Clinico-pathological factors associated with radioiodine refractory differentiated thyroid carcinoma status.

PURPOSE: Risk factors for developing radioiodine refractory thyroid cancer (RAIR-TC) have rarely been analyzed. The purpose of the present study was to find clinical and pathological features associated with the occurrence of RAIR-disease in differentiated thyroid cancers (DTC) and to establish an effective predictive risk score. METHODS: All cases of RAIR-DTC treated in our center from 1990 to 2020 were retrospectively reviewed. Each case was matched randomly with at least four RAI-avid DTC control patients based on histological and clinical criteria. Conditional logistic regression was used to examine the association between RAIR-disease and variables with univariate and multivariate analyses. A risk score was then developed from the multivariate conditional logistic regression model to predict the risk of refractory disease occurrence. The optimal cut-off value for predicting the occurrence of RAIR-TC was assessed by receiver operating characteristic (ROC) curves and Youden's statistic. RESULTS: We analyzed 159 RAIR-TC cases for a total of 759 controls and found 7 independent risk factors for predicting RAIR-TC occurrence: age at diagnosis ≥ 55, vascular invasion, synchronous cervical, pulmonary and bone metastases at initial work-up, cervical and pulmonary recurrence during follow-up. The predictive score of RAIR-disease showed a high discrimination power with a cut-off value of 8.9 out of 10 providing 86% sensitivity and 92% specificity with an area under the curve (AUC) of 0.95. CONCLUSION: Predicting the occurrence of RAIR-disease in DTC patients may allow clinicians to focus on systemic redifferentiating strategies and/or local treatments for metastatic lesions rather than pursuing with ineffective RAI-therapies.

SU-E-T-201: Safety-Focused Customization of Treatment Plan Documentation.

PURPOSE: Plan report documentation contains numerous details about the treatment plan, but critical information for patient safety is often presented without special emphasis. This can make it difficult to detect errors from treatment planning and data transfer during the initial chart review. The objective of this work is to improve safety measures in radiation therapy practice by customizing the treatment plan report to emphasize safety-critical information. METHODS: Commands within the template file from a commercial planning system (Eclipse, Varian Medical Systems) that automatically generates the treatment plan report were reviewed and modified. Safety-critical plan parameters were identified from published risks known to be inherent in the treatment planning process. Risks having medium to high potential impact on patient safety included incorrect patient identifiers, erroneous use of the treatment prescription, and incorrect transfer of beam parameters or consideration of accessories. Specific examples of critical information in the treatment plan report that can be overlooked during a chart review included prescribed dose per fraction and number of fractions, wedge and open field monitor units, presence of beam accessories, and table shifts for patient setup. RESULTS: Critical information was streamlined and concentrated. Patient and plan identification, dose prescription details, and patient positioning couch shift instructions were placed on the first page. Plan information to verify the correct data transfer to the record and verify system was re-organized in an easy to review tabular format and placed in the second page of the customized printout. Placeholders were introduced to indicate both the presence and absence of beam modifiers. Font sizes and spacing were adjusted for clarity, and departmental standards and terminology were introduced to streamline data communication among staff members. CONCLUSIONS: Plan reporting documentation has been customized to concentrate and emphasize safety-critical information, which should allow for a more efficient, robust chart review process.

Laparoscopic ultrasound-guided resection of gastric submucosal tumors.

BACKGROUND: The laparoscopic resection of gastric stromal tumors is being performed with increased frequency. Wedge resection of anterior wall lesions is generally performed. The treatment of posterior wall lesions is still controversial. METHODS: We report three cases of gastric submucosal tumors treated by a laparoscopic wedge resection of the stomach. All lesions were localized anterior gastric wall by intraoperative ultrasound on the. In the first patient the resection was performed with an endoscopic stapler; in the other patients, ultrasonic coagulation in association with an intracorporeal suture has been used. RESULTS: All patients were successfully treated laparoscopically; there were no conversions to open surgery. In all cases the operative course was uneventful. The postoperative hospital stay ranged from 6 to 8 days. CONCLUSIONS: The results suggest that laparoscopic surgery is an adequate strategy for gastric submucosal neoplasms including gastrointestinal stromal tumors (GIST). Intraoperative ultrasound is very useful in the selection of the technical approach with or without the endoscopic stapler.

Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy.

We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of "thalidomide embryopathy" might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.

[Positron emission-computed tomography in diagnosis and staging of lung neoplasms. Personal experience]. / La scintigrafia ad emissione di positroni nella diagnosi e stadiazione del carcinoma polmonare: la nostra esperienza.

BACKGROUND: Positron emission-computed tomography (PET) scans are obtained from the accumulation of a radiotracer in tissues with altered metabolism, such as malignant neoplasms. The authors present their experience with PET, performed in 50 selected patients with lung neoplasms in the 1998-2000 period. METHODS: The indications to PET corresponded to those most frequently reported in the literature, that is: diagnosis in solitary pulmonary nodule 8 patients; mediastinal lymph node staging, 16 patients; re-evaluation after neo-adjuvant therapy, 21 patients; increased markers blood levels in the follow-up of resected patients, 5 cases. Each indication is individually discussed and compared with the data of the literature, especially regarding the role of PET and its relationship with other noninvasive and invasive diagnostic tools. RESULTS: In 47 patients (94%) diagnostic yield was reached. A false positive (acute inflammatory lesion in solitary pulmonary nodule), a false negative (no demonstration of lymphangitic intrathoracic recurrence) and a non-diagnostic result (then pathologically proved non-neoplastic) were recorded. CONCLUSIONS: Thus the authors consider PET extremely useful in the diagnosis and staging of lung neoplasms; the high cost of PET may be compensated for the reduced need for invasive diagnostic tools and, avoiding inappropriate surgical options, with favourable cost-effectiveness.Thus, PET may be indicated in most, if not in all, patients with lung neoplasms.

Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation.

We have recently identified and cloned Foxp3, the gene defective in mice with the scurfy mutation. The immune dysregulation documented in these mice and in humans with mutations in the orthologous gene indicates that the foxp3 gene product, scurfin, is involved in the regulation of T cell activation and differentiation. The autoimmune state observed in these patients with the immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome, or X-linked autoimmunity-allergic dysregulation syndrome also points to a critical role for scurfin in the regulation of T cell homeostasis. FOXP3 encodes a novel member of the forkhead family of transcription factors. Here we demonstrate that this structural domain is required for nuclear localization and DNA binding. Scurfin, transiently expressed in heterologous cells, represses transcription of a reporter containing a multimeric forkhead binding site. Upon overexpression in CD4 T cells, scurfin attenuates activation-induced cytokine production and proliferation. We have identified FKH binding sequences adjacent to critical NFAT regulatory sites in the promoters of several cytokine genes whose expression is sensitive to changes in SFN abundance. Our findings indicate that the ability of scurfin to bind DNA, and presumably repress transcription, plays a paramount role in determining the amplitude of the response of CD4 T cells to activation.

[Follicular neoplasm of the thyroid: usefulness of extemporaneous histologic study of frozen sections]. / Neoplasia follicolare della tiroide: utilità dell'esame istologico estemporaneo al congelatore.

PURPOSE: The role of frozen section (FS) in determining thyroidectomy extent in patients with follicular neoplasms is debated. The Authors consider FS usefulness through experience retrospective review. MATERIAL AND METHODS: From January 1980 to June 1999, 1252 Fine Needle Aspirations (FNA) were performed in patients with thyroid nodules. Out of these, 155 (12.4%) resulted follicular neoplasms. All these patients were operated on: 54 had total thyroidectomy because of both lobes disease and 101 had emithyroidectomy with FS. FS results were compared to definitive histological examination. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of frozen section have been estimated. RESULTS: Out of 155 follicular neoplasms, 15 resulted malignant at definitive histological examination: 6 were diagnosed by FS. All 6 patients had a total thyroidectomy during the same operation. Of the rimanenti 9, 6 had a second operation for radicalization within 2-3 days. FS sensitivity was 42.9%, specificity 100%, accuracy 92.0%, PPV 100% and NPV 8.5%. DISCUSSION: Some Authors consider FS useful because it allows to radicalize the operation immediately, in case of positivity for malignancy. Even if only few patients, the possibility to solve the problem in a one-step procedure is a great advantage. Other Authors consider FS useless because to diagnose a poor number malignant neoplasms, a lot of intra-operative examination have to be done. Costs are higher than benefits. CONCLUSIONS: The Authors believe that both attitudes are correct and the decision of using or not FS cannot be standardized.

