Davide Mineo

Point: steady progress and current challenges in clinical islet transplantation.

The field of β-cell replacement therapies has evolved substantially over the last decades. The lesson learned from recent islet transplantation trials in patients with unstable type 1 diabetes is that primary goals are the achievement of stable, normalized glycemic control in the absence of severe hypoglycemic episodes with improvement of quality of life and the prevention of progressive, chronic diabetes complications. Insulin independence, although desirable, should not be considered the main objective, particularly in light of the sustained positive effects achieved even with a “marginal” functional islet mass via restoration of C-peptide secretion and reduction of insulin requirements. As present limitations of islet transplantation are progressively overcome, the clinical application will greatly expand from the currently limited indication in controlled clinical research trials to more widely available cellular therapies and regenerative medicine solutions that will eventually be offered as standard treatment to the majority of patients with insulin-requiring diabetes. Vantyghem et al. (1) in the article in this issue of Diabetes Care evaluated the predictive value of primary graft function on long-term clinical outcomes of islet transplantation alone (ITA). Surrogate measures have been proposed to monitor or predict β-cell function, but they are not yet fully validated (2–4). In this report, the use of the β-score in the early posttransplant period allowed to quantify primary graft function that, when “optimal,” was associated with prolonged graft survival and better metabolic control following islet transplantation (1). In agreement with previous reports using the “Edmonton Protocol” (5–10), this trial resulted in a significant improvement of metabolic control and long-term graft function (∼70% having measurable C-peptide at 5 years). Importantly, the investigators also showed prolonged insulin independence in 57% of the patients at 5 years, with the subjects with optimal primary graft …

Awake Nonresectional Lung Volume Reduction Surgery

Objective:To assess the feasibility, safety, and early results of awake lung volume reduction surgery (LVRS) performed under thoracic epidural anesthesia by a new nonresectional technique. Summary Background Data:So far, resectional LVRS under general anesthesia and one-lung ventilation is the more frequently used technique, but procedure-related morbidity has been considerable. Methods:The study cohort included 12 patients undergoing unilateral awake LVRS. Evaluated parameters included technical feasibility and anesthesia satisfaction scored into 4 grades (from 1 = poor to 4 = excellent), global operating room time, and arterial carbon dioxide tension (PaCO2). In addition, 6-month changes in outcome measures, including forced expiratory volume in 1 second (FEV1), residual volume (RV), 6-minute walking test (SMWT), and dyspnea index were recorded. Perioperative and 6-month results were comparable with those of a control group undergoing unilateral resectional LVRS. Results:Technical feasibility was excellent to satisfactory in 11 patients. One patient required conversion to one-lung ventilation. Differences between the awake and control group included global operating room time (90 ± 17 minutes versus 145 ± 19 minutes, P < 0.00001); PaCO2 24 hours after surgery (45 ± 6 mm Hg versus 49 ± 6 mm Hg, P = 0.02); and hospital stay (7.8 ± 5 days versus 11.7 ± 4 days, P = 0.02). Significant (P < 0.002) improvements occurred at 6 months in FEV1 (0.31 ± 0.17 L), RV (−1.41 ± 0.7 L), SMWT (73 ± 25 m), and dyspnea index (−1.3 ± 0.5) and were comparable with those of the control group. Conclusions:In this study, awake nonresectional LVRS proved feasible and safe. This new modality was associated with a faster recovery and satisfactory 6-month outcome, which did not differ from that of resectional LVRS.

Bilateral Thoracoscopic T2 to T3 Sympathectomy Versus Botulinum Injection in Palmar Hyperhidrosis

