Altered biodistribution of [68Ga]Ga-DOTA-TOC during somatostatin analogue treatment.

PURPOSE: The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. METHODS: Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. RESULTS: Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5 days, there was a significantly higher bloodpool activity than at longer intervals. CONCLUSION: Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5 days after the injection of lanreotide.

The brisk-standing-test for long QT syndrome in prepubertal school children: defining normal.

Aims: Long QT syndrome (LQTS) is associated with malignant arrhythmias and sudden death from birth to advanced age. Prolongation of the QT-interval, may however be concealed on standard electrocardiograms (ECG). The brisk-standing-test (BST) was developed to guide LQTS-diagnosis and treatment in adults. We hypothesized that the BST may be used in prepubertal children to identify LQTS subjects. Accordingly, reference values for the BST should be available to prevent incorrect diagnosis and treatment of LQTS. In this study, we aim to present reference values for prepubertal children. Methods and results: Healthy, prepubertal children, aged 7-13 years underwent a standard supine resting ECG and during continuous ECG recording performed a BST. The QT-interval and heart rate corrected QTc were measured during the different BST stages. Fifty-seven children, 29 boys (10.2 ± 1.1 years) and 28 girls (9.9 ± 1.1 years) were included. Baseline characteristics and response to standing were not statistically different for boys and girls: mean supine pre-standing heart rate 74 ± 9 vs. 77 ± 9 bpm, supine pre-standing QTc 406 ± 27 vs. 407 ± 17 ms, maximal heart rate upon standing 109 ± 11 vs. 112 ± 11 bpm, and QTc at maximal heart rate 484 ± 29 vs. 487 ± 35 ms. The QT interval corrected for heart rate-prolongation at maximal tachycardia after standing was 79 ± 26 (19-144) ms, which is significantly longer than previously published values in adults (50± 30 ms). Conclusions: The QT interval corrected for heart rate prolongation after brisk standing in healthy prepubertal children is more pronounced than in healthy adults. This finding advocates distinct prepubertal cut-off values because using adult values for prepubertal children would yield false positive results with the risk of incorrect LQTS-diagnosis and overtreatment.

Detection of optimal PEEP for equal distribution of tidal volume by volumetric capnography and electrical impedance tomography during decreasing levels of PEEP in post cardiac-surgery patients.

BACKGROUND: Homogeneous ventilation is important for prevention of ventilator-induced lung injury. Electrical impedance tomography (EIT) has been used to identify optimal PEEP by detection of homogenous ventilation in non-dependent and dependent lung regions. We aimed to compare the ability of volumetric capnography and EIT in detecting homogenous ventilation between these lung regions. METHODS: Fifteen mechanically-ventilated patients after cardiac surgery were studied. Ventilator settings were adjusted to volume-controlled mode with a fixed tidal volume (Vt) of 6-8 ml kg(-1) predicted body weight. Different PEEP levels were applied (14 to 0 cm H2O, in steps of 2 cm H2O) and blood gases, Vcap and EIT were measured. RESULTS: Tidal impedance variation of the non-dependent region was highest at 6 cm H2O PEEP, and decreased significantly at 14 cm H2O PEEP indicating decrease in the fraction of Vt in this region. At 12 cm H2O PEEP, homogenous ventilation was seen between both lung regions. Bohr and Enghoff dead space calculations decreased from a PEEP of 10 cm H2O. Alveolar dead space divided by alveolar Vt decreased at PEEP levels ≤6 cm H2O. The normalized slope of phase III significantly changed at PEEP levels ≤4 cm H2O. Airway dead space was higher at higher PEEP levels and decreased at the lower PEEP levels. CONCLUSIONS: In postoperative cardiac patients, calculated dead space agreed well with EIT to detect the optimal PEEP for an equal distribution of inspired volume, amongst non-dependent and dependent lung regions. Airway dead space reduces at decreasing PEEP levels.

Pulmonary neuroendocrine neoplasms with well differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature.

OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggested. We describe 7 of those cases analyzed for pRb expression and overall survival. MATERIAL AND METHODS: Cases with well differentiated morphology, but MI > 10/2mm2 and/or Ki-67 proliferation index >20% were selected based on pathology reports of consecutive NENs in our university medical center (Maastricht UMC+, 2007-2018) and confirmed by pathological review. Immunohistochemistry was performed to assess pRb expression. RESULTS: Seven stage IV cases were included in this study. Median overall survival was 8 months (95% confidence interval 5-11 months). Cases with well differentiated morphology and preserved pRb expression (4/7) had a median overall survival of 45 months. CONCLUSION: A subgroup of pulmonary NENs with well differentiated morphology but high proliferation rate likely exists. pRb staining might be helpful to predict prognosis, but clinical relevance remains to be studied.

Exploring imaging features of molecular subtypes of large cell neuroendocrine carcinoma (LCNEC).

