin and displayed significantly lower levels of nuclear phospho-SMAD2 and HES1, while retaining nuclear β-catenin.Conclusions: Primary colorectal carcinomas display aberrant expression of vimentin, and have activated Notch and TGFβ signaling pathways. Surprisingly, many regional and distant metastases have lost nuclear HES1 and pSMAD2, suggesting that the activity of the Notch and TGFβ pathways is reduced in secondary colorectal tumors.

Tissue microarray (TMA) technology has been developed to facilitate high-throughput immunohistochemical and in situ hybridization analysis of tissues by inserting small tissue biopsy cores into a single paraffin block. Several studies have revealed novel prognostic biomarkers in esophageal squamous cell carcinoma (ESCC) by means of TMA technology, although this technique has not yet been validated for these tumors. Because representativeness of the donor tissue cores may be a disadvantage compared to full sections, the aim of this study was to assess if TMA technology provides representative immunohistochemical results in ESCC. A TMA was constructed containing triplicate cores of 108 formalin-fixed, paraffin-embedded squamous cell carcinomas of the esophagus. The agreement in the differentiation grade and immunohistochemical staining scores of CK5/6, CK14, E-cadherin, Ki-67, and p53 between TMA cores and a subset of 64 randomly selected donor paraffin blocks was determined using kappa statistics. The concurrence between TMA cores and donor blocks was moderate for Ki-67 (kappa = 0.42) and E-cadherin (kappa = 0.47), substantial for differentiation grade (kappa = 0.65) and CK14 (kappa = 0.71), and almost perfect for p53 (kappa = 0.86) and CK5/6 (kappa = 0.93). TMA technology appears to be a valid method for immunohistochemical analysis of molecular markers in ESCC provided that the staining pattern in the tumor is homogeneous.

To determine, in a meta-analysis, the diagnostic performance of contrast material-enhanced magnetic resonance (MR) imaging in patients with breast lesions.Studies to assess the diagnostic performance of MR imaging in patients suspected of having breast cancer who underwent MR imaging and biopsy from January 1985 through March 2005 were reviewed for inclusion. A summary receiver operating characteristic curve was constructed, and pooled weighted estimates of sensitivity and specificity were calculated by using the recently developed bivariate approach for diagnostic meta-analysis.Of 251 eligible studies, 44 were included in the meta-analysis (sample size range, 14-821; cancer prevalence, 23%-84%). Pooled weighted estimates of sensitivity and specificity were 0.90 (95% confidence interval: 0.88, 0.92) and 0.72 (95% confidence interval: 0.67, 0.77), respectively. The performance of breast MR imaging was influenced by the prevalence of cancer in the studied population (P = .05) and by whether two criteria (ie, morphology, enhancement, and kinetic enhancement pattern)--versus one or three criteria--were used to differentiate benign from malignant lesions (P = .02).MR imaging of the breast has high sensitivity and lower specificity in the evaluation of breast lesions.http://radiology.rsnajnls.org/cgi/content/full/2461061298/DC1.

The COBRA (COre Biopsy after RAdiological localization) study showed that in a controlled study setting, stereotactic large core needle biopsy (LCNB) is as reliable for diagnosing nonpalpable breast lesions as open surgical biopsy. In the present study, we evaluated the diagnostic performance of stereotactic LCNB in routine clinical practice. Between February 2000 and June 2002, data on all patients (n = 955) with nonpalpable breast lesions referred for LCNB were collected. High risk underestimate rate, ductal carcinoma in situ (DCIS) underestimate rate and sensitivity rate after 2 years were calculated. The usefulness of the COBRA guidelines in clinical practice was determined. Nine hundred five successful biopsies were performed in 874 patients. Of the high-risk lesions, 27% were found to be carcinomas on open biopsy, which is comparable to the results of the COBRA study (23%). The DCIS underestimate rate (28%) was higher than found in the COBRA study (17%). No carcinomas were missed after a follow-up period of 2 years. Ninety-six percent of patients were treated according to the COBRA guidelines. The diagnostic performance of stereotactic LCNB in patients with nonpalpable breast lesions seems to be comparable in a controlled study setting and routine clinical practice.

