Real-World Outcome of Treatment with Single-Agent Ibrutinib in Italian Patients with Chronic Lymphocytic Leukemia: Final Results of the EVIdeNCE Study.

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients' clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3-4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.

Total 'rib'-preservation technique of internal mammary vessel exposure for free flap breast reconstruction: A 5-year prospective cohort study and instructional video.

INTRODUCTION: The total 'rib'-preservation method of dissecting out the internal mammary vessels (IMV) during microvascular breast reconstruction aims to reduce free flap morbidity at the recipient site. We review our five-year experience with this technique. PATIENTS & METHODS: An analysis of a prospectively collected free flap data cohort was undertaken to determine the indications, operative details and reconstructive outcomes in all breast reconstruction patients undergoing IMV exposure using the total 'rib'-preservation method by a single surgeon. RESULTS: 178 consecutive breast free flaps (156 unilateral, 11 bilateral) were performed from 1st June 2008 to 31st May 2013 in 167 patients with a median age of 50 years (range 28-71). There were 154 DIEP flaps, 14 SIEA flaps, 7 muscle-sparing free TRAMs, 2 IGAP flaps and one free latissimus dorsi flap. 75% of the reconstructions (133/178) were immediate, 25% (45/178) were delayed. The mean inter-costal space distance was 20.9 mm (range 9-29). The mean time taken to expose and prepare the recipient IMV's was 54 min (range 17-131). The mean flap ischaemia time was 95 min (range 38-190). Free flap survival was 100%, although 2.2% (4 flaps) required a return to theatre for exploration and flap salvage. No patients complained of localised chest pain or tenderness at the recipient site and no chest wall contour deformity has been observed. DISCUSSION & CONCLUSION: The total 'rib'-preservation technique of IMV exposure is a safe, reliable and versatile method for microvascular breast reconstruction and should be considered as a valid alternative to the 'rib'-sacrificing techniques.

The relationship between the intercostal distance, patient height and outcome in microsurgical breast reconstruction using the second interspace rib-sparing internal mammary vessel exposure.

PURPOSE OF THE STUDY: Rib-sparing internal mammary vessel (IMV) exposure in breast reconstruction is becoming common, with a smaller space in which to perform the microanastomoses. The objectives were to determine whether patient height could be used as a proxy measurement for intercostal distance (ICD), assess whether the complication rate or the flap ischemia time are affected in such surgery, and provide anatomical data about ICDs. METHODS: Data were collected from 95 consecutive patients (109 breasts) undergoing free flap breast reconstruction using rib-sparing vessel exposure over a 3-year period by one surgeon. Pearson's product moment correlation coefficient was used to assess the relation between height and ICD, body mass index (BMI), operative times, and flap outcomes. RESULTS: There was no correlation between patient height and ICD (r = 0.087), age, BMI, recipient vessel preparation time, and flap ischemia time. CONCLUSION: Being able to predict patients with a small ICD in whom microsurgery may be more challenging can influence surgical planning. The anatomy of the intercostal spaces is variable and was not predictable in relation to height, BMI, or age. Height was not a reliable proxy for ICD and where there is a concern about the available ICD it is suggested that it is measured directly through preoperative imaging. This study found no increase in the complication rate and flap ischemia time using the rib-sparing IMV exposure technique.

An unusual tumor in a rare localization: intravascular leiomyosarcoma of the cephalic vein. Case report.

Vascular leiomyosarcoma is a very rare soft tissue neoplasma, with a poor prognosis. We report a vascular leiomyosarcoma arising from an unusual site: the media-vascular wall of the cephalic vein. A 71-year-old man with a subcutaneous node on the volar side of right forearm, came to our attention with signs of vascular obstruction and venous stases, without functional or sensory loss of the right upper extremity. We successfully performed a surgical excision of the cancer with a wide margin resection. During surgery no ascellar lympnodes metastes were found. 4 months after surgery the wound had fully healed, and he suffered no effects by surgery, but he became lost to long-term follow-up and refused adjuvant radiotherapy or chemiotherapy. This case report shows that, in presence of venous stases or thrombosis signs of the upper extremity, leiomyosarcoma of the cephalic vein must be considered in the differential diagnosis among lung cancer, lymphoma or mesenchymal tumours.