Release kinetics of acyclovir from a suspension of acyclovir incorporated in a cubic phase delivery system.

Acyclovir is a widely used agent in the treatment of herpes virus infections of the skin, but owing to its poor physicochemical properties in terms of bioavailability and suboptimal formulations, the treatment is far from optimal. The liquid crystalline cubic phase system has been reported to act as a bioadhesive drug delivery system. In the present study, acyclovir was suspended in a cubic phase of glycerol monooleate (GMO) and water 65%:35% w/w, and the phase behavior and release kinetics were examined. X-ray diffraction and differential scanning calorimetry (DSC) measurements demonstrated that the cubic phase containing 1%-10% (w/w) acyclovir retains its phase condition in the temperature range investigated (20 degrees C-70 degrees C). Acyclovir can be incorporated in high amounts (approximately 40% w/w) without causing phase transition, as is shown in polarized light. This is probably because of its low solubility (approximately 0.11% w/w) in the cubic phase. The release characteristics of acyclovir incorporated as a suspension (1%-5% w/w) into a cubic phase were investigated using Franz diffusion cells. Acyclovir was quantified by high-performance liquid chromatography (HPLC). The drug was readily released from the system, and the release increased with the initial drug load concentration. About 25%-50% was released after 24 h. The release is dependent on the square root of time, and the kinetics can be described by the Higuchi theory. The rate-limiting step in the release process is most likely diffusion. The suggested theory is further supported by identical release data obtained for micronized and nonmicronized acyclovir. The fluxes for 1% and 5% w/w were 380 and 900 microg/h(1/2), respectively. Comparison of the release rates of acyclovir delivered from a cubic phase and from the commercial product, Zovir cream, showed the rate to be six times faster from the cubic phase. The results indicate that the cubic phase is a promising drug delivery system for acyclovir.

Post-thyroidectomy hypocalcemia and feasibility of short-stay thyroid surgery.

AIM: To study the feasibility of thyroid surgery in a short-stay hospitalization regimen, with particular reference to postoperative hypocalcemia. METHODS: The clinical files of 696 patients operated on from January 1977 to January 2000 for thyroid diseases were analyzed. They were divided into groups on the basis of extent of operation and type of disease. Hypocalcemia incidence was compared between the different groups of patients. Data were analyzed statistically using the chi-square and Fisher's exact tests. RESULTS: There were 74 temporary (10.6%) and 12 (1.7%) persistent hypocalcemia cases. None of these occurred in patients undergoing lobectomy. The incidence of hypocalcemia was higher in two-lobe vs. single-lobe operations (p < 0.05), in total thyroidectomy with lymphadenectomy vs. total thyroidectomy (p < 0.05) and in hyperthyroidism vs. patients with normal serum hormone levels (p < 0.05). 84.9% of hypocalcemia cases developed on postoperative day 1, with only one tetanic crisis. CONCLUSIONS: Thyroid surgery in the short-stay hospitalization regimen is feasible for all patients undergoing lobectomy. Patients undergoing subtotal or total thyroidectomy may be treated in a short-stay regimen, only if they are affected with non-hyperfunctioning benign diseases and if they have normal serum calcium levels on postoperative day 1.

The Asian Pacific Economic Cooperation Emerging Infections Network.

ISSUE: The Asia Pacific Economic Cooperation (APEC) has undertaken an initiative in emerging infections. PROJECT: The APEC Emerging Infections Network project uses collaborative telecommunications tools such as e-mail and a World Wide Web site to bridge the broad geographic expanse and diversity of APEC. Scientists and policymakers share information to effectively combat emerging infectious disease (EID) through surveillance, prevention, research, and control measures. RESULTS: In the project's first year, site visits compiled information on Internet access in selected economies. Information sharing via electronic lists has been successful; feedback suggests that these strategies will become increasingly useful. The Emerging Infections Network (EINet) Web site includes project information, library access, surveillance data, prevention guidelines, and distance learning resources. A pilot effort to promote the secure electronic exchange of surveillance data demonstrated that informal communications may be both preferable and more feasible during the early stages of this project. LESSONS LEARNED: Human networking is as important as technology-based networking in addressing emerging infections. Internet technology in some APEC economies is barely adequate, but is becoming more reliable and accessible. Numerous member economies are eager to be included in project activities.