BACKGROUND Bilateral T2 to T3 thoracoscopic sympathectomy and injection of botulinum toxin-A are presently the most effective modalities in the treatment of primary palmar hyperhidrosis. In this study we evaluated comparative merits of the two therapies. METHODS Patients suffering primary palmar hyperhidrosis were treated by either bilateral T2 to T3 thoracoscopic sympathectomy (n = 68) or by injection of botulinum toxin-A (n = 86). The groups were homogeneous for relevant demographic, physiologic, and clinical data. Quantification of sweat production was performed by Minors iodine starch and glove tests. Subjective changes were assessed by quality of life questionnaires (Hyperhidrosis, Dermatology Life Quality Index, Short Form-36, Nottinghams Health Profile) and patients satisfaction self-assessment. A cost comparison between groups was also carried out. RESULTS No operative mortality or major morbidity was recorded in either group. Minors test showed a more significant reduction in the surgical group: +94% versus +63% at 6 months and +94% versus +30% at 12 months. Compensatory sweating was significantly greater and long-lasting in the surgical group. All subjective tests improved rapidly and significantly in both groups. After 6 months, results mildly worsened in the surgical group and more significantly in the botulinum group. Patients satisfaction was initially greater in the botulinum group (p = 0.03), but after 6 months it significantly reversed (p = 0.04). Surgical treatment cost approximately as much as four botulinum treatments. CONCLUSIONS Thoracoscopic sympathectomy is superior to botulinum toxin-A injection. The greater initial costs and discomfort are offset by a greater reduction in compensatory sweating.

Postsurgical chemotherapy in stage IB nonsmall cell lung cancer: Long-term survival in a randomized study

Although surgical resection is considered the adequate treatment in early stages of nonsmall cell lung cancer, long‐term survival is not satisfactory and recurrence rate is high. We previously showed that postoperative chemotherapy at stage IB reduces recurrences and prolongs overall survival. We extended size and observation period of the study sample and performed a separate analysis for minimally resected patients. The trial was designed as a randomized, 2‐armed study with postoperative adjuvant chemotherapy versus surgery alone as control group. All patients had stage IB disease (pT2N0) assessed after a radical surgical procedure (defined as anatomical or minimal). Chemotherapy consisted of cisplatin (100 mg/m2 day 1) and etoposide (120 mg/m2 days 1–3) for 6 cycles. The primary endpoint was overall survival; secondary endpoint was disease‐free survival (DFS). One hundred and forty patients entered the study: 70 were assigned to the adjuvant chemotherapy group and 70 to the control group. Groups were homogeneous for conventional risk factors. There was no clinically significant morbidity associated to chemotherapy. Patients were followed for a mean period of 40.31 ± 30.86 months. A significant difference in overall (p = 0.02) and disease‐free (p = 0.0001) survival was observed between patients undergoing adjuvant chemotherapy vs. control group. Adjuvant chemotherapy significantly improved both overall (p = 0.02) and DFS (p = 0.003) of anatomically resected patients, but only the DFS (p = 0.02) of minimally resected patients. Our results confirm that adjuvant chemotherapy may have a real impact on long‐term survival in patients with stage IB nonsmall cell lung cancer being this effect especially evident for those anatomically resected.

Quality of life after tailored combined surgery for stage I non–small-cell lung cancer and severe emphysema

BACKGROUND We analyzed the early and long-term quality of life changes occurring in 16 patients undergoing tailored combined surgery for stage I non-small-cell lung cancer (NSCLC) and severe emphysema. METHODS Mean age was 65 +/- 5 years. All patients had severe emphysema with severely impaired respiratory function and quality of life. Tumor resection was performed with sole lung volume reduction (LVR) in 5 patients, separate wedge resection in 3 patients, segmentectomy in 2 patients, and lobectomy in 6 patients. A bilateral LVR was performed in 5 patients. Quality of life was assessed at baseline and every 6 months postoperatively by the Short-form 36 (SF-36) item questionnaire. RESULTS Mean follow-up was 44 +/- 21 months. All tumors were pathologic stage I. There was no hospital mortality nor major morbidity. Significant improvements occurred for up to 36 months in the general health (p = 0.02) domain and for up to 24 months in physical functioning (p = 0.02), role physical (p = 0.005), and general health (p = 0.01) SF-36 domains. Associated improvements regarded dyspnea index (-1.3 +/- 0.6) forced expiratory volume in one second (+0.28 +/- 0.2L), residual volume (-1.18 +/- 0.5L) and 6-minute-walking test distance (+86 +/- 67 m). Actuarial 5-year survival was similar to that of patients with no cancer undergoing LVRS during the same period (68% vs 82%, p = not significant). CONCLUSIONS Our study suggests that selected patients with stage I NSCLC and severe emphysema may significantly benefit from tailored combined surgery in terms of long-term quality of life and survival.