An algorithmic approach to perineal reconstruction after cancer resection--experience from two international centers.

AIM: This paper aims to simplify the approach to reconstruction of the perineum after resection of malignancies of the anal canal, lower rectum, vulva, and vagina. MATERIALS AND METHODS: The data were collected from 2 centers, namely, Addenbrooke's Hospital, University of Cambridge, United Kingdom and Christchurch Hospital, University of Otago, New Zealand. All patients who underwent perineal reconstruction from 1997 to 2009 at Christchurch Hospital (13 years) and 2001 to 2009 at Addenbrooke's Hospital (9 years) were included. The diagnosis (indication), primary surgery, reconstructive surgery, complications, tumor outcomes (recurrence and survival), and follow-up were entered into a database (Microsoft Excel; Redmond, Wash). The incidence of previous radiotherapy, requirement for adjuvant radiotherapy, and length of inpatient stay were also recorded. RESULTS: Forty-six patients were identified for this study--13 in New Zealand and 33 in Cambridge. Indications for perineal reconstruction included resection of anal and rectal malignancies (24), vulval and vaginal malignancy (19), perineal sarcoma (1), and perineal squamous cell carcinoma arising in an enterocutaneous fistula (Table 1). The reconstructive strategies adopted included rectus abdominis myocutaneous flaps (26), gluteal fold flaps (9), gracilis V-Y or advancement flaps (7) and others (4), gluteal rotation flaps (1), local flap (2), and free latissimus dorsi flaps (1). CONCLUSIONS: Although various surgeons performed the reconstructive surgeries at 2 different centers, the essential approach remained the same. Smaller defects were best treated by local flaps, whereas the rectus abdominis flap remained the standard option for larger defects that additionally required closure of dead space. On the basis of our 2 center experience, we propose a simple algorithm to facilitate the planning of reconstructive surgery for the perineum.

Previous multiple abdominal surgeries: a valid contraindication to abdominal free flap breast reconstruction?

UNLABELLED: PRESENTED IN PART AT THE FOLLOWING ACADEMIC MEETINGS: 57th Meeting of the Italian Society of Plastic, Reconstructive and Aesthetic Surgery, September 24-27, 2008, Naples, Italy.45th Congress of the European Society for Surgical Research (ESSR), June 9-12, 2010, Geneva, Switzerland.British Association of Plastic Reconstructive and Aesthetic Surgeons Summer Scientific Meeting, June 30-July 2, 2010, Sheffield Hallam University, Sheffield, UK. BACKGROUND: Patients with previous multiple abdominal surgeries are often denied abdominal free flap breast reconstruction because of concerns about flap viability and abdominal wall integrity. We therefore studied their flap and donor site outcomes and compared them to patients with no previous abdominal surgery to find out whether this is a valid contraindication to the use of abdominal tissue. PATIENTS AND METHODS: Twenty patients with multiple previous abdominal operations who underwent abdominal free flap breast reconstruction by a single surgeon (C.M.M., 2000-2009) were identified and retrospectively compared with a cohort of similar patients without previous abdominal surgery (sequential allocation control group, n = 20). RESULTS: The index and control groups were comparable in age, body mass index, comorbidities, previous chemotherapy, and RT exposure. The index patients had a mean age of 54 years (r, 42-63) and an average body mass index of 27.5 kg/m(2) (r, 22-38). The main previous surgeries were Caesarean sections (19), hysterectomies (8), and cholecystectomies (6). They underwent immediate (n = 9) or delayed (n = 11) reconstructions either unilaterally (n = 18) or bilaterally (n = 2) and comprising 9 muscle-sparing free transverse rectus abdominis muscle and 13 deep inferior epigastric perforator flaps. All flaps were successful, and there were no significant differences in flap and donor site outcomes between the 2 groups after an average follow up of 26 months (r, 10-36). CONCLUSION: Multiple previous abdominal surgeries did not predispose to increased flap or donor site morbidity. On the basis of our experience, we have proposed some recommendations for successful abdominal free flap breast reconstruction in patients with previous multiple scars. Careful preoperative planning and the use of some intraoperative adaptations can allow abdominal free flap breast reconstruction to be reliably undertaken in such patients.