OBJECTIVES: Radiological characteristics and radiomics signatures can aid in differentiation between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). We investigated whether molecular subtypes of large cell neuroendocrine carcinoma (LCNEC), i.e. SCLC-like (with pRb loss) vs. NSCLC-like (with pRb expression), can be distinguished by imaging based on (1) imaging interpretation, (2) semantic features, and/or (3) a radiomics signature, designed to differentiate between SCLC and NSCLC. MATERIALS AND METHODS: Pulmonary oncologists and chest radiologists assessed chest CT-scans of 44 LCNEC patients for 'small cell-like' or 'non-small cell-like' appearance. The radiologists also scored semantic features of 50 LCNEC scans. Finally, a radiomics signature was trained on a dataset containing 48 SCLC and 76 NSCLC scans and validated on an external set of 58 SCLC and 40 NSCLC scans. This signature was applied on scans of 28 SCLC-like and 8 NSCLC-like LCNEC patients. RESULTS: Pulmonary oncologists and radiologists were unable to differentiate between molecular subtypes of LCNEC and no significant differences in semantic features were found. The area under the receiver operating characteristics curve of the radiomics signature in the validation set (SCLC vs. NSCLC) was 0.84 (95% confidence interval (CI) 0.77-0.92) and 0.58 (95% CI 0.29-0.86) in the LCNEC dataset (SCLC-like vs. NSCLC-like). CONCLUSION: LCNEC appears to have radiological characteristics of both SCLC and NSCLC, irrespective of pRb loss, compatible with the SCLC-like subtype. Imaging interpretation, semantic features and our radiomics signature designed to differentiate between SCLC and NSCLC were unable to separate molecular LCNEC subtypes, which underscores that LCNEC is a unique disease.

Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype.

INTRODUCTION: Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40-80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small-cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small-cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up. METHODS: Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next-generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1). RESULTS: All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5-18.5 months). Mean Ki-67 PI was 59% (range 15-100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11-23 months) vs 5 months (95% CI 0.7-9 months), P = 0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified, and both SCLC-like (n = 6) and NSCLC-like (n = 2) subtypes were present. No MEN1 mutation was found. CONCLUSION: Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype.

Prevalence and prognostic value of PD-L1 expression in molecular subtypes of metastatic large cell neuroendocrine carcinoma (LCNEC).

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare tumor with high mutational burden. Two subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 group and the TP53 and STK11/KEAP1 group. We investigated PD-L1 and CD8 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes. METHODS: Immunohistochemical (IHC) analysis for PD-L1 and CD8 was performed on pathological reviewed pretreatment tumor samples for 148 stage IV LCNEC. Data about targeted next generation sequencing (TNGS) (TP53, RB1, STK11, KEAP1) and IHC for RB1 were available for most tumors. IHC staining for PD-L1 (DAKO 28-8) was performed and scored positive if tumors showed ≥1% membranous staining. CD8 was scored for intra-tumor T-cells and stromal cells. RESULTS: PD-L1 IHC expression data could be generated in 98/148 confirmed LCNEC samples along with RB1 IHC (n = 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); 5 (5%) with ≥50%. PD-L1 expression was equal in RB1 mutated and RB1 wildtype tumors. None of STK11 mutated tumors (n = 7) expressed PD-L1. PD-L1 expression was correlated with superior overall survival (OS), hazard ratio 0.55 ((95% Confidence Interval 0.31-0.96), p = 0.038). Intra-tumor CD8 was associated with PD-L1 expression (p = 0.021) and stromal and intra-tumor CD8 were correlated with improved OS (p = 0.037 and p = 0.026 respectively). CONCLUSIONS: PD-L1 expression was positive in 16% of stage IV LCNEC tumors. This was independent of molecular subtype but associated with CD8 expression. In LCNEC patients with PD-L1 and/or CD8 expression superior OS was observed.

DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile.

OBJECTIVES: For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics. MATERIALS AND METHODS: Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if ≥1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data. RESULTS: DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0-160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3+ in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3+ in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3+ . Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers. CONCLUSION: The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.

Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma--predominant testis cancer.