Symptomatic and quality of life changes after extrapleural pneumonectomy for malignant pleural mesothelioma

Extrapleural pneumonectomy for malignant pleural mesothelioma is considered an aggressive procedure, but symptomatic and quality of life changes are unknown.

Variations of inflammatory mediators and α1-antitrypsin levels after lung volume reduction surgery for emphysema.

RATIONALE In emphysema, chronic inflammation, including protease-antiprotease imbalance, is responsible for declining pulmonary function and progressive cachexia. OBJECTIVES To evaluate variations of inflammatory mediators and alpha(1)-antitrypsin levels after lung volume reduction surgery (LVRS) compared with respiratory rehabilitation. METHODS A total of 28 patients with moderate to severe emphysema, who underwent video-assisted thoracoscopic LVRS, were compared with 26 similar patients, who refused operation and followed a standardized rehabilitation program, and to a matched healthy group. Respiratory function, body composition, circulating inflammatory mediators, and alpha(1)-antitrypsin levels were evaluated before and 12 months after treatment. Gene expression levels of inflammatory mediators and protease-antiprotease were assessed in emphysematous specimens from 17 operated patients by matching to normal tissue from resection margins. MEASUREMENTS AND MAIN RESULTS Significant improvements were only obtained after surgery in respiratory function (FEV(1), +25.2%, P < 0.0001; residual volume [RV], -19.5%, P < 0.0001; diffusing lung capacity for carbon monoxide, +3.3%, P < 0.05) and body composition (fat-free mass, +6.5%, P < 0.01; fat mass, +11.9%, P < 0.01), with decrement of circulating inflammatory mediators (TNF-alpha, -22.2%, P < 0.001; IL-6, -24.5%, P < 0.001; IL-8, -20.0%, P < 0.001) and increment of antiprotease levels (alpha(1)-antitrypsin, +27.0%, P < 0.001). Supportive gene expression analysis demonstrated active inflammation and protease hyperactivity in the resected emphysematous tissue. Reduction of TNF-alpha and IL-6 and increment of alpha(1)-antitrypsin levels significantly correlated with reduction of RV (P = 0.03, P = 0.009, and P = 0.001, respectively), and partially with increment of fat-free mass (P = 0.03, P = 0.02, and P = 0.09, respectively). CONCLUSIONS LVRS significantly reduced circulating inflammatory mediators and increased antiprotease levels over respiratory rehabilitation, also improving respiratory function and nutritional status. Correlations of inflammatory mediators and antiprotease levels with RV and, partly, with body composition suggest that elimination of inflammatory emphysematous tissue may explain clinical improvements after surgery.

Recurrent intrathoracic thymomas: Potential prognostic importance of cell-cycle protein expression

OBJECTIVE Recurrent intrathoracic thymomas may have an unpredictable behavior. Cell-cycle protein expression has proven useful in predicting outcome in a variety of neoplasms. We investigated its potential prognostic importance in recurrent intrathoracic thymomas. METHODS We reviewed the case histories of 25 consecutive patients operated on between 1987 and 2004 for intrathoracic recurrence (7 mediastinal, 18 nonmediastinal) after radical thymomectomy. Complete resection was performed in 14 patients. In the other 11 patients incomplete resection was followed by chemotherapy and radiotherapy. Expression of cell-cycle proteins (p53, p21, and p27) was assessed by immunohistochemistry in specimens retrieved from both initial and recurrent thymomas. Univariate and multivariate analysis for prognostic factors present at the time of the recurrence was performed. RESULTS Eight of 14 patients who underwent complete resection had a second recurrence after a mean free interval of 20 +/- 9 months, and a new complete resection was reperformed in 4. After incomplete resection, chemotherapy and radiotherapy allowed total remission in 4 subjects and only 1 of these had a second recurrence. Survival after surgery of the recurrence was negatively influenced by incomplete recurrence resection (P = .03), first disease-free interval less than 24 months (P = .03), high p53 (P = .04), low p21 (P = .02), low p27 (P = .003) expressions, and combination of these proteins (p53 high, p21 low, p27 low expression) (P = .0001). Multivariate analysis selected the triple combination of cell-cycle protein expression as the most significant prognostic variable (P = .02, odds ratio = 11.96, 95% confidence interval = 1.39-102.63). CONCLUSIONS Cell-cycle protein expression, and namely the combination of high p53, low p21, and low p27 expression, may have a potential prognostic importance in recurrent intrathoracic thymomas.

