Resection of the irradiated esophagus: the impact of lymph node yield on survival.

There is debate surrounding the appropriate threshold for lymph node harvest during esophagectomy in patients with esophageal cancer, specifically for those receiving preoperative radiation. The purpose of this study was to determine the impact of lymph node yield on survival in patients receiving preoperative chemoradiation for esophageal cancer. The National Cancer Database (NCDB) was utilized to identify patients with esophageal cancer that received preoperative radiation. The cohort was divided into patients undergoing minimal (<9) or extensive (≥9) lymph node yield. Demographic, operative, and postoperative outcomes were compared between the groups. Kaplan-Meier analysis with the log rank test was used to compare survival between the yield groups. Cox proportional hazards model was used to determine the association between lymph node yield and survival. In total, 886 cases were included: 349 (39%) belonging to the minimal node group and 537 (61%) to the extensive group. Unadjusted 5-year survival was similar between the minimal and extensive groups, respectively (37.3% vs. 38.8%; P > 0.05). After adjustment using Cox regression, extensive lymph node yield was associated with survival (hazard ratio 0.80, confidence interval 0.66-0.98, P = 0.03). This study suggests that extensive lymph node yield is advantageous for patients with esophageal cancer undergoing esophagectomy following induction therapy. This most likely reflects improved diagnosis and staging with extensive yield.

Evaluation of trans-sphenoidal surgery in pituitary GH-secreting micro- and macroadenomas: a comparison between microsurgical and endoscopic approach.

AIM: Acromegaly is caused by a GH-secreting pituitary adenoma, associated with many comorbidities and increased risk of mortality. Surgery is the first-line therapy. Success of therapy is measured by symptomatic improvement, preservation of pituitary function and biochemical control. Trans-sphenoidal surgery (TSS), endoscopic or microscopic, is the preferred treatment. To evaluate surgery effectiveness and individuate the technique associated with a higher remission rate, patients undergoing TSS were retrospectively selected. METHODS: Thirty-seven consecutive patients underwent surgery between 1996 and 2006. Tumors were classified into macroadenomas or microadenomas and into intrasellar, extrasellar and extrasellar with cavernous sinus invasion. Surgery was performed in 22 patients with endoscopic technique, in 15 patients with microsurgical approach. The hormonal assays were performed 6 months and yearly after surgery for an average of 5 years. RESULTS: Ten patients were affected by microadenoma, 27 by macroadenoma. In microadenomas remission rate was independent of the used technique. Within macroadenomas, remission percentage in endoscopic approach (68.75%) was significantly higher than in microscopic approach (18.18%) (P=0.018). Postsurgical biochemical remission was calculated combining the surgical technique and tumor extension: the endoscopic approach was associated with a significantly higher remission rate in extrasellar than both in intrasellar and extrasellar with cavernous sinus invasion. In the latter group, any technique had not reached biochemical remission. CONCLUSION: TSS is able to induce a long-term remission of acromegaly, with low risk of recurrence and complications. Endoscopic approach is more suitable than microscopic technique in macroadenomas and adenomas with suprasellar extension.

Induction chemoradiation therapy prior to esophagectomy is associated with superior long-term survival for esophageal cancer.

