Time Of Definitive Surgery Research Articles

A phase II neoadjuvant study of cisplatin/paclitaxel with or without RAD001 in patients with triple-negative (TN) locally advanced breast cancer (BC).

TPS119 Background: In a fraction of TN BC, p63 is coordinately expressed with p73, and may be antagonizing p73 transcriptional and tumor suppressive activity. Based on findings that mTOR inhibitors can activate p73 and can enhance chemosensitivity of cancer cells to cisplatin (known to activate p73) and paclitaxel (known to inhibit p63 expression), we hypothesized that combined use of RAD001 (mTOR inhibitor), cisplatin, and paclitaxel would have synergistic effects in TN BC. Methods: This is a phase II trial, where patients with measurable clinical stage II/ III TN BC are assigned (2:1) to Cisplatin 25 mg/m2 ± RAD001 30 mg weekly for 3 weeks, followed by cisplatin + paclitaxel 80 mg/m2 ± RAD001 weekly for 9 weeks until the time of definitive surgery. Since June 2009 ten patients have been accrued. Biopsy specimens are obtained prior to therapy, and at 3-5 days after day 1 of treatment. The main endpoint is pathological complete response (pCR) for each individual treatment arm. We also assess rate of breast conservation surgery and tumor response prior to surgery. A two-stage optimal design was used to detect a 35% pCR rate if it exists in Arm 1. Initially, 27 eligible patients will be entered into the study. If less than 6 have pCR, the study will be stopped. If the study is not stopped early, an additional 36 patients will be enrolled (total of 63). If there are 17 or more pCR in these 63 patients, the combination therapy will be further studied. This design provides 90% power to detect a difference in pCR rate of 35% vs. 20% with a two-sided significance level equal to 0.1 (type I error). With a sample size of 32 patients, the half-width of the 95% confidence interval (CI) will be less than 14% if the pCR for Arm 2 is <20%. All collected tissue in this trial will be analyzed for therapy-mediated changes in cell cycle position, proliferation, apoptosis, as well as status, levels, and phosphorylation state of S6K, p53, p73, and p63, and select p53 family target genes. We will also isolate RNA and generate microarray data sets, which we will mine to test the ability of p63 and p73 gene signatures to predict patient response. This study may inform future selection of anticancer agents for patients with TN BC. No significant financial relationships to disclose.

Evaluation of Ki‐67 and Bcl‐2 antigen expression in breast carcinomas of women treated with raloxifene

To evaluate the effect of raloxifene on Ki-67 and Bcl-2 antigen expression in operable, stage II, oestrogen-receptor-positive invasive ductal breast carcinomas. Twenty post-menopausal women who had taken 60 mg of raloxifene daily for 28 days prior to definitive surgery were enrolled in the investigation. Two tumour samples were obtained by incisional biopsy during the study, one at the time of confirmation of diagnosis of invasive ductal carcinoma and evaluation of oestrogen receptor status, and the other 29 days later, at the time of definitive surgery. Immunohistochemistry was performed on tumour samples, prior to and after raloxifene treatment, to evaluate Ki-67 and Bcl-2 expression. Friedman and McNemar tests were used for statistical analysis of the data, significance being established at 5%. Mean percentage of Ki-67-stained nuclei was 24.86 +/- 2.95 prior to raloxifene treatment and 13.33 +/- 1.52 after treatment (P < 0.001). Prior to raloxifene treatment, only 9/20 cases (45%) were classified as Bcl-2-positive, whereas after treatment, 17/20 (85%) were classified as Bcl-2-positive (P < 0.013). Raloxifene treatment significantly reduced Ki-67 antigen expression and increased Bcl-2 expression in breast carcinomas of post-menopausal women.

The Effect of Neoadjuvant Metformin on Breast Cancer Related Genes Clinical Trial – A Preliminary Result.

