A Repurposing Programme Evaluating Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design.

AIMS: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. MATERIALS AND METHODS: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. RESULTS: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited. FUTURE: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.

Mogamulizumab efficacy is underscored by its associated rash that mimics cutaneous T-cell lymphoma: a retrospective single-centre case series.

BACKGROUND: Mogamulizumab is a humanized antibody against chemokine receptor type 4. It was recently approved by the US Food and Drug Administration for relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS). The most commonly reported adverse event in the phase III licensing trial was drug eruption (28%), now termed mogamulizumab-associated rash (MAR). Clinical recommendations about MAR and its treatment differ between the current package insert and postapproval insights reported from two single-centre studies that focused on its characterization, but less so on outcomes and clinicopathological differentiation from cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To describe our experience in the diagnosis of MAR and treatment of patients with CTCL with mogamulizumab. METHODS: This is a single-centre retrospective case series study. RESULTS: We found a higher incidence of MAR in patients with CTCL (17 of 24, 68%) than previously reported. MAR development is associated with complete (11 of 17) or partial (four of 17) responses, with an overall response rate of 88%, compared with 29% (two of seven) in patients without MAR. Diagnosis of MAR may be obscured by its ability to mimic key CTCL features both clinically and histologically, but an absence of T-cell-receptor clonality and relatively decreased CD4 : CD8 ratio compared with baseline lesions strongly favour MAR over recurrent disease. CONCLUSIONS: MAR has the potential to create a significant management problem for patients on mogamulizumab. Misidentification of MAR as recurrent CTCL may detrimentally result in the premature discontinuation of mogamulizumab in patients whose disease is historically hard to treat. Thorough clinicopathological investigation of new lesions during treatment with mogamulizumab is required to inform ideal treatment decisions and achieve better outcomes.

Mycosis fungoides-derived exosomes promote cell motility and are enriched with microRNA-155 and microRNA-1246, and their plasma-cell-free expression may serve as a potential biomarker for disease burden.

BACKGROUND: Literature regarding exosomes as mediators in intercellular communication to promote progression in mycosis fungoides (MF) is lacking. OBJECTIVES: To characterize MF-derived exosomes and their involvement in the disease. METHODS: Exosomes were isolated by ultracentrifugation from cutaneous T-cell lymphoma (CTCL) cell lines, and from plasma of patients with MF and controls (healthy individuals). Exosomes were confirmed by electron microscopy, NanoSight and CD81 staining. Cell-line exosomes were profiled for microRNA array. Exosomal microRNA (exomiRNA) expression and uptake, and plasma-cell-free microRNA (cfmiRNA) were analysed by reverse-transcriptase quantitative polymerase chain reaction. Exosome uptake was monitored by fluorescent labelling and CD81 immunostaining. Migration was analysed by transwell migration assay. RESULTS: MyLa- and MJ-derived exosomes had a distinctive microRNA signature with abundant microRNA (miR)-155 and miR-1246. Both microRNAs were delivered into target cells, but only exomiR-155 was tested, demonstrating a migratory effect on target cells. Plasma levels of cfmiR-1246 were significantly highest in combined plaque/tumour MF, followed by patch MF, and were lowest in controls (plaque/tumour > patch > healthy), while cfmiR-155 was upregulated only in plaque/tumour MF vs. controls. Specifically, exomiR-1246 (and not exomiR-155) was higher in plasma of plaque/tumour MF than in healthy controls. Plasma exosomes from MF but not from controls increased cell migration. CONCLUSIONS: Our findings show that MF-derived exosomes promote cell motility and are enriched with miR-155, a well-known microRNA in MF, and miR-1246, not previously reported in MF. Based on their plasma expression we suggest that they may serve as potential biomarkers for tumour burden.

Total extra peritoneal inguinal hernia repair: a single-surgeon preliminary findings report.