Bioadhesive drug delivery systems. I. Characterisation of mucoadhesive properties of systems based on glyceryl mono-oleate and glyceryl monolinoleate.

A group of fatty acid esters capable of forming liquid crystals has been identified as a new class of potential bioadhesive substances. The liquid crystals may act as a controlled release system. The experimental work was focused on the monoglycerides, glyceryl mono-oleate (GMO) and glyceryl monolinoleate (GML). The mucoadhesive properties of GMO and GML were demonstrated in vitro by a 'flushing' bioadhesion test system and a tensiometric method. The flushing system was validated with GMO. Mucoadhesion is influenced by the drug and excipient added, their concentrations, and the ability to form especially the cubic phase. It has been shown that the cubic phase is mucoadhesive when formed on wet mucosa, such as rabbit jejunum, and that drug added to the precursor formulation is incorporated in the cubic phase formed. Tensiometric measurements have shown that the unswollen monoglycerides have the greatest mucoadhesion, followed by the partly swollen lamellar phase and the fully swollen cubic phase. The values found for the work of adhesion were in the range 0.007-0.048 mJcm-2. The mechanism of mucoadhesion is unspecific and probably involves dehydration of the mucosa. The cubic phase of GMO and GML may be an interesting candidate for a bioadhesive drug delivery system.

Consistent transient transfection of DNA into non-transformed human and murine T-lymphocytes.

The ability to analyze transcriptional regulation in non-transformed T-cells has been hampered by the inability to reproducibly transiently transfect these cells with DNA constructs. We have previously demonstrated that normal human whole mononuclear and CD4 T-cells can be consistently transiently transfected with plasmid DNA. Human cells were most receptive to plasmid DNA uptake between 19.5 and 20 h after prestimulation with a submitogenic dose of the polyclonal T-cell activator, PHA. Here we report an alteration and optimization of this protocol for non-transformed murine splenic T-cells, using concanavalin A instead of PHA as the preactivation stimulus. When coupled with the high sensitivity of luciferase reporter gene constructs, this protocol facilitates the analysis of a variety of T-cell-specific promoters in non-transformed T-cells. In addition, we directly demonstrate that murine T-cells are specifically transiently transfected among a population of whole mononuclear cells by using an expression vector for green fluorescent protein.

Technical difficulties and complications during laparoscopic cholecystectomy: predictive use of preoperative ultrasonography.

The aim of this study was to evaluate ultrasound findings as predictors of potential operative difficulties and complications during laparoscopic cholecystectomy (LC). From October 1993 to June 1995 a total of 143 patients with symptomatic cholelithiasis (50 males, 93 females, mean age 49.5 +/- 15 years) were evaluated by ultrasound (US) the day before LC. The US examination assessed six parameters: gallbladder (GB) volume, GB wall thickness, GB neck position, GB stone mobility, stone maximum size, and GB adhesions. On the basis of these US findings, a predictive judgment of technical difficulties was expressed by degree: easy, difficult, and very difficult. Altogether 101 patients presented with uncomplicated symptomatic cholelithiasis, and 42 had acute cholecystitis. The operation was predicted to be easy in 38% of cases, difficult in 49%, and very difficult in 13% with a good correlation with the surgeon's intraoperative judgment (r = 0.66). A significant association was found between stone mobility (r = 0.37), presence of adhesions (r = 0.36), and the difficulty of the procedure. The predictive US evaluation was significantly correlated with some intraoperative technical steps [dissection of Calot's triangle (r = 0.41), dissection of the gallbladder bed (r = 0.41)], and intraoperative bleeding (r = 0.27). Our results suggest that preoperative US is a useful screening test for patients undergoing LC, and it can help predict technical difficulties. On the other hand, a relevant number of cases still exist wherein the concordance between the preoperative US classification and the surgical findings is unsatisfactory. In this group the surgeon cannot safely rely on the US examination alone.

Intraoperative ultrasonography (IOUS) during laparoscopic cholecystectomy.

