Odysseas Zoras

Laparoscopic vs open approach for Nissen fundoplication

Background: Several studies, most of them nonrandomized, have shown similar functional results for both laparoscopic and open Nissen fundoplication, the operation of choice for the treatment of gastroesophageal reflux disease (GERD). Methods: A total of 106 patients with documented GERD were randomized to receive either a laparoscopic or an open Nissen fundoplication. Preoperative and postoperative investigations included clinical assessment, esophagogram, upper gastrointestinal endoscopy, esophageal manometry, and 24-h ambulatory pHmetry. Results: Both approaches were successful in controlling reflux. There was an overall improvement in esophageal peristalsis and an increase in lower esophageal sphincter (LES) pressure in both groups. Open Nissen fundoplication was associated with a significantly increased rate of wound (p <0.001) and respiratory (p <0.05) complications. Hospitalization was also longer after the open technique (p <0.001). At 3-month follow-up, although the rate of postoperative dysphagia was similar for the two approaches, the open approach was associated with a significantly higher incidence of postprandial epigastric fullness (p <0.05) and bloating syndrome (p <0.01). Conclusions: The open and laparoscopic approaches for the Nissen fundoplication are equally effective in controlling GERD. The open approach is associated with a significantly higher rate of wound and respiratory complications and, at early stages, an increased rate of postprandial epigastric fullness and abdominal bloating. The dysphagia rate is similar with both methods.

Rectoanal Intussusception: Presentation of the Disorder and Late Results of Resection Rectopexy

BACKGROUNDRectoanal intussusception may cause symptoms of obstructed defecation, and functional results of prosthesis rectopexy are usually not satisfactory. The aim of this study was to assess several parameters of the disorder and to evaluate the outcome of resection rectopexy.METHODSDuring a 10-year period, 27 female patients with symptomatic large rectoanal intussusception had resection rectopexy (23 laparoscopy; 4 laparotomy). Conservative treatment, including biofeedback treatment in 22 patients, had failed in all cases. Preoperative and postoperative evaluation included clinical assessment, anorectal manometry, evacuation defecography, and colon transit studies. Follow-up ranged between one and five years.RESULTSLength of intussusception was 2 to 4.9 cm and was significantly related to pelvic floor descent (P = 0.003) and inversely related to resting anal pressures (P < 0.001). Eleven patients had undergone a previous hysterectomy, 9 had enterocele-sigmoidocele, 7 had incontinence of varying severity, and 8 had a solitary rectal ulcer. Colon transit was abnormal in all but five cases. Immediate functional results were bad in two-thirds of the cases; tenesmus, urge to defecate, and frequent stools were the main complaints. By the time these symptoms had subsided, and one year after surgery, all but two patients were satisfied with the outcome. Intussusception was reduced in all cases, anal sphincter tone recovered (P = 0.002), perineal descent decreased (P < 0.001), and colonic transit was accelerated (P < 0.001). Patients available at five-year follow-up had no or only minor defecatory problems.CONCLUSIONResection rectopexy improves symptoms of obstructed defecation attributed to large rectoanal intussusception.

Mutational analysis of CDKN2A genes in patients with squamous cell carcinoma of the skin

Summary Background Nonmelanoma skin cancers [squamous cell carcinomas (SCC) and basal cell carcinomas (BCC)] are the most common neoplasias of the Caucasian population.

Genomic instability, mutations and expression analysis of the tumour suppressor genes p14ARF, p15INK4b, p16INK4a and p53 in actinic keratosis