Ischemia/reperfusion (I/R) is often inevitable during hepatic surgery and may stimulate the outgrowth of colorectal micrometastases. Postischemic microcirculatory disturbances contribute to I/R damage and may induce prolonged tissue hypoxia and consequent stabilization of hypoxia-inducible factor (HIF)-1alpha. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1alpha to I/R-accelerated tumor growth. Partial hepatic I/R attributable to temporary clamping of the left liver lobe induced microcirculatory failure for up to 5 days. This was accompanied by profound and prolonged perinecrotic tissue hypoxia, stabilization of HIF-1alpha, and massive perinecrotic outgrowth of pre-established micrometastases. Restoration of the microcirculation by treatment with Atrasentan and L-arginine minimized hypoxia and HIF-1alpha stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1alpha by the HSP90 inhibitor 17-DMAG caused an increase in tissue necrosis but reduced I/R-stimulated tumor growth by more than 70%. In conclusion, prevention of postischemic microcirculatory disturbances and perinecrotic hypoxia reduces the accelerated outgrowth of colorectal liver metastases after I/R. This may, at least in part, be attributed to the prevention of HIF-1alpha stabilization. Prevention of tissue hypoxia or inhibition of HIF-1alpha may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery.

The aim of this study was to investigate whether younger age at surgery is associated with the increased incidence of postoperative complications after prophylactic thyroidectomy in pediatric patients with multiple endocrine neoplasia (MEN) 2. The shift toward earlier thyroidectomy has resulted in significantly less medullary thyroid carcinoma (MTC)-related morbidity and mortality. However, very young pediatric patients might have a higher morbidity rate compared with older patients. Hardly any literature exists on complications in the very young. A retrospective single-center analysis was performed on the outcomes of MEN2 patients undergoing a prophylactic total thyroidectomy at the age of 17 or younger. Forty-one MEN2A and 3 MEN2B patients with thyroidectomy after January 1993 and at least 6 months of follow-up were included, subdivided in 9 patients younger than 3 years, 15 patients 3 to 6 years, and 20 patients older than 6 years. Postoperative hypocalcemia and other complications were registered. Twelve (27%) patients developed transient hypocalcemia and 9 (20%) patients suffered from permanent hypocalcemia, with a nonsignificant trend toward higher incidence with decreasing age. Three (7%) patients had other complications, of whom 2 were younger than 3 years. For patients younger than 3 years, the average length of stay (LOS) was 6.7 days, versus 1.7 and 3.5 days, respectively, for the older patient groups (P

Thyroid nodules are frequently found and pose a dilemma to the clinician, as only a few harbor a malignancy, and the majority of nodules are benign. The standard work-up of thyroid nodules consists of ultrasound and fine needle aspiration (FNA), both having their limitations [1, 2]. In particular, ultrasound lacks criteria for determining whether a nodule is malignant [3]. FNA shows good sensitivities and specificities, but inconclusive and indeterminate results are frequently found, resulting in the need for a diagnostic thyroid lobectomy to obtain a final diagnosis [4]. In the long lasting search to reduce the number of invasive diagnostic procedures, real-time qualitative elastography has been proposed to fulfill this need. Elastography determines the elasticity of the thyroid nodule. Soft nodules are assumed to be benign, whereas hard nodules are considered to be malignant. Qualitative elastography represents the elasticity of the nodule in a colored image projected over the ultrasound image. Multiple elasticity scoring systems are used, which makes reviewing literature challenging. Most common is the 4-point scale developed by Asteria et al., in which elastography 1 (ES 1) is assigned to nodules with elasticity in the entire nodule, ES 2 is assigned to nodules with elasticity in a large portion of the nodule, ES 3 is assigned to nodules with stiffness in a large portion of the nodule, and ES 4 is assigned to hard nodules. A cut-off between ES 2 and ES 3 is widely accepted to discriminate benign from malignant nodules [5]. Studies on thyroid nodule elastography have focused on different target populations: (1) patients referred for FNA with the aim to reduce the number of FNAs, and (2) patients with an indeterminate FNA result (i.e., Bethesda classification III or IV), with the aim to reduce the number of futile lobectomies. Recently, we performed a meta-analysis of studies that investigated the first population: patients referred for FNA. The aim of this study was to determine whether elastography could determine the nature of thyroid nodules and thereby identify those that require further analysis by FNA [6]. In this study, analyzing twenty reports including 3908 nodules, two different cut-offs were examined. The first was the standard cut-off between ES 2 and 3. The second used a cut-off between ES 1 and 2, meaning that only the completely soft nodules were considered benign and the rest of the nodules as potentially malignant. Both cut-offs showed that elastography is an excellent tool to diagnose benignity, with a respective negative predictive value (NPV) of 97 and 99 %. Based on these outcomes, it was concluded that in these cases FNA could be omitted safely. However, considering the modest positive predictive value (PPV) of only 40 % of elastography, this implies that any nodule with an elastography score above ES 2 requires further analysis [6]. In the current issue of Endocrine, Trimboli et al. published an extensive review and meta-analysis on nodules with an indeterminate FNA [7]. Although the majority of these nodules are benign, around one in four harbors a malignancy [4]. Diagnostic lobectomies are often Jakob W. Kist and Sjoerd Nell have contributed equally to the manuscript.