BACKGROUND: The purpose of this study was to evaluate the usefulness of intraoperative ultrasonography (IOUS), a new method of imaging the biliary tree and related structures, during laparoscopic cholecystectomy. METHOD: An IOUS probe (Aloka, Tokyo, Japan) with a 7.5-MHz linear-array transducer was used during cholecystectomy in 124 patients with symptomatic cholelithiasis (45 men, 79 women; mean age, 48 +/- 14 years). RESULTS: The examination of the common bile duct (CBD) was excellent in 117 patients but unsatisfactory in 7 cases (5.6%) at the level of the head of the pancreas. In 5 patients, IOUS showed unsuspected choledocholithiasis: a subsequent intraoperational cholangiogram confirmed this. In five cases IOUS was able to help the surgeon to localize a Calot area obscured by inflammation. Postoperatively, one patient had an injury of the cystic duct stump: a nasobiliary tube resolved the bile leakage after 7 days. Another patient was submitted to postoperative endoscopic retrograde cholangiopancreatography (ERCP) for a choledocholithiasis recognized by a trans-cystic-tube cholangiography: the stone was suspected but not demonstrated either by laparoscopic IOUS or by intraoperative cholangiography. During the follow-up period, one patient had an episode of acute pancreatitis. ERCP showed a small stone wedged in the sphincter of Oddi. CONCLUSIONS: IOUS may be a real alternative to cholangiography during laparoscopic cholecystectomy since it is safer and offers a complete examination of the biliary tree. It has some disadvantages which can solved by additional experience.

Coexpression of the interleukin-13 and interleukin-4 genes correlates with their physical linkage in the cytokine gene cluster on human chromosome 5q23-31.

Interleukin-13 (IL-13) and IL-4 are cytokines produced by T cells that are encoded by the q23-31 region of human chromosome 5. To investigate the regulation of IL-13 gene expression by T cells, we isolated and sequenced the human IL-13 gene, analyzed its 5'-flanking region for potential transcriptional activation elements, and examined its expression in nontransformed T-lineage cell populations. The human IL-13 gene was located 12.5-kb upstream of the IL-4 gene and 2-kb downstream of a CpG island. The IL-13 gene 5' flank region included a segment with sequence homology to P elements of the IL-4 promoter involved in transcriptional activation in T cells. Mutation of the IL-13 P element site significantly reduced IL-13 promoter activity in response to T-cell activation. Oligonucleotides containing the IL-13 or IL-4 P element sites specifically bound the transcriptional activator protein, nuclear factor-activated T cells, preformed (NF-ATp), when incubated with nuclear protein extracts from activated T cells. Similar to IL-4, IL-13 mRNA expression was highest in T-cell populations enriched for cells that had previously been primed in vivo or in vitro, indicating that priming increases the expression of the IL-13 and IL-4 genes in a coordinate manner. Because the primed T cells contain higher levels of nuclear NF-ATp, capable of binding to P elements of the IL-4 and IL-13 promoters, than do freshly-isolated T cells, the NF-AT-binding P elements are attractive candidates to mediate the coordinate expression of these two cytokine genes.

The human gp39 promoter. Two distinct nuclear factors of activated T cell protein-binding elements contribute independently to transcriptional activation.

gp39, a cytokine expressed on the surface of activated T cells, is essential for T cell-dependent antibody responses in vivo. We cloned and sequenced 1.2 kilobases of the 5' flank region of the human gp39 gene promoter and determined its transcription start site. When used in reporter gene assays, this DNA segment conferred promoter activity in response to T cell activation. gp39 promoter function in transfectants was inhibited by cyclosporin A, as is expression of the endogenous gp39 gene in T-lineage cells. At least 0.5 kilobase of the 5' flank region was required for promoter activity. Two putative binding sites for the NF-AT family of transcriptional activator proteins were identified at -259 to -265 and -62 to -69 with respect to the transcription start site. Both sites contributed significantly and independently to promoter activity in response to T cell activation. Additionally, when incubated in vitro with nuclear protein purified from activated human CD4 T cells, both of these sites preferentially bound the NF-AT family member, NF-ATp. These results suggest that NF-ATp, via binding to at least two cis-elements, is essential for the induction of gp39 gene expression in response to T cell activation.

[Apropos of 59 cases of peripheral arterial embolisms]. / A proposito di 59 casi di embolie arteriose periferiche.

59 cases of embolic occlusion of the peripheral arteries treated with surgical disobliteration by Fogarty catheter are described. Some considerations and conclusions on the cases are discussed.