Massimiliano D’Aiuto

Awake Single-Access (Uniportal) Video-Assisted Thoracoscopic Surgery for Peripheral Pulmonary Nodules in a Complete Ambulatory Setting

PURPOSE Traditional 3-port video-assisted thoracoscopic surgery (VATS) in a patient who is awake has been proposed as a breakthrough in the direction of fast tracking patients through routine thoracic surgical procedures. We wanted to explore the possibility of further reducing surgical invasiveness by resecting a peripheral pulmonary nodule with single-access (uniportal) VATS in an awake, nonintubated, nonventilated patient, with selective occlusion of the tributary lobar bronchus. DESCRIPTION A 47-year-old woman with bilateral peripheral nodules underwent uniportal VATS wedge resection of an undetermined nodule in the right middle lobe. The patient was awake and under mild sedation for the entire procedure. Single-shot epidural regional anesthesia was administered. Under guidance provided by a reusable, portable flexible bronchoscope, a Fogarty balloon was positioned to occlude the right middle lobe bronchus to facilitate collapse of the targeted parenchyma. At the end of the procedure, the chest drain was connected to a portable vacuum system delivering autonomous suction. EVALUATION Awake uniportal VATS resection of peripheral nodules in selected patients is feasible and appears to be safe. Available technology may enable further reduction of costs related to length of hospitalization. CONCLUSIONS The concept of ambulatory thoracic surgery may further evolve by utilizing uniportal VATS in an awake patient to solve the often-challenging diagnostic dilemmas represented by undetermined lung lesions.

Triple negative breast cancer: looking for the missing link between biology and treatments

The so called “Triple Negative Breast Cancer” (TNBC) represents approximately 15-20% of breast cancers. This acronym simply means that the tumour does not express oestrogen receptor (ER) and progesterone receptor (PR) and does not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene. Despite this unambiguous definition, TNBCs are an heterogeneous group of tumours with just one common clinical feature: a distinctly aggressive nature with higher rates of relapse and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Because of the absence of well-defined molecular targets, cytotoxic chemotherapy is currently the only treatment option for TNBC. In the last decades, the use of more aggressive chemotherapy has produced a clear improvement of the prognosis in women with TNBC, but this approach results in an unacceptable deterioration in the quality of life, also if some support therapies try to relieve patients from distress. In addition, there is the general belief that it is impossible to further improve the prognosis of TNBC patients with chemotherapy alone. In view of that, there is a feverish search for new “clever drugs” able both to rescue chemo-resistant, and to reduce the burden of chemotherapy in chemo-responsive TNBC patients. A major obstacle to identifying actionable targets in TNBC is the vast disease heterogeneity both inter-tumour and intra-tumour and years of study have failed to demonstrate a single unifying alteration that is targetable in TNBC. TNBC is considered the subtype that best benefits from the neoadjuvant model, since the strong correlation between pathological Complete Response and long-term Disease-Free-Survival in these patients. In this review, we discuss the recent discoveries that have furthered our understanding of TNBC, with a focus on the subtyping of TNBC. We also explore the implications of these discoveries for future treatments and highlight the need for a completely different type of clinical trials.

Molecular profiles of screen detected vs. symptomatic breast cancer and their impact on survival: results from a clinical series.

BackgroundStage shift is widely considered a major determinant of the survival benefit conferred by breast cancer screening. However, factors and mechanisms underlying such a prognostic advantage need further clarification. We sought to compare the molecular characteristics of screen detected vs. symptomatic breast cancers and assess whether differences in tumour biology might translate into survival benefit.MethodsIn a clinical series of 448 women with operable breast cancer, the Kaplan-Meier method and the log-rank test were used to estimate the likelihood of cancer recurrence and death. The Cox proportional hazard model was used for the multivariate analyses including mode of detection, age at diagnosis, tumour size, and lymph node status. These same models were applied to subgroups defined by molecular subtypes.ResultsScreen detected breast cancers tended to show more favourable clinicopathological features and survival outcomes compared to symptomatic cancers. The luminal A subtype was more common in women with mammography detected tumours than in symptomatic patients (68.5 vs. 59.0%, p=0.04). Data analysis across categories of molecular subtypes revealed significantly longer disease free and overall survival for screen detected cancers with a luminal A subtype only (p=0.01 and 0.02, respectively). For women with a luminal A subtype, the independent prognostic role of mode of detection on recurrence was confirmed in Cox proportional hazard models (p=0.03). An independent role of modality of detection on survival was also suggested (p=0.05).ConclusionsMolecular subtypes did not substantially explain the differences in survival outcomes between screened and symptomatic patients. However, our results suggest that molecular profiles might play a role in interpreting such differences at least partially.Further studies are warranted to reinterpret the efficacy of screening programmes in the light of tumour biology.