Effects of lung volume reduction surgery for emphysema on glycolipidic hormones.

BACKGROUND Pulmonary emphysema is associated with cachexia and disregulation of the hormones regulating the glycolipid metabolism, insulin resistance, and altered substrate utilization. This study aimed at identifying the effects of lung volume reduction surgery (LVRS) on glycolipidic hormones compared to respiratory rehabilitation (RR). METHODS Thirty-three patients with moderate-to-severe emphysema who were undergoing video-assisted thoracoscopic LVRS were compared to 31 similar patients who refused the operation and followed a standardized RR program. All patients were evaluated before and 12 months after treatment for respiratory function, body composition, glycolipidic hormones, metabolic parameters, and insulin resistance, which was calculated using the homeostatic model assessment index for insulin resistance (HOMA-IR). These groups were compared to a matched healthy control population. RESULTS Only after LVRS significant improvements were obtained in respiratory function (FEV1, +25.2%; p<0.0001; residual volume, -19.5%; p<0.0001), metabolic parameters (total cholesterol, +13.1%; p<0.01; high-density lipoprotein cholesterol, +11.2%; p<0.01; triglycerides, +18.4; p<0.001; nonesterified fatty acid, -19.7%; p<0.001), and body composition (fat-free mass [FFM], +6.5%; p<0.01; fat mass [FM], +11.9%; p<0.01). The leptin/FM ratio (-6.1%; p<0.01) and resistin/FM ratio (-5.6%; p<0.01) decreased, whereas the adiponectin/FM ratio (+6.9%; p<0.01) and ghrelin (+9.2%; p<0.01) increased, together with reductions in glycemia (-8.8%; p<0.01), insulin level (-20.4%; p<0.001), and HOMA-IR (-27.2%; p<0.0001). The decrement in residual volume was correlated with increment of FFM (rho=-0.49; p<0.02), FM (rho=-0.55; p<0.009), and ghrelin (rho=-0.52; p<0.01), and also with decreases in leptin corrected for FM (rho=0.50; p<0.02) and, marginally, HOMA-IR (rho=0.35; p=0.07). CONCLUSIONS After LVRS, glycolipidic hormone levels and nutritional status significantly improved, along with insulin resistance reduction and more physiologic utilization of substrates. Correlations between residual volume and body composition as well as glycolipidic hormone levels suggest that postoperative recovery in respiratory dynamics may induce favorable clinical changes when compared to RR.

Analysis of Cell Cycle Regulator Proteins in Encapsulated Thymomas

Purpose: Although survival of encapsulated thymomas is usually good, some patients present a higher incidence rate of recurrence and a shorter long-term survival. Abnormalities in the components of cell cycle checkpoints are extremely common among virtually all neoplasms. In this study, three components of the cell cycle machinery (i.e., p21, p27 and p53) were examined in a series of well-characterized encapsulated thymoma specimens to analyze coregulation and influence on recurrence and survival. Experimental Design: Sixty-eight consecutive patients with thymoma were operated in our center from 1987 to 2000. Expression of p53, p21, and p27 was studied in specimens from 25 encapsulated thymomas using immunohistochemistry. Generic factors and gene expression influencing the probability of recurrence were studied. Positive expression was dichotomized defining positive when present in more than 5% of tumor cells. Mean follow up was 85.9 months; clinical data about recurrence were recorded. Results: Univariate analysis suggests that positive p53 (P < 0.05), negative p21 (P = 0.01), and especially negative p27 expressions (P = 0.001) significantly correlate with poor prognosis for disease-free survival. Multivariate Cox regression analysis suggests that negative p27 immunohistology is the only significant variable for poor prognosis (P = 0.03; odds ratio, 0.08; 95% confidence interval, 0.01-0.88). Conclusions: These results show that loss of control of cell cycle checkpoints is a common occurrence in thymomas and support the idea that functional cooperation between different cell cycle inhibitor proteins constitutes another level of regulation in cell growth control and tumor suppression.