PURPOSE: To determine the incidence of metastatic disease and usage of chemotherapy (adjuvant or metastatic) after primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) I embryonal carcinoma (EC)-predominant testicular cancer. EC predominance was defined as the presence of EC at a level greater than that of any other histologic diagnosis. PATIENTS AND METHODS: All CS I patients with nonseminomatous germ cell tumors who underwent RPLND at Indiana University from 1990 to 1995 were reviewed retrospectively. RESULTS: Two-year follow-up was available for 292 of 320 patients. EC-predominant disease was found in 125 (42.8%) of 292. Eighty-five (68.0%) of 125 patients with EC-predominant disease had pathologic stage (PS) I, and 18 (21.2%) of this group of 85 relapsed. A significantly lower PS I relapse rate of 3% was found for patients who had non-EC-predominant disease (P <.0001). PS II disease was more frequent in patients with EC predominance, as 40 (32.0%) of 125 had retroperitoneal metastases, compared with 26 (15.6%) of 167 patients with a non-EC-predominant histologic diagnosis (P =.0024). Chemotherapy was administered to 48 (38.4%) of the 125 patients with CS I EC-predominant disease after RPLND. This included 25 CS I patients with PS II disease who received adjuvant chemotherapy in addition to 23 patients who subsequently required chemotherapy for relapse after RPLND. Ten (66. 6%) of 15 PS II EC-predominant patients were cured by surgery alone. Currently, all 125 EC-predominant patients are disease-free. CONCLUSION: Patients with CS I EC-predominant disease are at a relatively high risk for metastatic disease.

Radical esophageal resection for adenocarcinoma arising in Barrett's esophagus.

BACKGROUND: Esophagectomy with extensive lymph node dissection is the best way to give Barrett's patients with locally advanced adenocarcinoma a good chance of cure. MATERIAL AND METHODS: Fifty-five patients underwent subtotal (n = 47) or distal (n = 8) esophagectomy for Barrett's adenocarcinoma (n = 43) or high-grade dysplasia (HGD) (n = 12). Thirteen patients (23.6%) never had had any reflux symptom before disclosure of the neoplastic lesion, and 20 patients (36.4%) had esophageal shortening. Ro resections (n = 50) included removal of the esophageal tube en bloc with the locoregional lymph nodes. RESULTS: An invasive carcinoma was found in the resected specimen of 4 of the 12 patients operated on for HGD. Two of the 5 patients whose metaplasia was surveyed endoscopically were operated on for an advanced lesion (T2N1, T3N1) because they had not strictly complied with the proposed schedule. One of the 4 patients whose HGD was followed up endoscopically until disclosure of deeper mucosal invasion had positive lymph nodes at operation. The prevalence of early lesions (Tis, T1, T2, No) was 7.4% in patients with tumor-related symptoms versus 85.7% in those having unrelated symptoms (P = 0.0000), which resulted in a 5-year survival rate of 33.8% and 82.4%, respectively (P = 0.0012). Five-year survival rate after Ro resection made for invasive carcinoma was 59.3% (all cases), 73.1% (No), 61.5% (< or =5 positive lymph nodes), and 0% (>5 positive lymph nodes). CONCLUSIONS: High-grade dysplasia is an indication for esophageal resection. Early detection of the neoplastic transformation of Barrett's metaplasia prior to the onset of obstructive symptoms gives the best chance of cure. Esophagectomy with radical lymph node clearance is capable of curing a large proportion of the patients having no or a limited number of metastatic lymph nodes.

Soft cervical disc herniation. Influence of cervical spinal canal measurements on development of neurologic symptoms.

STUDY DESIGN: In 100 consecutive patients who underwent surgery because of soft cervical disc herniation, the sagittal and transverse diameters, the area of the bony cervical spinal canal, the sagittal diameter of the hernia, and the minimal bony intervertebral foramen diameter were measured by computed tomography. The data were compared with measurements from a control group of 35 matched healthy individuals. OBJECTIVES: To evaluate the relation between the severity of concurrent neurologic symptoms and the sagittal and transverse diameters, the cross-sectional area of the bony spinal canal, the sagittal diameter of the hernia, and diameter of the minimal bony intervertebral foramen in patients with soft cervical disc herniation. SUMMARY OF BACKGROUND DATA: Traumatic injury and spondylotic changes have a far greater impact on the spinal cord and nerve roots if the sagittal diameter of the bony cervical spinal canal is small. However, in the case of soft cervical disc herniation, no computer tomographic measurements are available for sagittal and transverse diameters, cross-sectional area of the bony spinal canal, sagittal diameter of the hernia, and diameter of the minimal bony intervertebral foramen in relation to the severity of concurrent neurologic symptoms. METHODS: Computed tomography was used to measure sagittal and transverse diameters, cross-sectional area of the bony cervical spinal canal, sagittal diameter of the hernia, and diameter of the minimal bony intervertebral foramen in 100 patients with symptomatic monosegmental cervical soft disc herniation. All patients had undergone an anterior discectomy with removal of the hernia and subsequent interbody fusion using an autologous bone graft taken from the iliac crest. RESULTS: A mean sagittal diameter of the bony cervical spinal canal of 12.9 mm was found, indicating a certain degree of developmental stenosis. Patients with motor disturbances had a significantly smaller sagittal diameter of the bony spinal canal than did patients without motor disturbances. There was a linear correlation between the sagittal diameter of the bony cervical spinal canal and that of the hernia. The sagittal diameter, the area of the bony spinal canal, and diameter of the minimal bony intervertebral foramen were significantly smaller in patients with soft cervical disc herniation than in the control group. CONCLUSIONS: Results from this study strongly suggest that the degree and severity of neurologic symptoms accompanying cervical soft disc herniation are inversely related to the sagittal diameter and the area of the bony cervical spinal canal. The latter area is reduced in cases of developmental stenosis or because of soft disc herniation. Moreover, patients with soft cervical disc herniation have a significantly smaller sagittal diameter of the bony spinal canal, a significantly smaller minimal bony intervertebral foramen diameter, and a significantly smaller cross-sectional area of the bony cervical canal than do healthy matched individuals.