INTRODUCTION: Inguinal hernia repair is one of the most frequent operations in general surgery. Various techniques have been used to repair inguinal hernias since the first reconstructive technique described by Bassini in 1887. In 1989 Lichtenstein reported a new technique: tension free inguinal hernia repair. Laparoscopic inguinal hernia repair was introduced in the early 1990s, and soon also became popular. Literature has shown the benefits of laparoscopy (in comparison with open repair) to be mostly related to the more minimally invasive nature of the surgery, having lower wound infection rates, faster recovery, and less postoperative pain. AIM: To evaluate our totally extraperitoneal (TEP) inguinal hernia repair initial results and compare them to literature data. MATERIALS AND METHODS: In a prospective review and analysis, we examined 61 cases of hernia repair via laparoscopy (specifically TEP), performed by a single surgeon, between April 2019 and December 2019 at the Kaspela University Hospital in Plovdiv. The centre's Institutional Review Board approved the study with no specific consents required due to the retrospective, minimal risk nature of the study. The routine informed consent required by the National Insurance Fund has been considered sufficient for the study objectives.The surgical outcome measures included operating time (hours/minutes), conversion, peritoneal injury, surgical emphysema; and the clinical outcome measures included postoperative seroma, post-operative infection, and post-operative chronic groin pain. RESULTS: Inguinal pain on discharge was characterized as mild by 56 (96.55%) patients and moderate by 2 (3.44%), there were no patients describing the pain as severe. The most frequently reported postoperative complications were annoyance and discomfort (10.34%), swelling (6.9%), seroma (3.44), hematoma (1.72%), paresthesia 1.72% (1); however, only those with seromas required special treatment. CONCLUSIONS: Limitations of the present study include the relatively small number of patients, all cases were operated on by a single surgeon and short postoperative follow-up period, but we are sharing our initial six months results. These results demonstrate that laparoscopic TEP inguinal hernia repair without mesh fixation is a reliable technique, which can reduce postoperative morbidity when applied by experienced surgeons.

Comparison of preoperative versus postoperative transversus abdominis plane and rectus sheath block in patients undergoing minimally invasive colorectal surgery.

AIM: Ultrasound-guided transversus abdominis plane and rectus sheath block (TAPRSB) decreases pain scores and narcotic use postoperatively after colorectal surgery (CRS). It is unclear if the effectiveness of TAPRSB varies according to whether it is performed preoperatively or postoperatively. Our aim was to investigate this. METHOD: We compared patients who underwent preoperative TAPRSB or postoperative TAPRSB during minimally invasive CRS. Primary end-points were pain scores and oral morphine milligram equivalent (MME) use postoperatively. Secondary end-points included perioperative factors affecting pain scores and postoperative MME. Summary statistics and univariate analysis by nonparametric tests were utilized. The mixed-effect model was applied to model the repeatedly measured pain score. RESULTS: From April 2015 until May 2018 168 patients received TAPRSB before (115) or after (53) minimally invasive CRS. The cohort included 79 (47.0%) women, and had an average age of 59.11 (±12.32) years and mean body mass index of 28.32 (±5.82) kg/m2 . Indication for surgery was cancer in 66 (39.3%), polyp in 43 (25.6%) and diverticulitis in 43 (25.6%). Right colectomy was performed in 61 (36.3%), low anterior resection in 46 (27.4%) and sigmoid colectomy in 40 (23.8%) patients. The demographics of the groups were similar. Postoperative TAPRSB was only associated with lower pain scores at 12 h postoperatively. As secondary outcomes, average pain scores and MME were lower in patients who were older, had right colectomy or intracorporeal anastomosis. CONCLUSIONS: Postoperative TAPRSB resulted in lower pain scores than preoperative TAPRSB 12 h after minimally invasive CRS, but otherwise no differences were seen in pain scores or MME use.

Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.

Background: We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized. Patients and methods: Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. Results: Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. Conclusions: Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).

The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer.

PURPOSE: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy. METHODS AND MATERIALS: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression. RESULTS: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model. CONCLUSIONS: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients.

Introduction of a Team Based Approach to Radiation Dose Reduction in the Enhancement of the Overall Radiation Safety Profile of FEVAR.

OBJECTIVES: Fenestrated endovascular aneurysm repair (FEVAR) exposes operators and patients to considerable amounts of radiation. Introduction of fusion of three-dimensional (3D) computed tomography (CT) with intraoperative fluoroscopy puts new focus on advanced imaging techniques in the operating environment and has been found to reduce radiation and facilitate faster repair. The aim of this study is to evaluate the radiation dose effect of introducing a team-based approach to complex aortic repair. METHODS: Procedural details for a cohort of 21 patients undergoing FEVAR after fusion-guided (Modern Group) imaging was introduced are compared with 21 patients treated in the immediate 12 months prior to implementation (Historic Group) at a centre with expertise in FEVAR. Non-parametric tests were used to compare procedure time (PT), air kerma, dose-area product (DAP), fluoroscopy time (FT), estimated blood loss (EBL) and pre- and post-operative estimated glomerular filtration rate (eGFR) between the groups. RESULTS: Change in operative approach resulted in a significant reduction in PT for the Modern group (median 285 mins; interquartile range 268-322) compared with the Historic group (450 mins; IQR 360-540 p = <0.001). There were reductions in skin dose for the Modern group (1.6 Gy; IQR 1.09-2.1) compared with the Historic group (4.4 Gy; 3.2-7.05 p = <0.001), and DAP (Modern 159 Gy.cm2; IQR 123-226 vs 264.93 Gy.cm2; 173.3-366.8 for Historic (p = 0.006). There were no significant differences in FT, and pre- and post-operative eGFR between the two groups. Weight and height were distributed equally across both groups. Structured dose reports including the changes in frame rate were not available for analysis. CONCLUSIONS: Implementation of a team-based approach to radiation reduction significantly reduces radiation dose. These findings suggest that the radiation safety awareness that accompanies the introduction of fusion imaging may improve the overall radiation safety profile of FEVAR for patients and providers.