The purpose of this study was to examine the role of induction chemoradiation in the treatment of potentially resectable locally advanced (T2-3N0 and T1-3N+) esophageal cancer utilizing a large national database. The National Cancer Data Base (NCDB) was queried for all patients undergoing esophagectomy for clinical T2-3N0 and T1-3N+ esophageal cancer of the mid- or lower esophagus. Patients were stratified by the use of induction chemoradiation therapy versus surgery-first. Trends were assessed with the Cochran-Armitage test. Predictors of receiving induction therapy were evaluated with multivariable logistic regression. A propensity-matched analysis was conducted to compare outcomes between groups, and the Kaplan-Meier method was used to estimate long-term survival. Within the NCDB, 7921 patients were identified, of which 6103 (77.0%) were treated with chemoradiation prior to esophagectomy, while the remaining 1818 (23.0%) were managed with surgery-first. Use of induction therapy increased over time, with an absolute increase of 11.8% from 2003-2011 (P < 0.001). As revealed by the propensity model, induction therapy was associated with higher rates of negative margins and shorter hospital length of stay, but no differences in unplanned readmission and 30-day mortality rates. In unadjusted survival analysis, induction therapy was associated with better long-term survival compared to a strategy of surgery-first, with 5-year survival rates of 37.2% versus 28.6%, P < 0.001. Following propensity score matching analysis, the use of induction therapy maintained a significant survival advantage over surgery-first (5-year survival: 37.9% vs. 28.7%, P < 0.001). Treatment with induction chemoradiation therapy prior to surgical resection is associated with significant improvement in long-term survival, even after adjusting for confounders with a propensity model. Induction therapy should be considered in all medically appropriate patients with resectable cT2-3N0 and cT1-3N+ esophageal cancer, prior to esophagectomy.

Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the surveillance, epidemiology, and end results registry from 1998 to 2008.

We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five-year cancer-specific survival (CSS) and overall survival (OS) were analyzed using propensity-score adjusted Cox proportional-hazard models. Overall 5-year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3-20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8-42.5%, P = 0.01) and radiation alone (29.3-44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used.

Randomised clinical trial: mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease--a double-blind, randomised, placebo-controlled study.

BACKGROUND: Placebo-controlled studies in maintaining remission of symptomatic uncomplicated diverticular disease (SUDD) of the colon are lacking. AIM: To assess the effectiveness of mesalazine and/or probiotics in maintaining remission in SUDD. METHODS: A multicentre, double-blind, placebo-controlled study was conducted. Two hundred and ten patients were randomly enrolled in a double-blind fashion in four groups: Group M (active mesalazine 1.6 g/day plus Lactobacillus casei subsp. DG placebo), Group L (active Lactobacillus casei subsp. DG 24 billion/day plus mesalazine placebo), Group LM (active Lactobacillus casei subsp. DG 24 billion/day plus active mesalazine), Group P (Lactobacillus casei subsp. DG placebo plus mesalazine placebo). Patients received treatment for 10 days/month for 12 months. Recurrence of SUDD was defined as the reappearance of abdominal pain during follow-up, scored as ≥5 (0: best; 10: worst) for at least 24 consecutive hours. RESULTS: Recurrence of SUDD occurred in no (0%) patient in group LM, in 7 (13.7%) patients in group M, in 8 (14.5%) patients in group L and in 23 (46.0%) patients in group P (LM group vs. M group, P = 0.015; LM group vs. L group, P = 0.011; LM group vs. P group, P = 0.000; M group vs. P group, P = 0.000; L group vs. P group, P = 0.000). Acute diverticulitis occurred in six group P cases and in one group L case (P = 0.003). CONCLUSION: Both cyclic mesalazine and Lactobacillus casei subsp. DG treatments, particularly when given in combination, appear to be better than placebo for maintaining remission of symptomatic uncomplicated diverticular disease. (ClinicalTrials.gov: NCT01534754).

A case of GH deficiency and beta-thalassemia.

A 23-year-old male patient, who suffers from beta-thalassemia major, came to us for an endocrine-metabolic evaluation. Medical history showed a diagnosis of heart disease with heart failure since the age of 16, type 1 diabetes mellitus diagnosed at the age of 18, treated with an intensive insulin therapy with a poor glycometabolic control. Patient performed regular blood transfusions and iron chelation with deferasirox. An echocardiogram revealed an enlarged left ventricle. Patient had undergone a comprehensive study of buoyancy both basal and hormone-stimulated and it was therefore carried out a diagnosis of GH deficiency and hypogonadotropic hypogonadism. A recombinant GH replacement therapy was then prescribed. After six months of therapy, the patient reported a net improvement of asthenic symptoms. Physical examination showed a reduction in abdominal adiposity in waist and an increase of 5 cm in stature. Laboratory tests showed an amelioration of glycometabolic control, such as to justify a reduction in daily insulin dose. The stature observed was thought appropriate to begin the administration of testosterone. Moreover, the cardiological framework showed a reduction of left ventricular dilatation, good ventricular motility, global minimum persistent tricuspid but not mitral regurgitation and no alteration on ECG.