Purpose: Chemotherapy treatment of metastatic colon cancer ultimately fails due to development of drug resistance. Identification of chemotherapy-induced changes in tumor biology may provide insight into drug resistance mechanisms. Experimental Design: We studied gene expression differences between groups of liver metastases that were exposed to preoperative chemotherapy or not. Multiple patient-derived colonosphere cultures were used to assess how chemotherapy alters energy metabolism by measuring mitochondrial biomass, oxygen consumption, and lactate production. Genetically manipulated colonosphere-initiated tumors were used to assess how altered energy metabolism affects chemotherapy efficacy. Results: Gene ontology and pathway enrichment analysis revealed significant upregulation of genes involved in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in metastases that were exposed to chemotherapy. This suggested chemotherapy induces a shift in tumor metabolism from glycolysis towards OXPHOS. Indeed, chemotreatment of patient-derived colonosphere cultures resulted in an increase of mitochondrial biomass, increased expression of respiratory chain enzymes, and higher rates of oxygen consumption. This was mediated by the histone deacetylase sirtuin-1 (SIRT1) and its substrate, the transcriptional coactivator PGC1α. Knockdown of SIRT1 or PGC1α prevented chemotherapy-induced OXPHOS and significantly sensitized patient-derived colonospheres as well as tumor xenografts to chemotherapy. Conclusions: Chemotherapy of colorectal tumors induces a SIRT1/PGC1α-dependent increase in OXPHOS that promotes tumor survival during treatment. This phenomenon is also observed in chemotherapy-exposed resected liver metastases, strongly suggesting that chemotherapy induces long-lasting changes in tumor metabolism that potentially interfere with drug efficacy. In conclusion, we propose a novel mechanism of chemotherapy resistance that may be clinically relevant and therapeutically exploitable. Clin Cancer Res; 21(12); 2870–9. ©2015 AACR.

Background Early oral feeding is currently considered the optimal routine feeding strategy after pancreatoduodenectomy (PD). Some have suggested that patients with preoperative symptoms of gastric outlet obstruction (GOO) who undergo PD have such a high risk of developing delayed gastric emptying that these patients should rather receive routine postoperative tube feeding. The aim of this study was to determine whether clinical outcomes after PD in these patients differ between postoperative early oral feeding and routine tube feeding. Methods We analyzed a consecutive multicenter cohort of patients with preoperative symptoms of GOO undergoing PD (2010–2013). Patients were categorized into two groups based on the applied postoperative feeding strategy (dependent on their center's routine strategy): early oral feeding or routine nasojejunal tube feeding. Results Of 497 patients undergoing PD, 83 (17%) suffered from preoperative symptoms of GOO. 49 patients received early oral feeding and 29 patients received routine tube feeding. Time to resumption of adequate oral intake (primary outcome; 14 vs. 12 days, p = 0.61) did not differ between these two feeding strategies. Furthermore, overall complications and length of stay were similar in both groups. Of the patients receiving early oral feeding, 24 (49%) ultimately required postoperative tube feeding. In patients with an uncomplicated postoperative course, early oral feeding was associated with shorter time to adequate oral intake (8 vs. 12 days, p = 0.008) and shorter hospital stay (9 vs. 13 days, p Conclusion Also in patients with preoperative symptoms of GOO, early oral feeding can be considered the routine feeding strategy after PD.