Surgical management of the osteoradionecrotic mandible with free vascularised composite flaps.

Osteoradionecrosis (ORN) of the mandible is a serious sequel to radiotherapy administered for malignant neoplasms of the head and neck. In a retrospective/prospective study, 28 patients with mandibular defects due to ORN were reviewed. Monocortical and bicortical defects as well as pathological fractures were reconstructed by means of a free serratus anterior/rib (n = 8) or a vascularised iliac crest flap (n = 25). All the former survived; a pathological fracture, however, occurred postoperatively in 2 of the patients (25%). Five iliac crests were lost (20%). The remaining bone struts healed well. The donor site morbidity was very low. Clinical and radiological longterm follow-up showed that a very acceptable functional and cosmetic result was achieved in all cases. Progress of ORN was prevented in ca. 90% of all patients. The radiological follow-up was facilitated with the use of high-resolution CT-scans.

Extensive lymph node clearance for cancer of the esophagus or cardia: merits and limits in reference to 5-year absolute survival.

BACKGROUND/AIMS: The present study evaluates both merits and limits of extensive lymph node clearance in the mediastinum and upper abdomen on patients operated on more than 5 years ago. MATERIALS AND METHODS: One hundred forty-four esophageal cancer patients underwent subtotal (n = 97) or distal (n = 47) esophageal resection more than 5 years ago. Twenty-six patients operated on in a curative attempt were given radiotherapy (n = 14) or radiochemotherapy (n = 12). RESULTS: Esophagectomy with extensive lymph node clearance was feasible in 102 of the 144 patients (70.8%). In-hospital mortality was 1.4%. Thirty-six patients lived more than 5 years, ie. 25% of all the esophagectomized patients and 35.3% (36/102) of those who were operated on in a curative attempt. Five-year absolute survival was 38.4% after combined therapy v.s. 34.2% after surgery alone (p > 0.05). In the latter instance, it was 57.1% for those patients with normal lymph nodes v.s. 14.6% for those with metastatic lymph nodes, and it was 64% for those with non-transmural tumors v.s. 19.6% for those with transmural tumors. One half of those patients who were not given adjuvant therapy following esophagectomy with extensive lymph node clearance died of neoplastic spread, namely distant metastases (27.6%), cervical spread (3.9%), and local recurrence (10.5%). CONCLUSIONS: Esophagectomy with extensive lymph node clearance is not feasible in 30% of the patients in whom it is attempted, and it does not prevent further neoplastic spread in one half of those in whom it is feasible. It is capable of curing 15 to 20% of those patients with locally advanced neoplasms and shelters 90% of the patients from local recurrence.

Laparoscopic appendicectomy: pros & cons--literature review of 4190 cases.

The aim of this literature review is to evaluate current data on laparoscopic and open appendicectomy in order to establish a new gold standard in surgery. The authors have reviewed 4190 appendicectomies, 3322 laparoscopic appendicectomies (LA) and 868 open appendicectomies (OA), from 22 studies published between February 1992 and June 1994. Four studies dealt exclusively with pediatric patients (n = 1558). The analysis compares surgical technique, operating time, pathological findings, major and minor complications, postoperative pain and costs. The strongest arguments against LA are the increased rate of major complications, the increase of overall cost and the negative effect of the learning curve. The argument in favour of LA are the significant reduction of minor complications, the shortening of the postoperative hospitalization and of the time to resume full activity. The benefit of LA regarding the amount of analgesia requirement and the time needed to resume normal feeding after surgery is still controversial. The authors have reached the conclusion that LA might emerge as the first choice for appendicectomy. More studies are necessary to confirm this trend.

A conceptual model of health care law making in central and eastern Europe.

Defective law making (processes) is considered as one of the main problems in reforming health care systems in Central and Eastern Europe. To improve this situation, authors propose a theoretical method of law making advocating progressive legislative changes. Reflected by a simplified model such a method integrates the functions of health care law into a general concept of law making. Such a theoretical concept reflects both normative and instrumental qualities and can support the legislature in redefining health care legislation in a more rational manner. Particularly in a state of flux with rapid and profound changes, rational decision-making in law making activity could enhance the success of intended health care reforms.