[Efficacy of external conventional radiotherapy in short and long term control of acromegaly; a comparison with stereotactic irradiation]. / Efficacia della Radioterapia Convenzionale nel controllo abreve e a lungo termine della malattia acromegalica: confrontocon la metodica stereotassica.

AIMS: The aim of this study was to follow up two groups of patients with active acromegaly, who underwent to external irradiation and radio-surgery and to value the efficacy of irradiation in the control of the growth of the adenoma, hypersecretion and incidence of adverse events. MATERIALS AND METHODS: In 2 groups of patients, (A) of 47 subjects treated with conventional irradiation at a dose of 45 Gy, (B) of 6 subjects irradiated with stereo taxis radiotherapy at a dose of 15-20 Gy, were evaluated GH, IGF1 levels and pituitary function at 2, 5, 10 and 15 years after treatment. A cerebral MRI scan with detailed study of the sellar region was performed every year. RESULTS: Group (A): decrease of GH levels in 9% of patients after 2 years from therapy, 29% after 5 years, 52% after 10 years, 77% after 15 years; normalization of IGF1 levels in 8% of cases after 2 years, 23%, 42% and 61% respectively after 5, 10 and 15 years; hypopituitarism in 57, 78, 85% of patients, respectively after 5, 10 and 15 years. Group (B):normalization of IGF1 levels in 4 of 6 patients after 5 years and in all subjects after 10 and 15 years; progressive decrease of GH levels in all patients and GH normalization in 2 of 6 cases after 10 years; hypopituitarism in 1 patient after 2 years. CONCLUSIONS: We confirm the long term efficacy of external Radiotherapy in active acromegaly. Stereo taxis annuls the risks of neurological and neurovascular complications of conventional RT. Although comparison between the two techniques is not statistical significant in our cases we can affirm a faster normalization of IGF1 levels after stereotactic treatment.

[Thoracic wall defect reconstruction and dead space obliteration with an intra-/extrathoracic free flap]. / Thoraxwandrekonstruktion und Totraumobliteration. Einsatz einer intra-/extrathorakalen freien Lappenplastik.

Presented is the case of a 61-year-old male patient with a chronic thoracic wall defect, including a bronchopleural fistula, after multiple resections of a desmoid tumor. After partial lung resection to remove the bronchopleural fistula, dead space was partially obliterated and the thoracic wall reconstructed with a free combined intra- and extrathoracic rectus abdominis muscle flap.

Prevalence of celiac disease in patients with autoimmune thyroiditis.

AIM: Many autoimmune disorders are associated to celiac disease (CD) but the association with autoimmune thyroiditis has been more frequently documented; this is in part explained by a shared immunogenetic make-up, and in part caused to time gluten-exposition, as suggested by the significant correlation observed in celiac patients between the increase occurrence of autoimmune diseases and the length of exposure to gluten. The aim of this study was to establish the prevalence of celiac disease in a group of subjects with autoimmune thyroiditis newly diagnosed on the basis of antibodies anti-peroxidase (TPO). METHODS: A total of 113 untreated patients with TPO >70 IU/mL were enrolled. CD was screened by measuring anti-endomysial antibodies (EMA) both IgA and IgG; an high prevalence of positive serology was resulting in this group, justified, in part, from EMA IgG investigation. RESULTS: In fact 31/113 patients showed IgA and/or IgG positivity and were diagnosed as celiacs with jejunal biopsy. CONCLUSION: On the basis of this paper, such as in according to current research-setting studies, the greater frequency of CD in association to autoimmune thyroid disease suggests that all subjects with TPO should be routinely screened for CD, through EMA IgA and IgG. However, the performance of this screening has never been evaluated until now, even if it could, in fact, be valid in order to increment diagnosis of CD, today still undiagnosed.