The three dermoglandular flap support in reduction mammaplasty.

BACKGROUND: Bilateral breast reduction is an established procedure performed to relieve the physical pain and psychological discomfort associated with heavy, pendulous breasts. Numerous techniques have been developed over the years with several refinements to obtain safe nipple-areola complex transposition and harmonious breast shape. Based on the experience of the senior author (M.P.), the three dermoglandular flap technique is proposed to achieve a safe and aesthetically pleasing breast reduction through the surgical concept of dermal support. METHODS: The authors analyzed the benefits of the three dermoglandular flap technique performed in a selected group of smoking patients with a potentially high risk of postoperative complications and high probability of breast ptosis recurrence (each patient had breast volume >1000 cc, breast nipple ptosis grade 3 on Regnault's scale, and body mass index >27). Blood supply to the nipple-areola complex was based on an inferior-central pedicle. RESULTS: Between 1995 and 2007, 47 smokers underwent bilateral breast reduction using the three dermoglandular flap technique. Their ages ranged from 37 to 63 years (mean, 49 years), and their average body mass index was 31.2 kg/m (range, 27 to 38). The overall complications rate was 14.9 percent. No wound breakdowns and no complete or partial necrosis of the nipple-areola complex was observed. Follow-up ranged from 18 to 48 months (mean, 32 months). CONCLUSIONS: : Three dermoglandular flap reduction mammaplasty produced good cone shape, soft texture, and fullness in the central and inferior pole with satisfactory breast projection and was stable over time. It offers a safe and practical approach in the treatment of challenging breast hypertrophy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Versatility of the anterolateral thigh free flap: the four seasons flap.

UNLABELLED: Presented at the following academic meetings:○ 56th Meeting of the Italian Society of Plastic, Reconstructive and Aesthetic Surgery (SICPRE) Fasano (Brindisi), Italy, September 26-29, 2007○ 42nd Meeting of the European Society for Surgical Research (ESSR), Warsaw, Poland, May 21-24, 2008○ Winter Meeting, British Association of Plastic, Reconstructive and Aesthetic Surgeons, (BAPRAS) London, December 1-3, 2009BACKGROUND: The anterolateral free flap has become increasingly popular at our institution year on year. We decided to review our experience with this flap and study the reasons for this trend. METHODS: A retrospective review of all anterolateral thigh free flaps performed at Addenbrooke's University Hospital from the available charts was carried out. This chart review included patients' demographics, indications, flap size, recipient vessels used, ischemia time, flap, and donor site outcomes. All flap perforator vessels were located preoperatively using a handheld Doppler ultrasound probe. RESULTS: From October 1999 to December 2008, 55 anterolateral thigh flaps were performed in 55 patients to reconstruct a variety of soft-tissue defects (upper and lower limbs, chest wall, skull base, head and neck). Flap size ranged 12 to 35 cm in length and 4 to 11 cm in width. During flap elevation, the main supply to the flap was found to be a direct septocutaneous perforator in 41% (n = 23) of the cases as opposed to a musculocutaneous perforator, which was found in 59% (n = 32). The mean ischemia time was 82 minutes (range, 62-103). The overall flap success rate was 100%. Two flaps were successfully salvaged after reexploration for venous congestion. The donor site morbidity was minimal. The mean follow-up time was 18 months (range, 2-48). DISCUSSION AND CONCLUSION: The anterolateral thigh free flap was found to be a very reliable flap (100% success) across a wide range of clinical indications. It facilitates microvascular anastomoses as evidenced by the short ischemia time. It provided ample skin with volume that could be tailored to the defect. These advantages have led to its widespread use by different consultants and trainees in our department.

Rhytidectomy approach for recurrent Madelung disease.