Abstract Other authoring group: Dougal Adamson, Lee Baker, Douglas C Brown, Sally Chalmers, Amanda Degabriele, Janet Flinn, Kenneth Fowler, Avril Gunning, Grahame Hardie, Julie Lindsay, Gillian Little, Denis McLean, Robert Murdoch, Colin Purdie, Marta Reis, Valerie Walker.IntroductionMetformin, used in the treatment of diabetes for 50 years, has been linked to a reduced incidence of breast cancer and to an enhanced pathological response when administered concurrent with neoadjuvant chemotherapy. It has been postulated that the anti-neoplastic effect of metformin is through activation of AMP-activated protein Kinase (AMPK). The aim of this open label, randomised clinical trial was to investigate the effect of neoadjuvant metformin on gene expression in primary breast cancer.MethodsNon-diabetic women with histologically proven, operable, primary invasive breast cancer of ≥1cm in size were offered the trial following regional Research Ethics Committee approval.The trial had 2 arms, A and B: in arm A (8 patients), patients had core biopsies at three time points: one at presentation; one after a week of no treatment (internal control); and a further biopsy at the time of definitive surgery after at least 2 weeks of metformin. In trial arm B (47 patients), patients had core biopsies at two time points: one before randomisation to either take metformin or not, and one at the time of definitive breast surgery. Metformin was given as 500mg o.d. orally for one week, increased to 1g b.d. orally for at least another week and until the day prior to excisional breast surgery.RNA was extracted from formalin fixed cores and examined using a Disease-Specific Array for breast cancer on an Affymetrix platform (ALMAC Diagnostics Group, Craigavon, UK). Subsequent confirmatory polymerase chain reaction and immunohistochemistry techniques were used to examine the histological material.ResultsType of results expected:[Change of target gene expression in response to neoadjuvant metformin; symptomatic drug toxicities; potential for therapeutic effects of metformin in non-diabetic patients in vivo.]Results from the first arm:The triplet of core biopsies from 6/8 (75%) of the A arm patients passed the GeneGhip QC and data integrity assessment. Patients were 41-65 (mean: 53) years, with IDC NST, grade II-III, and all ER positive. 270 genes were differentially expressed significantly by wounding, and 63 by metformin. Among the genes significantly over-expressed by metformin were AMPK-beta and PI3K; and those down regulated by metformin were AMPK-gamma and ADCY1. Samples from the B arm patients are in analysis.ConclusionThe gene expression changes identified in response to neoadjuvant metformin suggest that metformin improves DNA damage recognition and repair and regulates cancer cell metabolism. These results suggest mechanisms by which metformin could be efficacious in the treatment of breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3145.

The impact of sentinel lymph node biopsy in patients with a core biopsy diagnosis of ductal carcinoma in situ

When ductal carcinoma insitu (DCIS) is found on core biopsy, histological underestimation can occur due to sampling error. When an invasive cancer is subsequently found, another operation is required for nodal staging. Sentinel lymph node biopsy (SLNB) enables nodal staging at the same operation. We examine the value of SLNB in patients with a preoperative diagnosis of DCIS focusing on the need for reoperation. Patients with a preoperative core biopsy of DCIS underwent SLNB at the time of definitive surgery. The results of SLNB in relation to histological upstaging were analyzed. One hundred and seven patients with a core biopsy diagnosis of DCIS underwent simultaneous SLNB at the time of definitive surgery. SLNB was successful in 103 patients (96.3%) and 12 (11.7%) had SLN metastases. Thirty-two patients (29.9%) had histological upstaging and SLN was positive in nine (28.1%). Seventy-five patients had "pure DCIS" but three (4%) had SLN metastases. The presence of a palpable mass and radiological mass lesion were associated with histological upstaging. If SLNB were not performed, 32 patients (29.9%) with upstaging would require another surgery to stage the axilla. In the present series, 84% of these patients had appropriate axillary staging without the need for a second operation. Underestimation of invasive disease was frequent on core biopsy. Performing SLNB during definitive surgery allowed correct nodal staging in a single operation. SLN metastasis was rare in patients with "pure DCIS" on final pathology. However, additional systemic treatment may be indicated for patients with SLN micrometastases.