Polyglandular autoimmune endocrine insufficiency complicated by severe osteoporosis.

In literature different cases of polyglandular autoimmune type II syndrome (PGA II) are reported, where Addison's disease is associated with gonadal insufficiency. The lack in the production of sexual steroids causes a severe postmenopausal osteoporosis. The case we report is related to a 38-year-old woman we met in 1988 and who was suffering from deep asthenia, cramps, cutaneous hyperpigmentation, nausea, vomiting, abdominal pain, weight loss and hypotension. The biochemical data were indicative for autoimmune adrenal failure. Between 1988 and 1997 the patient developed a progressive insufficiency of other endocrine glands, leading to the classic feature of PGA II. In 1998, this clinical status was complicated by a severe osteoporosis. We thought that the sudden decrease in the bony mineral density was due to the lack of the protective role played by adrenal gland androgens in postmenopausal osteoporosis. They would directly act on the bony tissue, independently from oestrogens peripheral conversion, thus producing a stimulant effect on the bone formation. A new therapeutical approach, in case of osteoporosis, is today represented by DHEA replacement therapy in women showing low hormone levels.

The impact of pre-radiotherapy surgery on radiation-induced lung injury.

AIMS: The use of postoperative radiation therapy (PORT) is predicated by an assessment of the potential benefits and risks, including radiation-induced lung injury. In this study, the risk of radiation-induced lung injury is assessed in patients who received PORT, and compared with a group of patients who received radiation without prior surgery, to determine if surgery increases the risk of radiation pneumonitis. MATERIALS AND METHODS: From 1991 to 2003, 251 patients with lung cancer were enrolled into a prospective study to assess radiation-induced lung injury. All patients received three-dimensional-planned, external-beam radiotherapy. One hundred and seventy-seven patients with over 6-months follow-up were eligible. For the current analysis, 49 patients (28%) had surgical intervention before radiotherapy. The rates of Grade 2 symptomatic pneumonitis in subgroups, based on the type of pre-radiation surgery, were computed and compared using Fisher's Exact Test. To consider the confounding factor of irradiated lung volume, patient subgroups were further defined on the basis of the mean lung dose. RESULTS: Surgical procedures included pneumonectomy (n=9), lobectomy (n=16), wedge resection (n=8) and exploration without resection (n=16). Radiation-induced lung injury occurred in 33 out of 177 (19%) patients, including 18% of the surgical group and 19% of the non-surgical group. Additionally, no statistically significant difference was found in the rate of radiation-induced lung injury based on the extent of resection. CONCLUSIONS: The incidence of pneumonitis is similar in the surgical and non-surgical groups. Thus, PORT may be safely given to selected patients after surgical exploration or resection.

Predicting the sites of metastases from lung cancer using molecular biologic markers.

BACKGROUND: The use of molecular markers in staging non-small cell lung cancer (NSCLC) has been supported in retrospective prognostic models but has not been evaluated in predicting sites of metastases. METHODS: Pathologic specimens were collected from 202 patients after complete resection for stage I NSCLC, who were subsequently found to have no metastases at 5 years (n = 108), isolated brain metastases (n = 25), or other distant metastases (n = 69). A panel of eight molecular markers of metastatic potential was chosen for immunohistochemical analysis of the tumor: p53, erbB2, angiogenesis factor viii, EphA2, E-cadherin, urokinase plasminogen activator (UPA), UPA receptor, and plasminogen activator inhibitor. RESULTS: Patients with isolated brain relapse had significantly higher expression of p53 (p = 0.02) and UPA (p = 0.002). The quantitative expression of E-cadherin was used to predict the site of metastases using recursive partitioning: 0 of 92 patients with E-cadherin expression of 0, 1, or 2 developed isolated cerebral metastases; 0 of 33 patients with E-cadherin expression of 3 with UPA of 1 or 2 and ErbB2 of 0 developed brain metastases. Of the remaining patients at risk (UPA = 3), the risk of isolated cerebral metastases was 21 of 57 patients (37%). CONCLUSIONS: This study demonstrates that molecular markers may predict the site of relapse in early stage NSCLC. If validated in an ongoing prospective study, these results could be used to select patients with isolated brain metastases for adjuvant therapy, such as prophylactic cranial irradiation.