Combination of inositol and alpha lipoic acid in metabolic syndrome-affected women: a randomized placebo-controlled trial

BackgroundInositol has been reported to improve insulin sensitivity since it works as a second messenger achieving insulin-like effects on metabolic enzymes. The aim of this study was to evaluate the inositol and alpha lipoic acid combination effectiveness on metabolic syndrome features in postmenopausal women at risk of breast cancer.MethodsA six-month prospective, randomized placebo-controlled trial was carried out on a total of 155 postmenopausal women affected by metabolic syndrome at risk of breast cancer, the INOSIDEX trial. All women were asked to follow a low-calorie diet and were assigned randomly to daily consumption of a combination of inositol and alpha lipoic acid (77 pts) or placebo (78 pts) for six months. Primary outcomes we wanted to achieve were both reduction of more than 20% of the HOMA-IR index and of triglycerides serum levels. Secondary outcomes expected were both the improvement of high-density lipoprotein cholesterol levels and the reduction of anthropometric features such as body mass index and waist-hip ratio.ResultsA significant HOMA-IR reduction of more than 20% was evidenced in 66.7% (P <0.0001) of patients, associated with a serum insulin level decrease in 89.3% (P <0.0000). A decrease in triglycerides was evidenced in 43.2% of patients consuming the supplement (P <0.0001). An increase in HDL cholesterol (48.6%) was found in the group consuming inositol with respect to the placebo group. A reduction in waist circumference and waist-hip ratio was found in the treated group with respect to the placebo group.ConclusionsInositol combined with alpha lipoic acid can be used as a dietary supplement in insulin-resistant patients in order to increase their insulin sensitiveness. Daily consumption of inositol combined with alpha lipoic acid has a significant bearing on metabolic syndrome. As metabolic syndrome is considered a modifiable risk factor of breast tumorigenesis, further studies are required to assess whether inositol combined with alpha lipoic acid can be administered as a dietary supplement in breast cancer primary prevention.Trial registrationCurrent Controlled Trial ISRCTN74096908.

Surgery of the chest wall for involvement by breast cancer

Chest wall involvement by breast cancer remains a difficult clinical challenge that may occur at the time of the primary diagnosis or later as a result of locoregional breast cancer recurrence. A case-by-case multidisciplinary approach is strongly recommended, and a multimodality therapy should be always considered. Full-thickness resection of the chest wall can be done with acceptable morbidity and mortality, providing a good palliation and a better quality of life even to patients with poor prognosis. Moreover, in well-selected cases, chest wall resection results in locoregional control of disease and prolongation of life.