Neoadjuvant platinum-based chemotherapy (CT) for triple-negative locally advanced breast cancer (LABC): Retrospective analysis of 125 patients

625 Background: Triple-negative breast cancer (TNBC), defined by lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, accounts for 15–20% of all breast cancers and is associated with poor prognosis. There is no consensus regarding optimal CT for treatment of such patients. Preclinical data suggests TNBC may be sensitive to platinums because of deficiencies in BRCA-associated DNA repair. The aim of this study was to evaluate pathologic complete response (pCR) and overall survival (OS) in patients with TNBC treated with neoadjuvant platinum-based CT. Methods: We identified 674 patients with LABC who received neoadjuvant CT between January 1999 and June 2008 at University of Miami. Of these, 125 (18.5%) had histopathologic confirmation of TNBC. All patients received neoadjuvant platinum salts + docetaxel. 76 (61%) also received neoadjuvant AC, while 42 (34%) received adjuvant AC. pCR was defined as no residual invasive disease in breast and axilla. OS was calculated according to Kaplan-Meier. Results: Demographics: median age 50 (28–86 years). 60% premenopausal. TNM stage distribution: T1 0.9%, T2 5.2%, T3 53.4%, T4 40.5%, N0 25.0%, N1 36.2%, N2 35.4%, N3 3.4%, M0 100%, inflammatory 11%, median tumor size = 9.5 cm. Follow up duration ranged from 0.3 to 8.9 years. pCR was observed in 42 of 125 patients (34%; 95% CI 26–43%). Among patients receiving neoadjuvant AC, 30 of 76 (40%; 95% CI 28–51%) had pCR, while amongst those receiving adjuvant AC, 12 of 42 (29%, 95% CI 16–45%) had pCR at the time of definitive surgery. Patients achieving pCR had significantly higher OS (5-yr rate = 73% in pCR, vs. 49% in non-pCR; p &lt; 0.001). OS in TNBC patients receiving cisplatin/docetaxel was significantly superior to those receiving carboplatin/docetaxel (11 mortality events out of 78 patients receiving cisplatin based CT vs 24 out of 47 receiving carboplatin based CT logrank p = 0.001). Conclusions: To date, this is the largest single institution cohort of locally advanced TNBC uniformly treated with platinum+docetaxel-based CT regimens. Platinum/docetaxel-based neoadjuvant CT provided high rates of pCR and excellent OS for women with locally advanced TNBC. No significant financial relationships to disclose.

The prospective experience of a maxillofacial surgeon with the percutaneous endoscopic gastrostomy technique

Abstract Insertion of a percutaneous endoscopic gastrostomy (PEG) was attempted on 225 occasions, mainly for oral malignancy. Seventy-five percent (169/225) were inserted at the time of definitive surgery. There were significant incidental findings during 5% (11/225). The rate of successful insertion was 97% (219/225). The incidence of minor complications was 12% (26/225) and major complications 3% (7/225). There was no procedure-related mortality. The 30-day mortality rate, including those with terminal malignant disease, was 6% (14/225). An increased risk of death was associated with age of 65 years and over ( P =0.004). The median PEG duration was 337 (SE 31) days. Duration was significantly longer for stage T3–4 tumours ( P =0.028), N1 or greater neck disease ( P =0.034), following surgery with radiotherapy when compared to surgery alone ( P P =0.038) and maxillectomy procedures ( P =0.003), after two separate surgical procedures and radiotherapy ( P =0.046) and following a composite bone resection ( P =0.031), or radiotherapy alone when compared to surgery alone ( P =0.003). There was no relationship to the type of flap used for reconstruction. Four patients have a long-term PEG. Only two patients did not use the PEG. The early insertion of a PEG in all patients undergoing free or pedicled flap reconstruction appears to be appropriate. The PEG procedure may be safely performed by an appropriately trained maxillofacial surgeon.