Tumor marker expression is predictive of survival in patients with esophageal cancer.

BACKGROUND: This study was designed to determine the prognostic value of immunohistochemical tumor marker expression in a population of patients with node-negative esophageal cancer treated with complete resection alone. METHODS: Resection specimens were collected from 61 patients with node-negative T1 (n = 31), T2 (n = 14), and T3 (n = 16) esophageal cancer. A panel of 10 tumor markers was chosen for immunohistochemical analysis, based on associations with differing oncologic mechanisms: apoptosis (p53), growth regulation (transforming growth factor-alpha, epidermal growth factor receptor, and Her2-neu), angiogenesis (factor VIII), metastatic potential (CD44), platinum resistance (p-glycoprotein and metallothionein), 5-fluorouracil resistance (thymidylate synthetase), and carcinogenic detoxification (glutathione S-transferase-pi). RESULTS: Complete resection was performed in all patients (44 adenocarcinoma, 17 squamous cell carcinoma), with no operative deaths. Multivariable analysis demonstrated a significant relationship between cancer-specific death and the following variables: low-level P-gp expression (p = 0.004), high-level expression of p53 (p = 0.04), and low-level expression of transforming growth factor-alpha (p = 0.03). In addition, the number of involved tumor markers present was strongly predictive of negative outcome (p = 0.0001). CONCLUSIONS: This study supports the prognostic value of immunohistochemical tumor markers, specifically the expression pattern of P-gp, p53, and transforming growth factor-alpha, in patients with esophageal carcinoma treated with complete resection alone.

The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer.

The purpose of this study was to define the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer. The original pretreatment paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 118 patients treated with concurrent cisplatin + 5-fluorouracil (5-FU) + 45 Gy radiation followed by resection from 1986 until 1997 at the Duke University Comprehensive Cancer Center. Three markers of possible platinum chemotherapy association [metallothionein (MT), glutathione S-transferase-pi (GST-pi), P-glycoprotein (P-gp or multidrug resistance)] and one marker of possible 5-FU association [thymidylate synthase (TS)] were measured using immunohistochemistry. The median cancer-free survival was 25.0 months, with a significantly improved survival for the 38 patients who had a complete response (P < 0.001). High-level expression of GST-pi, P-gp, and TS were associated with a decreased survival. MT was not significant in this population. Multivariate analysis identified high-level expression in two of the platinum markers (GST-pi and P-gp) and the 5-FU marker TS as independent predictors of early recurrence and death. In conclusion, this investigation measured three possible markers associated with platinum and one possible marker associated with 5-FU in a cohort of esophageal cancer patients. Independent prognostic significance was observed, which suggests that it may be possible to predict which patients may benefit most from trimodality therapy. These data need to be reproduced in a prospective investigation.

Thymopoiesis in HIV-infected adults after highly active antiretroviral therapy.