Actinic keratosis (AK) is a well-established pre-cancerous skin lesion that has the potential to progress to squamous cell carcinoma (SCC). We investigated the involvement of the CDKN2A, CDKN2B and p53 genes in AK and in the progression of AK to SCC. Mutational analysis on exons 1a, 1b and 2 of the CDKN2A locus and exon 1 of the CDKN2B locus as well as allelic imbalance was performed in 26 AK specimens. Expression levels of the genes p14(ARF), p15(INK4b), p16(INK4a) and p53 were examined in 16 AKs and 12 SCCs by real-time RT-PCR. A previously described polymorphism of p16(INK4a) (Ala148Thr) was detected at an allelic frequency of 12%. Six samples carried novel mutations at codon 71 of the CDKN2A locus and one sample presented an additional mutation at codon 65. Two AK samples carried a not-previously described non-UV type missense mutation at codon 184 (Val184Glu) of exon 1b in the p14(ARF) gene. Regarding the CDKN2B locus a new mutation at codon 50 (Ala50Thr) and another at codon 24 (Arg24Arg), were detected. Microsatellite instability (MSI) was found in 15% of AKs in at least one marker, indicating that genetic instability has some implication in the development of AK. Down-regulation of p16(INK4a) and p53 mRNA levels was noted in SCC compared to AK. TSGs expression levels in sun-exposed morphologically normal-appearing skin, suggests that abnormal growth stimuli might exist in these tissues as well. Furthermore, we suggest a possible role of p15(INK4b), independently from the intracellular pathway mediated by p16(INK4a), and of p14(ARF) in AK development, as well as in the progression of AK to SCC. The deregulation of the expression profiles of the CDKN2A, CDKN2B and p53 genes may, independently of mutations and LOH at 9p21, play a significant role in AK and progression of AK to SCC.

The effect of erythromycin on human esophageal motility is mediated by serotonin receptors

OBJECTIVE:Erythromycin exhibits prokinetic properties. The drug enhances esophageal and gastric motility by acting as a motilin agonist and promoting acetylocholine release. 5-HT3 receptors are involved in the spontaneously occurring migrating motor complex and the effect of erythromycin on antral motility in dogs. The aim of the study was to investigate the hypothesis that 5-HT3 receptors are also involved in the action of erythromycin on the human esophagus.METHODS:A total of 18 healthy volunteers underwent standard esophageal manometry on three different occasions in a double-blind, placebo-controlled, randomized manner, as follows: 1) after placebo, 2) after 200 mg of erythromycin i.v., and 3) after 200 mg of i.v. erythromycin subsequent to pretreatment with either 4 mg of i.v. ondansetron (serotonin receptor antagonist) (10 subjects) or 12 μg/kg of i.v. atropine (8 subjects).RESULTS:Erythromycin significantly increased a) the amplitude of peristalsis at 5 cm (from 87 ± 19 mm Hg to 108 ± 26 mm Hg; p= 0.0007), 10 cm (from 72 ± 24 mm Hg to 81 ± 26 mm Hg; p= 0.016), and 15 cm (from 47 ± 15 mm Hg to 55 ± 17 mm Hg; p= 0.014) proximal to LES, b) the duration of peristalsis at 5 cm (from 4.5 ± 0.9 s to 5.7 ± 1.2 s; p < 0.0001) and 10 cm (from 4.1 ± 1 s to 4.9 ± 1 s; p < 0.0001) proximal to the LES and c) the strength of peristalsis at 5 cm proximal to the LES (from 180 ± 49 mm Hg · s to 276 ± 100 mm Hg · s; p < 0.0001), and decreased the velocity of peristalsis at distal esophagus (from 4.1 ± 1 cm/s to 3.8 ± 0.9 cm/s; p= 0.03). In addition, erythromycin significantly increased the resting pressure of the LES (from 36 ± 10 mm Hg to 44 ± 12 mm Hg; p= 0.002). Pretreatment with ondansetron totally reversed all of the effects of erythromycin to the placebo state. Pretreatment with atropine not only prevented the effects of erythromycin, but it reduced the amplitude and strength of peristalsis at the distal esophagus at significantly lower levels than after placebo.CONCLUSIONS:Erythromycin exerts its prokinetic action on the lower esophagus by stimulating cholinergic pathways. This action includes not only an increase in LES pressure, but significant increases in the amplitude and duration of esophageal peristalsis, as well. 5-HT3 receptors are also involved in this process.