Organo-Metallic Compounds: Novel Molecules in Cancer Therapy

The discovery of cis-platin in the treatment of cancer there has been a considerable exploration on the antitumoral activity of other transition metal complexes. One of the main problems about the application of transition metal complexes for chemotherapy is their potential toxicity. Recently the attention has been focused on titanium based complexes, which could have significant potential effect against solid tumor. The advantage of Ti (IV) complexes is their relative biological compatibility, which mostly leads to mild and revisable side effects. However, the hydrolytic instability of known Ti(IV) complexes and formation of different species upon water addition makes their therapeutic application problematic, and raises a strong interest in the development of relatively stable Ti(IV) complexes with well defined hydrolytic behavior that demonstrate appreciable cytotoxic activity. Strong ligand binding is also of interest to avoid complete ligand stripping by transferrin, so that the ligand may be used as a target for structure–activity relationship investigations. Titanocene dichloride (Cp2TiCl2) shows an average antiproliferative activity in vitro and promising result in vivo. Recent work has been performed in developing therapeutic analogues of Cp2TiCl2 by varying the central metal, the labile ligands (Cl) and the biscyclopentadienyl moiety. In particular, small changes to the Cp ligand can strongly affect the hydrolytic stability and water solubility properties of the metallocenes and have an impact on the cytotoxic activity. In this review we want summarize the importance of different organo-mettalic compounds in cancer therapy with focus on possible structure modification.

External radiotherapy for breast cancer in the elderly

BackgroundBreast cancer is the most common malignancy amongst elderly women and the main cause of mortality. A specific management for elderly woman is not clear because clinical trials are usually not customized for this subset of patients.AimsThe aim of this paper is to provide an overview of the available information on the main issues in the field of breast cancer radiotherapy in the elderly population.Materials and methodsAuthors discuss on different radiation treatments for breast cancer in the elderly, based on the data of the literature with a focus on new strategy: hypo-fractionation, accelerated partial breast irradiation, and the utility of a dose boost.DiscussionThe treatment of breast cancer is not standardized in the elderly. The optimal management in this population often requires complex multidisciplinary supportive care due to multiple comorbidities to optimize their cancer care.ConclusionsNew options such as APBI or HyRT regimens should be taken into consideration and offered as a breach of duty to the elderly population. Furthermore, they should be extensively investigated through randomized clinical trials.

Management of Implant Exposure in One-Stage Breast Reconstruction Using Titanium-Coated Polypropylene Mesh: Sub-Mammary Intercostal Perforator Flap

IntroductionOne-stage implant-based breast reconstruction using titanium-coated polypropylene mesh is a novel approach widely used in Europe. Complication rates in breast reconstruction with the use of titanium-coated meshes seem to be comparable to those in patients with implant-based breast reconstruction alone. However, the use of synthetic meshes in implant-based breast reconstructive surgery leads to new clinical scenarios with the need for the breast surgeon to face new complications. We present an innovative treatment of implant exposure in the absence of infection in patients who underwent nipple-sparing mastectomy and immediate breast reconstruction with silicone implants and titanium-coated polypropylene mesh by using a pedicled sub-mammary intercostal perforator flap.Cases PresentationFour patients who experienced implant exposure without infection have been treated with the use of a sub-mammary intercostal perforator flap. Whole coverage of the exposed implant/mesh with a sub-mammary intercostal perforator flap was obtained in all cases. No post-operative complications have been observed, whereas a pleasant aesthetic result has been achieved. Patients’ post-operative quality of life and satisfaction levels were measured by the European Organisation for Research and Treatment of Cancer breast cancer-specific quality of life QLQ-BR23 questionnaire and showed an average good satisfaction with the post-operative outcomes (mean QLQ-BR23 score 1.9).DiscussionFor the first time, a sub-mammary intercostal perforator flap has been used with the aim of treating implant exposures without removing the prosthesis even in the presence of synthetic meshes, when wound infection was excluded. Although tested on a small series, the sub-mammary intercostal perforator flap might represent a simple, versatile and cost-effective procedure for the management of implant exposure following nipple-sparing mastectomy and immediate reconstruction with silicone implants and synthetic meshes. It should be considered to avoid implant removal followed by delayed free flap reconstruction as “salvage surgery.”Level of Evidence VThis journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Preoperative Systemic Therapy