Context Only a minority of thyroid nodules is malignant; nevertheless, many invasive diagnostic procedures are performed to distinguish between benign and malignant nodules. Qualitative ultrasound elastography is a non-invasive technique to evaluate thyroid nodules. Objective To investigate the diagnostic value of qualitative elastography in distinguishing benign from malignant thyroid nodules in patients referred for fine-needle aspiration (FNA). Data sources A systematic literature search (PubMed, Embase and Cochrane Library) was performed. Study selection Included studies reported thyroid nodule elastography color scores and the related cytologic or histologic findings in patients with a thyroid nodule referred for FNA. Data extraction Two independent reviewers extracted study data and assessed study quality. Pooled sensitivities and specificities of different populations were calculated using a bivariate Bayesian framework. Data Synthesis Twenty studies including thyroid nodules were analyzed. Pooled results of elastography indicate a summary sensitivity of 85% (95% confidence interval [CI], 79–90%) and specificity of 80% (95% CI, 73–86%). The respective pooled negative predictive and positive predictive values were 97% (95% CI, 94–98%) and 40% (95% CI, 34–48%). The pretest probability of a benign nodule was 82%. Only 3.7% of the false-negative nodules was a follicular thyroid carcinoma. A pooled negative predictive value of 99% (95% CI, 97–100%) was found when only complete soft nodules (Asteria elastography 1) were classified as benign, which included 14% of the studied population. Conclusions Elastography has a fair specificity and sensitivity for diagnostic accuracy. Its major strength entails the detection of benignity, especially when only completely soft nodules are qualified as benign. The outcomes of our analysis show that FNA could safely be omitted in patients referred for analysis of their thyroid nodule when elastography shows it to be completely soft (Asteria elastography 1). This could prevent unnecessary invasive diagnostic procedures in a substantial portion of patients .

Background & Aims Colon tumors contain a fraction of undifferentiated stem cell−like cancer cells with high tumorigenic potential. Little is known about the signals that maintain these stem-like cells. We investigated whether differentiated tumor cells provide support. Methods We established undifferentiated colonosphere cultures from human colon tumors and used them to generate stably differentiated cell lines. Antibody arrays were used to identify secreted factors. Expression of genes involved in stemness, differentiation, and the epithelial to mesenchymal transition was measured using reverse transcription quantitative polymerase chain reaction. Expression of KIT in human tumors was analyzed with gene expression arrays and by immunohistochemistry. Colonospheres were injected into the livers of CBy.Cg-Foxn1nu/J mice. After liver tumors had formed, hypoxia was induced by vascular clamping. Results Differentiated cells from various tumors, or medium conditioned by them, increased the clonogenic capacity of colonospheres. Stem cell factor (SCF) was secreted by differentiated tumor cells and supported the clonogenic capacity of KIT + colonosphere cells. Differentiated tumor cells induced the epithelial to mesenchymal transition in colonosperes; this was prevented by inhibition of KIT or SCF. SCF prevented loss of clonogenic potential under differentiation-inducing conditions. Suppression of SCF or KIT signaling greatly reduced the expression of genes that regulate stemness and the epithelial to mesenchymal transition and inhibited clonogenicity and tumor initiation. Bioinformatic and immunohistochemical analyses revealed a correlation between expression of KIT- and hypoxia-related genes in colon tumors, which was highest in relapse-prone mesenchymal-type tumors. Hypoxia induced expression of KIT in cultured cells and in human colon tumor xenografts and this contributed to the clonogenic capacity of the tumor cells. Conclusions Paracrine signaling from SCF to KIT, between differentiated tumor cells and undifferentiated stem-like tumor cells, helps maintain the stem-like features of tumor cells, predominantly under conditions of hypoxia.