Prediction of Survival in Patients With Thin Melanoma: Results From a Multi-Institution Study

PURPOSE Cutaneous melanoma incidence is increasing. Most new cases are thin (≤ 1 mm) with favorable prognoses, but survival is nonetheless variable. Our aim was to investigate new prognostic factors and construct a nomogram for predicting survival in individual patients. PATIENTS AND METHODS Data from 2,243 patients with thin melanoma were retrieved from prospectively maintained databases at six centers. Kaplan-Meier survival and crude cumulative incidences of recurrence were estimated, and competing risks were taken into account. Multivariable Cox regression was used to investigate survival predictors. RESULTS Median follow-up was 124 months (interquartile range, 106 to 157 months); 12-year overall survival was 85.3% (95% CI, 83.4% to 87.2%). Median times to local, regional, and distant recurrence were 79, 78, and 107 months, respectively. Relapse was significantly related to age, Breslow thickness, mitotic rate (MR), ulceration, lymphovascular invasion (LVI), and regression; incidence was lower and subgroup differences were less marked for distant metastasis than for regional relapse. The worst prognosis categories were age older than 60 years, Breslow thickness more than 0.75 mm, MR ≥ 1, presence of ulceration, presence of LVI, and regression ≥ 50%. Breslow thickness more than 0.75 mm, MR ≥ 1, presence of ulceration, and LVI (all P = .001) were significantly associated with sentinel node positivity. Age, MR, ulceration, LVI, regression, and sentinel node status were independent predictors of survival and were used to construct a nomogram to predict 12-year overall survival. The nomogram was well calibrated and had good discriminative ability (adjusted Harrell C statistic, 0.88). CONCLUSION Our findings suggest including LVI and regression as new prognostic factors in the melanoma staging system. The nomogram appears useful for risk stratification in clinical management and for recruiting patients to clinical trials.

Potential of antibody–drug conjugates and novel therapeutics in breast cancer management

Progress in the treatment of cancer over the past decade has been slow. Targeting a mutated gene of an individual patient tumor, tumor-guided agents, and the first draft of the human genome sequence have created an overenthusiasm to achieve personalized medicine. However, we now know that this effort is misleading. Extreme interpatient and intratumor heterogeneity, scarce knowledge in how genome-wide mutational landscape and epigenetic changes affect transcriptional processes, gene expression, signaling transduction networks and cell regulation, and clinical assessment of temporary efficacy of targeted drugs explain the limitations of these currently available agents. Trastuzumab and a few other monoclonal antibodies or small-molecule tyrosine kinase inhibitors (TKIs) represent an exception to this rule. By blocking ligand-binding receptor in patients with human epidermal growth factor receptor 2 (HER2) amplification and overexpression, trastuzumab added to chemotherapy in HER2-positive patients has been proven to provide significant overall survival benefit in both metastatic and adjuvant settings. Lapatinib, a small-molecule dual inhibitor (TKI) of both HER2 and EGFR (epidermal growth factor receptor) pathways, has an antitumor activity translated into progression-free survival benefit in HER2-positive metastatic patients previously treated with a taxane, an anthracycline, and trastuzumab. Despite these advances, ~25% of patients with HER2-positive breast cancer experience recurrence in the adjuvant setting, while in the metastatic setting, median survival time is 25 months. In this review, we discuss the safety, efficacy, and limitations of the trastuzumab emtansine (T-DM1) conjugate in the treatment of HER2-positive metastatic breast cancer. We also highlight Phase III randomized trials, currently underway, using either the T-DM1 conjugate or various combinations of monoclonal antibodies and TKIs. Moreover, in contrast with all these agents developed on the basis of “central dogma” of simplified reductionist transcription and single gene–phenotype linear relationship, we summarize the emerging, amazing era of next-generation, transcriptional circuitry and intracellular signaling network-based drugs guided by the latest advances in genome science and dynamics of network biology.

Radical dissection after positive groin sentinel biopsy in melanoma patients: rate of further positive nodes.