Invited Commentary

Disruption of the gastrointestinal autonomic nervous system after esophagogastrectomy causes myriad difficulties that affect recovery and lifestyle. Atony of the gastric remnant transposed to the chest is a vexing and an all too common problem. The aperistaltic, distended gastric remnant becomes a reservoir of fluid and electrolyte loss, bacterial growth, and a source of pulmonary aspiration. If that is not enough, dumping syndrome and disorders of intestinal motility may follow on the heels of early woes caused by a paralyzed residual stomach. In 1998, McCallum and colleagues [1McCallum R.W. Chen J.D. Lin Z. et al.Gastric pacing improves emptying and symptoms in patients with gastroparesis.Gastroenterology. 1998; 114: 456-461Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar] used multiple pairs of cardiac pacing wires affixed to the serosa of the stomach in 9 patients suffering from gastroparesis. They concluded that gastric pacing improved symptoms of gastroparesis and accelerated gastric emptying in patients with gastroparesis. Gastric electrical stimulation (GES) received the Food and Drug Administration’s Humanitarian Use Device approval for use in medically refractory gastroparesis in 2000. In 2002, the senior author’s successful multicenter study of 33 patients concluded that GES offers a safe and effective alternative for patients with intractable, symptomatic gastroparesis [2Abell T.L. Van Cutsem E. Abrahamsson H. et al.Gastric electrical stimulation in intractable symptomatic gastroparesis.Digestion. 2002; 66: 204-221Crossref PubMed Scopus (242) Google Scholar, 3Salameh J.R. Aru G. Bolton W. Abell T. Electrostimulation for intractable delayed emptying of intrathoracic stomach after esophagectomy.Ann Thorac Surg. 2008; 85: 1417-1420Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. The authors have now tested GES in the setting of medically refractory gastroparesis after Ivor Lewis esophagogastrectomy. The use of GES had already demonstrated significant and persistent improvements in symptoms, health-related quality of life, and solid and liquid gastric emptying at long-term follow-up in gastroparesis not associated with surgery. After a successful pilot study, the authors have recommended extending the indications of GES to include postsurgical gastroparesis. The authors are presently proposing GES be tested at the outset with temporarily placed electrodes. However, there seems to be good correlation of outcomes between temporary and permanent GES. As long as the stomach remains responsive to electrical stimulation, it only makes sense to implant permanent electrodes at the time of definitive surgery, leaving them subcutaneously accessible for later use, thus circumventing a second major surgery in an already debilitated individual. Successfully restoring gastric motility, albeit artificially, soon after esophagogastrectomy, can only jumpstart the process of nutritional repair and recovery. Sadly, more than 50% of patients with esophageal cancer already have metastatic disease and are debilitated by poor nutrition at presentation. Nevertheless, esophagogastrectomy remains the standard of care for patients who have clinically resectable disease. In this complex setting, preserving and repairing nutrition remains a focus of attention before, during, and after surgery. The overall scenario may become more complicated by the use of multimodal induction therapy (ie, chemotherapy and radiotherapy) for this patient group followed by esophagogastrectomy and perhaps follow-up adjuvant therapy. In practical terms, more aggressive treatment translates into even more pressing problems of maintaining and improving nutrition during convalescence after esophagogastrectomy. The use of GES has the potential of removing the troubles caused by an atonic gastric remnant in these complex patients. Electrostimulation for Intractable Delayed Emptying of Intrathoracic Stomach After EsophagectomyThe Annals of Thoracic SurgeryVol. 85Issue 4PreviewThe use of the denervated intrathoracic stomach as esophageal substitute can rarely lead to severe delayed gastric emptying. We describe the use of electrostimulation for this condition. Full-Text PDF

Combination of fillet and triangular flaps for the web reconstruction in pollicization: A case report