Elevated incidence of fractures in women with invasive breast cancer.

UNLABELLED: This study evaluates the incidence of bone fractures in women with BC.We found that women with invasive breast cancer are at an increased risk for bone fractures, with fractures most commonly occurring at lower extremity and vertebral sites. The risk is further increased in women undergoing cancer therapy. INTRODUCTION: Bone loss and fractures in breast cancer have generally been attributed to aromatase inhibitor use. This study assessed the incidence of fractures after invasive breast cancer diagnosis and evaluated bone density and FRAX risk calculation at time of fracture occurrence. METHODS: Retrospective cohort study of women with invasive breast cancer [June 2003-December 2011] who participated in an academic hospital based genetic biobank. Demographic and clinical characteristics were abstracted from the electronic medical record (EMR). RESULTS: A total of 422 women with invasive breast cancer were assessed; 79 (28 %) sustained fractures during the observation period; fractures occurred at multiple skeletal sites in 27 cases (116 fractures). The incidence of fractures was 40 per 1000 person-years. Women who sustained fractures were mostly white and had a family history of osteoporosis (36.9 %, p = 0.03) or history of a prior fracture (6/79, p = 0.004). Fractures occurred 4.0 years (range 0-12 years) after cancer diagnosis. Fracture cases had femoral neck bone mineral density (BMD) of 0.72 + 0.12 g/cm(2), T-score of -1.2, that is, within the low bone mass range. Fractures most commonly occurred in lower extremities, vertebral, and wrist sites. Hip fractures accounted for 11 % of fractures, occurring at a median age of 61 years. CONCLUSIONS: Fractures occur shortly after commencing cancer therapy. Rapid bone loss associated with cancer therapy may precipitate fractures. Fractures occur at relatively higher BMD in BC. Occurrence of fractures in invasive breast cancer raises the possibility of cancer-induced impairment in bone quality.

Poland Syndrome: Use of Vertical Expandable Prosthetic Titanium Rib System before Walking Age-A Case Report.

Aim To present a new therapy for Poland syndrome (PS) using a novel surgical approach: the vertical expandable prosthetic titanium rib (VEPTR) system. Methods The VEPTR system rib-to-rib variant was used to enhance the chest wall and vertebral column support in a young patient before walking age. Case Report We present a 12-month-old infant diagnosed with left-sided PS at the age of 6 months associated with missing ribs, scoliosis, and absence of the left pectoral muscles. Because of four missing ribs, paradoxical breathing was present. In addition, the left scapula was protruding into the chest due to the missing rib support. Scoliosis was caused by a left-sided nonsegmented bar of the thoracic spine. Results We decided to use the VEPTR system before the patient reached walking age to prevent progression of column deformation and future pulmonary problems. To improve the spinal deformity, to stabilize the thorax, and to improve thoracic function, we performed the operation at 1 year of age. At 10-month follow-up, the patient was reevaluated. The construction was still stable and scoliosis had not deteriorated. Conclusion The VEPTR system is a choice of treatment in young patients with PS to prevent late complications after a child reaches walking age.

Diagnosis and treatment of pleuropulmonary blastoma-single center experience.