Neoadjuvant (preoperative) therapy is defined as the first systemic treatment a patient receives when nonmetastatic breast cancer is diagnosed. Neoadjuvant treatment has the ability to shrink tumors and was first used, in the 1970s, in patients with inoperable locally-advanced or inflammatory disease. Data from several retrospective analyses showed that the application of multimodal treatment consisting of neoadjuvant chemotherapy, surgery, radiotherapy, and hormonal therapy improved survival for patients with locally-advanced breast cancer (LABC) [1–2]. The role of neoadjuvant treatment has evolved since this time; indeed, in the last two decades, preoperative chemotherapy has also been performed in women with large operable breast cancer in order to downstage the tumor and thus enabling breast-conservative surgery. More recently, the preoperative approach has also been tested in patients with early breast cancer, suitable for conservative surgery, in order to allow a more rapid evaluation of new therapies without the need for long-term follow-up to demonstrate a survival advantage [3–27]. The absence after neoadjuvant chemotherapy of residual tumor (pCR; pathologic complete response) is associated with a very favorable long-term outcome, suggesting that pCR could be a marker for long-term effects on disseminated tumor cells [28]. However, different definitions of pCR have been reported in the past (i.e. no residual tumor in breast, no residual tumor in breast and axilla, only residual DCIS), since there was not a general agreement about the prognostic impact of residual carcinoma in situ in the breast, and of the persistence of residual tumor only in the axillary nodes.

Breast cancer screening, body mass index and prognosis benefit.

Beeken et al hypothesized that screening compliance would be lower for obese individuals than for those with healthy weight status, but their study found no association between weight status and breast cancer screening in England. The study, one of the few to investigate body mass index (BMI) and breast cancer screening, was conducted in a country with high breast cancer screening compliance. In southern Italy, conversely, there is low screening compliance, causing delays in breast cancer diagnosis and also increased mortality. The positive association between BMI and increased incidence and mortality is well recognized, but there are few studies on the association between BMI, mode of breast cancer detection, and prognosis. We undertook a study to verify whether there were differences in breast cancer prognosis between screen-detected v.s. symptomatic women, according to BMI status. We analyzed data from a clinical series of 448 women diagnosed with incident, histologically-confirmed breast cancer at the G. Pascale Foundation, National Cancer Institute of Naples. Detailed eligibility criteria are reported elsewhere. BMI was categorized as: normal weight (<25 kg/m), overweight (25–29 kg/m) and obese (530 kg/m). Tumours were considered screen-detected if suspicious findings were first detected by breast imaging within the routine national screening programme. Women were followed for a median of 4.6 years and rates of recurrence were calculated among screened and symptomatic patients by dividing the number of events by the total person-time at risk. Unadjusted relative risks (rate ratios) were obtained by dividing the event rate in the screened group by that in symptomatic group. Multivariate associations were estimated using the Cox regression model. Relative risks (hazard ratios) and 95% confidence intervals (CIs) were calculated, adjusting for influential factors. We found no association comparing screen-detected and symptomatic women with BMI categories using the Chi-Square test (p1⁄4 0.24) (Table 1). Breast cancer recurrence was diagnosed in 12 women in the screen-detected group (11.2%) and 81 women in the symptomatic group (26%) (Table 2). The rate of recurrence was 22 per 1000 person-years for screen-detected (95% CI 11-39) and 64 per 1000 person-years for symptomatic women (95% CI 51-80). The unadjusted relative risk for screen-detected women was 0.37 (95% CI 0.21-0.66). Adjusting for age, education, lymph-nodes, tumour size, Ki-67, and receptor status using a Cox model yielded a relative risk of 0.46 (95% CI 0.23-0.91). The relative risk was lower when restricting to a BMI <25: adjusted risk of recurrence associated with screen-detected women was 0.07 (95% CI 0.13-0.73). In the other BMI categories, adjusted relative risks associated with screen-detected women were closer to 1. Our findings confirmed that screen-detected women have better prognosis and, similarly to Beeken et al, there was no association between weight status and breast cancer screening. Our study highlighted the potential impact of weight on breast cancer prognosis. Heavier women seemed to have more aggressive cancers and this was evident among the screen-detected group. This unexpected finding may be partly due to the association with higher BMI and metabolic syndrome, both negative factors for breast cancer risk and prognosis, and partly explained by the strong positive correlation between BMI and absolute breast density, a biomarker of breast