The aim of this retrospective study was to analyze the incidence of further nonsentinel node metastases at completion lymphadenectomy of the groin after a positive sentinel node biopsy to evaluate whether radical dissection remains the treatment of choice for these patients. Patients treated at the National Cancer Institute of Milan between January 1999 and December 2006 were reviewed retrospectively. The analysis included patients with a diagnosis of positive sentinel node biopsy of the groin (clinically negative) who underwent completion groin, iliac, and obturatory dissections. The primary melanoma was located on the lower extremities and trunk in 82.5 and 17.5%, respectively. The median follow-up was more than 30 months. The number of positive sentinel nodes was considered, as well as the size and location of the metastases (micro vs. macro). After radical dissection, the number and the location (groin, iliac, or groin+iliac nodes) of further nonsentinel node metastases were analyzed. The frequency of further nonsentinel node metastases at completion of groin dissection was correlated to Breslows thickness and to the characteristics of the positive sentinel node biopsy. A total of 1581 patients with primary melanoma (>1 mm, or Clarks IV–V) underwent lymphatic mapping and sentinel node biopsy: 752 patients had sentinel node biopsy at the groin basin; among these, 150 (20%) patients presented positive sentinel node biopsy and underwent completion radical dissection (groin, obturatory, and external iliac+obturatory radical node dissections). We found further positive nonsentinel node metastases in 36 of 150 (24%) patients, 69% (25 of 36) of which were located in the iliac–obturator area and 31% in the groin area only: 16 patients (44.4%) had one additional metastatic node and seven patients (19.4%) had two, whereas 13 (36.1%) had three or more. In 22 cases (61.1%), the sentinel node showed a macrometastasis (>2 mm deposit in the node) and in 14 cases (38.9%) a micrometastasis (<2 mm deposit). In conclusion, there is clear evidence that patients with a positive sentinel node biopsy could have further positive nonsentinel node metastases (in our series, 24%). Although it is well known that the impact of sentinel node biopsy on survival of melanoma patients has yet to be defined, to obtain a clear nodal basin and regional control a groin+iliac–obturatory radical node dissection remains an appropriate procedure in the presence of a positive sentinel node biopsy at the groin level. This could be considered a standard treatment until new data, provided by ongoing studies, indicate new parameters for selecting patients for completion lymph node dissection.

Rectoanal motility in Crohn's disease patients.

PURPOSE: It has been documented that Crohns disease affects anorectal function when anorectal manifestations of the disease are present. The aim of this study was to investigate whether the presence of histologic lesions in rectal biopsy affected anorectal motility in patients with Crohns disease but no evidence of macroscopic anorectal involvement. METHODS: Forty-one patients with documented Crohns disease were included in the study. Twenty-one of them had no endoscopic or histologic lesions in the rectum, and 20 patients had a positive histology for Crohns disease on rectal biopsy, with or without macroscopic or endoscopic involvement of the anorectum. All patients underwent a standard anorectal manometry, with an eight-channel, water-perfused catheter. RESULTS: Patients with positive rectal biopsy but no evidence of endoscopic rectal involvement had lower anal resting and squeeze pressures (76±16 standard deviationvs. 86±19 standard deviationP=0.002; 152±56 standard deviationvs. 192±52 standard deviationP<0.001, respectively), and a lower sphincter and high-pressure zone length (2.8±0.8 standard deviationvs. 3.2±0.8 standard deviationP=0.006; 1.7±0.6 standard deviationvs. 2±0.6 standard deviationP=0.005, respectively) compared with patients with negative rectal histology. Also, slow and ultra slow wave amplitude and ultra slow wave frequency were significantly lower (10±6 standard deviationvs. 13±7 standard deviationP=0.04; 17±16 standard deviationvs. 34±24 SDP=0.004; 0.9±0.8 standard deviationvs. 1.3±0.6 standard deviationP=0.05, respectively), rectal sensation more affected, and rectal compliance significantly reduced (7.4±1 standard deviationvs. 11.1±2.2 standard deviationP<0.001) in the former group of patients. Simultaneous presence of endoscopic and histologic lesions in the rectum was associated with further impairment of the anorectal function. CONCLUSION: Microscopic presence alone of Crohns disease in the rectum appears to induce anorectal motility disorders. The synchronous presence of endoscopic rectal and macroscopic anal involvement is associated with further deterioration of anorectal function.

Pilot study of breast sensation after breast reconstruction: Evaluating the effects of radiation therapy and perforator flap neurotization on sensory recovery

Some sensation to the breast returns after breast reconstruction, but recovery is variable and unpredictable. We primarily sought to assess the impact of different types of breast reconstruction [deep inferior epigastric artery perforator (DIEP) flaps versus implants] and radiation therapy on the return of sensation.