Pleuropulmonary blastoma (PPB) is a rare and potentially aggressive intrathoracic disembryonic neoplasm typically occurring in children less than 6 years of age. We assessed the relative incidence, clinical characteristics, treatment outcome, and the prognostic factors for long-term survival in patients with PPB treated at our institution over a 25-year period, and compared these data with reports in the literature. From 1985 to 2010, 11 children (4 males and 7 females), with a median age of 5.4 years (range, 1-12 years) were treated at our hospital. Here we described the main characteristics of these patients, the diagnostic methods, and treatment modalities used. During a median follow-up period of 80, 9 months, the overall survival (OS) and disease-free survival (DFS) rates were 54, 6% and 45, 5%, respectively. Two patients survived for more than 20 years. The main prognostic factors for long-term survival were the diseases type I and II and treatment with radical surgery. Our results show that in order to improve the prognosis of patients with PPB a timely in our opinion and accurate diagnosis needs to be established and treatment should be offered according to the disease type and extend of dissemination.

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy.

BACKGROUND: Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. PATIENTS AND METHODS: We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. RESULTS: PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. CONCLUSIONS: This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Laparoscopic resection of the pancreatic tail with preservation of the spleen in a patient with a large pseudopapillary tumor of the pancreas.

Laparoscopic resections of the pancreas have gained in popularity in the last few years. Those preserving the integrity of the spleen are performed very rarely and are a challenge for every surgeon. We hereby report a case of laparoscopic resection of the pancreatic tail with preservation of the spleen and the integrity and the blood supply to the spleen in a 26 year-old patient with a large pseudopapillary tumor of the pancreas. Postoperative recovery was quick and without complications. The functional and aesthetic result was satisfactory. Laparoscopic resection of the pancreas is a safe and effective therapeutic procedure in selected patients.

Laparoscopic exploration of bile ducts in patients with calculosis. Indications, methods and first results.

INTRODUCTION: In the last few years there has been a resurgence of laparoscopic exploration of the common bile duct as an alternative to endoscopic retrograde cholangiopancreatography (ERCP), the primary method for diagnosis and treatment of biliary tract calculosis. AIM: The aim of this study was to clarify the indications and methods for performing laparoscopic bile duct exploration, based on our experience in the field and data from the literature. PATIENTS AND METHODS: We recruited 12 patients who underwent laparoscopic exploration and stone extraction from the common bile duct (CBD) in the surgical ward of Kaspela Hospital, Plovdiv over the period January 2011 to January 2012. The diagnostic and therapeutic modalities used in the study included laboratory tests, ultrasound study, CT, ERCP, digital cholangiography, clamp and balloon stone extraction, primary suture and choledochoduodenostomy. RESULTS: Stone extraction was successfully performed in 8 patients using the transcystic approach through an incision used in the cholangiography. The procedure failed in the remaining four patients and we used here 2-cm longitudinal choledochotomy. In two patients the control cholangiography following the extraction of stones demonstrated complete clearance of the biliary tree and free passage of contrast agent from bile duct to duodenum (patent ampulla of Vater). In these two patients we performed a primary closure of the choledochotomy with a single interrupted suture ("ideal choledochotomy"). In two patients from the choledochotomy group, the control cholangiography showed the presence of residual stones or fragments trapped above the sphincter of Oddi with no contrast medium in the duodenum. In these cases we completed this procedure with latero-lateral choledochoduodenostomy by Flërken. All patients had a smooth postoperative course with no recorded complications. The average hospital stay was 5 days. CONCLUSIONS: Laparoscopic exploration of the biliary ducts in calculosis is an efficient, safe and reliable method to manage this serious complication of gall-stone disease in the hands of an experienced laparoscopic surgeon. The results of its application are comparable and in some cases even better than those of ERCP used as a therapeutic procedure as regards clearance of the CBD and the complications involved in these two procedures.

Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.

Heparan sulfate (HS) proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate their signaling. 6-O-sulfation (6S) of glucosamine within HS chains is critical for many of these ligand interactions. Sulf-1 and Sulf-2, which are extracellular neutral-pH sulfatases, provide a novel post-synthetic mechanism for regulation of HSPG function by removing 6S from intact HS chains. The Sulfs can thereby modulate several signaling pathways, including the promotion of Wnt signaling. We found induction of SULF2 transcripts and Sulf-2 protein in human lung adenocarcinoma and squamous cell carcinoma, the two major classes of non-small-cell lung carcinomas (NSCLCs). We confirmed widespread Sulf-2 protein expression in tumor cells of 10/10 surgical specimens of human lung squamous carcinomas. We studied five Sulf-2(+) NSCLC cell lines, including two, which were derived by cigarette-smoke transformation of bronchial epithelial cells. shRNA-mediated Sulf-2 knockdown in these lines caused an increase in 6S on their cell surface and in parallel reversed their transformed phenotype in vitro, eliminated autocrine Wnt signaling and strongly blunted xenograft tumor formation in nude mice. Conversely, forced Sulf-2 expression in non-malignant bronchial epithelial cells produced a partially transformed phenotype. Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.