Thumb hypoplasia represents a major disability requiring sophisticated reconstructive procedures. One of the basic criteria of the pollicization to construct a functional thumb is scar free web reconstruction. In this article, a technique to avoid excessive scarring in the first web space reconstruction by filleting out the hypoplasic thumb combining with a triangular flap is presented. A 5-year-old girl was presented. She had a Back-Gramcko type IV thumb hypoplasia. A triangular flap was planned on radial border of the long finger. Floating thumb was filleted out with preservation of the neurovascular bundle and transferred to the first web space while cooperating with triangular flap. Patient was followed up for 18 months. No early or late major complication was seen. Flap healed without any necrosis. The ratio of active motion in pollicized finger was measured 60% after cerebral reorientation. A satisfactory grip and pinch were seen in pollicized finger. Patient as well as her parents was satisfied with the results. Filleting out the floating thumb and combining with a triangular flap harvested by a V-Y flap design is a good option to avoid excessive scarring in reconstruction of the first web space in pollicization. It is strongly recommended that floating thumb should be preserved for future pollicization, and any attempt to amputate it in early years of life should be postponed till the time of definitive surgery.

The prospective experience of a maxillofacial surgeon with the percutaneous endoscopic gastrostomy technique

Insertion of a percutaneous endoscopic gastrostomy (PEG) was attempted on 225 occasions, mainly for oral malignancy. Seventy-five percent (169/225) were inserted at the time of definitive surgery. There were significant incidental findings during 5% (11/225). The rate of successful insertion was 97% (219/225). The incidence of minor complications was 12% (26/225) and major complications 3% (7/225). There was no procedure-related mortality. The 30-day mortality rate, including those with terminal malignant disease, was 6% (14/225). An increased risk of death was associated with age of 65 years and over ( P = 0.004). The median PEG duration was 337 (SE 31) days. Duration was significantly longer for stage T3–4 tumours ( P = 0.028), N1 or greater neck disease ( P = 0.034), following surgery with radiotherapy when compared to surgery alone ( P < 0.001), particularly glossectomy ( P = 0.038) and maxillectomy procedures ( P = 0.003), after two separate surgical procedures and radiotherapy ( P = 0.046) and following a composite bone resection ( P = 0.031), or radiotherapy alone when compared to surgery alone ( P = 0.003). There was no relationship to the type of flap used for reconstruction. Four patients have a long-term PEG. Only two patients did not use the PEG. The early insertion of a PEG in all patients undergoing free or pedicled flap reconstruction appears to be appropriate. The PEG procedure may be safely performed by an appropriately trained maxillofacial surgeon.

Impact of poor prognostic features on the surgical treatment of breast cancer in an intergroup adjuvant chemotherapic trial

612 Background: The adoption of new breast surgical techniques has been rapid for early stage breast cancer. The utilization of these techniques in patients with high risk operable breast cancer has not been thoroughly investigated. Methods: Retrospective surgical data was summarized for patients entered into N9831 “Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Over-expressing or Amplified Node Positive or High-Risk Node Negative Breast Cancer.” Results: 3,505 patients were entered into N9831 from 2000–2005 following primary surgery for breast cancer. The median age was 50 and 43% were premenopausal. 93% of patients underwent a diagnostic biopsy prior to their definitive surgical procedure. Whether HER2-neu status was available at time of definitive surgery is unknown. 61% underwent a mastectomy whereas 39% underwent breast conserving surgery (BCS). The rate of BCS was relative stable over the course of the trial. Patients with T1 tumors had a higher rate of BCS (49%) compared to T2 tumors (37%) and T3 tumors (6%). Sentinel lymph node (SLN) biopsy was performed in 54% of the cases. The rate of SLN biopsy increased from 40% in 2000 to 66% in 2005. Patients who underwent mastectomy had a lower rate of SLN biopsy than patients who underwent BCS (44% versus 71%, respectively). Tumor size was also associated with the rate of SLN biopsy: T1 (60%), T2 (53%), and T3 (36%). Data on local and regional recurrences are still maturing. Conclusions: Surprisingly, low numbers of patients on this trial underwent BCS whereas the adoption of the SLN biopsy procedure among the same group of surgeons was relatively high. The relatively low rate of BCS in this study population needs further investigation to determine what surgeon and patient factors impacted the surgical decision. No significant financial relationships to disclose.