Benign symmetrical lipomatosis (Madelung disease) is a rare metabolic disorder characterized by the presence of multiple, symmetric, nonencapsulated fat masses in the face, neck, and shoulders. The clinical course is slow, typically one of slow progressive enlargement with cosmetic and functional sequelae. The authors describe a case in which an open surgical approach was performed to treat this disorder, with good results. There are many aspects of treatment currently lacking a consensus, and the authors discuss these, principally in relation to the location of the fat, the role of liposuction versus surgery, the staging of surgical procedures, and the placement of the incisions.

Gene expression profiling identifies eleven DNA repair genes down-regulated during mouse neural crest cell migration.

Neural Crest Cells (NCCs) are transient multipotent migratory cells that derive from the embryonic neural crest which is itself derived from the margin of the neural tube. DNA repair genes are expressed in the early stages of mammalian development to reduce possible replication errors and genotoxic damage. Some birth defects and cancers are due to inappropriate or defective DNA repair machinery, indicating that the proper functioning of DNA repair genes in the early stages of fetal development is essential for maintaining DNA integrity. We performed a genome-wide expression analysis combining laser capture microdissection (LCM) and high-density oligo-microarray of murine NCCs at pre-migratory embryonic days 8.5 (E8.5), and at E13.5, as well as on neural crest-derived cells from the adrenal medulla at postnatal day 90. We found 11 genes involved in DNA repair activity (response to DNA damage stimulus, DNA damage checkpoint, base-excision repair, mismatch repair), over-expressed in the early stages of mouse embryo development. Expression of these 11 genes was very low or undetectable in the differentiated adrenal medulla of the adult mouse. Amongst the 11 genes, 6 had not been previously reported as being over-expressed during mouse embryonic development. High expression of DNA repair genes in enriched NCCs during early embryonic development may contribute to maintaining DNA integrity whilst failure of some of these genes may be associated with the onset of genetic disease and cancer. Our model of enriched murine NCCs and neural crest-derived cells can be used to elucidate the key roles of genes during normal embryonic development and in cancer pathogenesis.

Aesthetic and functional abdominal wall reconstruction after multiple bowel perforations secondary to liposuction.

This report describes a case of aesthetic and functional abdominal wall reconstruction performed to salvage a deformed, scarred, and herniated anterior abdomen after severe peritonitis and partial rectus muscle necrosis secondary to multiple bowel perforations sustained during liposuction performed in a cosmetic clinic. The diagnosis of intestinal perforation was missed intraoperatively and in the immediate postoperative period. The patient was admitted 4 days after the surgery to the intensive therapy unit in septicemic shock. After resuscitation and stabilization, she was treated by debridement of the abdominal wall, bowel resection, and temporary jejunostomy and colostomy (reversed 10 months later). She was referred 18 months after liposuction to the Plastic Surgery Service with a large central midline abdominal incisional hernia presenting with thinned out skin (14 × 11 cm) overlying adherent bowel. A components separation technique was successfully used to reconstruct the abdominal wall, with no recurrent herniation 2 years later. Survivors of bowel perforations sustained during abdominal liposuction may later present with challenging aesthetic and functional problems, as described in this report. These long-term sequelae have not been addressed hitherto in the literature.

Tips for successful microvascular abdominal flap breast reconstruction utilizing the "total rib preservation" technique for internal mammary vessel exposure.