Interleukins in the treatment of mycosis fungoides.

Mycosis fungoides is typified by a cutaneous infiltrate of CD4+ lymphocytes with a Th2 phenotype. As the disease advances, there is increased expression of Th2 cytokines. This results in a subsequent suppression of Th1 cytokines and impaired cell mediated cytotoxic host response to the lymphoma cells. Disarming this cell mediate cytotoxic immune response creates a relentless cycle of disease progression. A cell mediated cytotoxic immune response can be stimulated with the use of Th1 cytokines such as IL-2 and IL-12. In this report, the Authors review the rational for the use of these particular cytokines in the treatment of mycosis fungoides. Further they comment on the experience and success regarding these two agents in phase I and II trials for the treatment of mycosis fungoides. Lastly, they discuss other potential cytokine therapies which could play a role in the future treatment of mycosis fungoides.

Acute perforated diverticulitis of the colon as a rare cause for development of abdominal compartment syndrome.

AIM: The aim of the present retrospective study was to assess the surgical approaches to acute perforated diverticulitis of the colon causing peritonitis and in some cases complicated with abdominal compartment syndrome (ACS). PATIENTS AND METHODS: A total of eight patients (6 males and 2 females) have been operated on for 5 years for perforated diverticulum of the colon. The males had a mean age of 72 +/- 2.6 years and the females--69 +/- 3.1 years. Case history records of the patients were studied retrospectively to evaluate the effectiveness of different surgical approaches used in patients with such disorders. The females had perforation of cecal diverticulum, five of the males had perforated diverticulum of the sigmoid colon and one had perforation of diverticulum of the descending colon. The diagnosis in all patients was made intraoperatively and only in two cases was it assumed prior to operation. In the female patient with cecal pathology right-sided hemicolectomy with primary anastomosis was performed. In the other six patients Hartmann's procedure was applied with a subsequent second-stage intervention to restore the intestinal continuity. RESULTS: Total feculent peritonitis was found in four of the patients with perforated diverticulum of the sigmoid colon, with signs of multiorgan failure, intra-abdominal hypertension (IAH >25 cm H2O level) and developed ACS. Despite the severity of the condition there was no lethal outcome. Two patients developed incisional hernia on the anterior abdominal wall. CONCLUSION: Based on the retrospective clinical analysis the authors conclude that primary hemicolectomy with one-stage anastomosis is the best procedure in patients in good condition and early stage on Hinchey classification. Total feculent peritonitis, associated with stage IV on Hinchey classification and signs of ACS requires Hartmann's procedure, following the principles of damage control surgery with obligatory use of temporary abdominal closure technique to control the syndrome and prevent a secondary one in the postoperative period. The indirect intravesical method of verification of IAH and ACS (the golden standard) is sufficiently precise for the clinical practice.

[Trends and characteristics of diabetes-related lower limb amputations in the Negev, 1996-1999].

BACKGROUND: The loss of a lower limb because of diabetic foot problems such as infections is an important complication of diabetes mellitus. The goals of this study were: (1) to examine trends in incidence of diabetic-related lower limb amputations in the Negev, (2) to describe the clinical characteristics of patients who underwent amputations in the Soroka University Medical Center and (3) to estimate in-hospital mortality and its predictors. METHODS: This study included all diabetic patients who underwent non-traumatic lower limb amputation in the Soroka Hospital during the period 1996-1999. The computerized hospitalization files and surgery logs during the study period were reviewed for ICD-9 diagnoses of diabetes and amputations. For each patient, hospitalization records were abstracted and data on socio-demographic and clinical characteristics were collected. RESULTS: During the study period 411 amputations were performed on 250 diabetic patients (1.6 amputation/person). The estimated mean annual incidence rate of lower limb amputations in the Negev was 5 per 1000 diabetic patients, 27.3 per 100,000 total population, and 45 per 100,000 adults above 18 years of age. The mean age was 68 (SD +/- 11.4) years. The most frequent types of surgery were standard below-knee amputation. Fourteen percent of patients died during hospitalization. Systolic blood pressure, white blood count and serum creatinine at admission were independent predictors of in-hospital mortality. CONCLUSIONS: The incidence of lower limb amputation in the Negev is similar to that reported in other countries. Interventions directed to early detection of diabetic foot problems may have an impact on the reduction of lower limb amputations and related mortality.