The thymus of HIV-seropositive patients can enlarge as CD4+ T cell counts increase on highly active anti-retroviral therapy (HAART). This may indicate development of new T cells or represent mature peripheral T cells recirculating to the thymus. To define the etiology of the enlargement, the thymuses of two HIV-infected individuals on HAART were biopsied. For more than 3 years before initiation of HAART, both patients (38 and 41 years of age) had documented CD4+ T lymphopenia. Peripheral blood samples were obtained to assess circulating CD4+ CD45RA+ CD62L+ T cells, which were thought to have recently developed in the thymus. Peripheral blood T cells from both patients and thymocytes from the second patient were also tested for levels of DNA episomes formed during T cell receptor gene rearrangement (T cell receptor rearrangement excision circles, TRECs). With HAART, peripheral blood CD4+ T cell counts increased from approximately 60/mm(3) to 552/mm(3) and 750/mm(3) for patients 1 and 2, respectively. Thymic biopsies from both patients showed normal thymus histology with active thymopoiesis. Percentages of peripheral blood CD4+ CD45RA+ CD62L+ T cells and quantitation of T cell TRECs also reflected active thymopoiesis in both patients. Thus, in these two HIV-seropositive adults examined after initiation of HAART, thymic enlargement represented active thymopoiesis. Thymopoiesis in adult AIDS patients may contribute to immune reconstitution even after prolonged CD4+ T lymphopenia.

Molecular biology of esophageal cancer.

Several mechanisms of resistance to chemotherapy have been identified among the agents that are commonly used in the systemic treatment of patients with esophageal cancer: paclitaxel, platinum, and 5-FU. A recent study from our laboratory evaluated the initial endoscopic biopsy material from patients who subsequently underwent trimodality therapy, including chemotherapy with cisplatin and 5-FU, radiation therapy, and surgery. IHC analysis was performed on seven markers of chemotherapy or radiation therapy resistance: P-gp, GST-pi, MT (platinum inhibitors); EGF-R, TGF-alpha, erb-B2 (activation of cell growth cascade); and p53 (interferes with chemotherapy-induced apoptosis). In this study, elevated expression of GST-pi and P-gp were associated with decreased survival and may be markers of treatment resistance. Expression of erb-B2 was associated with enhanced survival and may be a marker of treatment sensitivity. Assessment of the probability of chemoresistance of a particular tumor using the expression of molecular biologic markers may allow for the selection of a more favorable chemotherapeutic agent. Furthermore, understanding the mechanisms of resistance, including the mechanisms of DNA repair, may provide insight into mechanisms to reverse or to inhibit resistance to chemotherapy. DNA repair mechanisms are used by cells to protect themselves against mutagens and carcinogens. DNA repair inhibitors may increase the mutagenicity associated with DNA damage and may prove to be an ineffective oncologic treatment strategy; however, the possibility exists that DNA repair inhibition may improve the efficacy of anticancer agents, and this should be tested. The value of this strategy may be in allowing treatment doses to be decreased and lessening side effects while maintaining therapeutic efficacy.

Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients.

BACKGROUND: Panel-reactive antibody (PRA) is used to estimate the degree of humoral sensitization in the recipient before transplantation. Although pretransplant sensitization is associated with increased complications in other solid organ transplant recipients, less is known about the outcome of sensitized lung transplant recipients. Therefore, we sought to determine the impact of elevated pretransplant PRA on clinical outcomes after lung transplantation. METHODS: The records of the first 200 lung transplant operations performed at Duke University Medical Center were reviewed. The outcomes of sensitized patients, PRA greater than 10% before transplantation (n = 18), were compared with the outcomes of nonsensitized patients. RESULTS: Sensitized patients experienced a significantly greater number of median ventilator days posttransplant (9 +/- 8) as compared with nonsensitized recipients (1 +/- 11; p = 0.0008). There were no significant differences between the number of episodes of acute rejection; however, there was a significantly increased incidence of bronchiolitis obliterans syndrome occurring in untreated sensitized recipients (56%) versus nonsensitized (23%; p = 0.044). In addition, there was a trend towards decreased survival in the sensitized recipients, with a 2-year survival of 58% in sensitized recipients as compared with 73% in the nonsensitized patients (p = 0.31). CONCLUSIONS: Sensitized lung transplant recipients experience more acute and chronic complications after transplantation. These patients probably warrant alternative management strategies.