INTRODUCTION: The internal mammary vessels (IMVs) are increasingly the recipients for free flap breast reconstruction (FFBR). Access traditionally entails removing a segment of the third costal cartilage. Despite excellent exposure, some authors have reported localized tenderness as well as a thoracic contour deformity. We introduced the "total rib preservation" technique for IMV exposure after specific request by a patient, and have used it for all subsequent reconstructions. METHODS: All patients who underwent FFBR with rib preservation by a single surgeon in the year beginning June 2008 were studied prospectively. Intraoperative measurements of the inter-rib space available for microvascular anastomosis were taken. Operative details and flap outcomes were compared with a cohort of earlier patients who underwent rib sacrifice. RESULTS: Over a 12-month period, 42 FFBRs in 37 patients (36 deep inferior epigastric perforator, five muscle-sparing transverse rectus abdominis myocutaneous, and one superficial inferior epigastric artery flap) were performed by a single operator. All flap transfers were successful. In the first 4 patients, the interspace between the third and fourth ribs was used; but for all subsequent patients the second and third rib interspace was used. The average distance between adjacent ribs was 21.3 mm (range, 9-28 mm) and the vessel preparation time decreased from an average of 93 to 49 minutes (first and last 5 cases). There was no significant difference in mean ischemia time between the rib preservation and the rib sacrifice groups (104.4 vs. 103.6 minutes). CONCLUSIONS: The total rib preservation method of IMV exposure is a viable, reproducible, and reliable option for microvascular breast reconstruction. It does not increase warm ischemia, which suggests time taken for anastomosis is not affected by rib preservation. There is a learning curve and care has to be taken to avoid possible pitfalls. We recommend the use of a higher rib interspace than originally described because of the greater vessel calibre, superior vessel exposure, and therefore, easier anastomosis.

Anterolateral thigh free flap for complex composite central chest wall defect reconstruction with extrathoracic microvascular anastomoses.

BACKGROUND: Complex central chest wall resection defects present a challenging management problem for both thoracic and reconstructive surgeons. Although most chest wall defects can be repaired using local and regional flaps, more complicated cases require increasingly sophisticated techniques such as microsurgical free tissue transfer. This study reviews a single plastic surgeon's experience over a 4-year period with complex chest wall reconstruction using the anterolateral thigh free flap. METHODS: Five female patients who underwent the above procedure between 2004 and 2007 were reviewed retrospectively. The clinicopathologic details recorded included histologic diagnosis, extent of resection, type of skeletal defect, flap size, receipt vessels, ischemia time, and flap/donor-site complications. Skeletal reconstruction used methylmethacrylate/polypropylene mesh sandwich prostheses. RESULTS: The indications for surgery were metastatic breast cancer (n=3), advanced primary fibrosarcoma (n=1), and extensive radionecrosis (n=1). The average surface area of the chest wall resection was 197 cm (range, 156 to 270 cm). The four patients who underwent partial sternectomy and rib resection required skeletal reconstruction and subsequent ventilatory support postoperatively in the intensive care unit. The mean anterolateral thigh flap size was 188 cm (range, 143 to 252 cm); none of the donor sites was skin grafted. There was 100 percent flap survival, and the prostheses remained fully covered in all cases after a mean follow-up of 16 months (range, 5 to 28 months). No major complications were observed. CONCLUSIONS: The anterolateral thigh free flap is a safe and reliable option for reconstructing complicated composite chest wall defects. It therefore provides a practical alternative when regional pedicled flap options are unavailable or inadequate.

Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels.

SCN(-) (thiocyanate) is an important physiological anion involved in innate defense of mucosal surfaces. SCN(-) is oxidized by H(2)O(2), a reaction catalyzed by lactoperoxidase, to produce OSCN(-) (hypothiocyanite), a molecule with antimicrobial activity. Given the importance of the availability of SCN(-) in the airway surface fluid, we studied transepithelial SCN(-) transport in the human bronchial epithelium. We found evidence for at least three mechanisms for basolateral to apical SCN(-) flux. cAMP and Ca(2+) regulatory pathways controlled SCN(-) transport through cystic fibrosis transmembrane conductance regulator and Ca(2+)-activated Cl(-) channels, respectively, the latter mechanism being significantly increased by treatment with IL-4. Stimulation with IL-4 also induced the strong up-regulation of an electroneutral SCN(-)/Cl(-) exchange. Global gene expression analysis with microarrays and functional studies indicated pendrin (SLC26A4) as the protein responsible for this SCN(-) transport. Measurements of H(2)O(2) production at the apical surface of bronchial cells indicated that the extent of SCN(-) transport is important to modulate the conversion of this oxidant molecule by the lactoperoxidase system. Our studies indicate that the human bronchial epithelium expresses various SCN(-) transport mechanisms under resting and stimulated conditions. Defects in SCN(-) transport in the airways may be responsible for susceptibility to infections and/or decreased ability to scavenge oxidants.