Multiple Drug Resistance in Osteogenic Sarcoma: INT0133 From the Children's Oncology Group

Multiple drug resistance due to P-glycoprotein (P-gp) expression has been reported to be a cause of disease recurrence in osteosarcoma. Tumor specimens derived from children and young adults with osteosarcoma enrolled onto a national Intergroup trial (INT0133) were analyzed prospectively to determine the role of multiple drug resistance in osteosarcoma. From October 15, 1992, to November 25, 1997, 685 patients with localized, high-grade osteosarcoma were enrolled onto INT0133. Paraffin-embedded diagnostic tumor specimens were assayed for P-gp using monoclonal antibodies C-494 (139 patients) and JSB-1 (133 patients). Percent necrosis at the time of definitive surgery (NEC), event-free survival (EFS), and overall survival (OS) were evaluated as outcome measures for patients with P-gp-positive disease and were compared with patients with P-gp-negative disease. P-gp expression in the biopsy specimen did not significantly increase the risk for adverse outcomes as measured by EFS, OS, or NEC. EFS for those patients with C-494-positive tumors was 59% at 4 years versus 61% at 4 years for patients with C-494-negative tumors (P = .79), or 58% at 4 years versus 61% at 4 years for patients with JSB-1-positive versus JSB-1-negative tumors (P = .65). OS for patients with C-494-positive tumors was 82% at 4 years versus 82% at 4 years for patients with C-494-negative tumors (P = .61). Prospective analysis of the role of multiple drug resistance in localized osteosarcoma did not find that immunohistochemical analysis of P-gp expression predicted outcome for patients treated on INT0133.

Arrhythmias in Adult Patients With Congenital Heart Disease

By the time patients with congenital heart disease (CHD) reach adolescence and early adulthood, rhythm status has often become an active issue, if not the central issue, in their cardiac management. For some, arrhythmias are intrinsic to the structural malformation itself, as is the case with Wolff-Parkinson-White syndrome in the setting of Ebstein’s anomaly, or atrioventricular (AV) block in the setting of “congenitally corrected” transposition of the great arteries (L-TGA). For most other CHD patients, arrhythmias represent an acquired condition related to the unique myocardial substrate created by surgical scars in conjunction with cyanosis and abnormal pressure/volume loads of long duration. This review will attempt to address the major rhythm difficulties faced by adults with CHD, concentrating on electrophysiological features that distinguish CHD from more conventional forms of adult heart disease. A listing of specific arrhythmias and commonly associated congenital defects is provided in Table 1 to serve as an outline for the discussion. View this table: TABLE 1. Specific Arrhythmias and Associated Defects in Adults With Congenital Heart Disease As of 2001, there were estimated to be 800 000 adults with CHD living in the United States,1 a number that has grown steadily as more survivors of childhood surgery reach maturity. Of these, roughly 45% are considered to have mild forms of CHD (eg, atrial septal defect, valvar pulmonary stenosis), 40% are classified as having moderate disease (eg, tetralogy of Fallot, Ebstein’s anomaly), and 15% are considered to have complex disease (eg, single ventricle, transposition of the great arteries). Although arrhythmias can develop within any of the 3 subgroups, the incidence is highest for patients in the moderate and severe categories. Tetralogy of Fallot is an instructive example of moderate CHD with a large arrhythmia burden. As many as one third of patients with repaired tetralogy develop symptomatic atrial tachycardias by …

P‐3 THE VALUE OF PERITONEAL WASHING CYTOLOGY IN THE STAGING OF GYNAECOLOGICAL MALIGNANCY

Introduction: Current protocols for staging gynaecological cancers include cytopathological examination of peritoneal washings taken at the time of definitive surgery. We investigated the clinical usefulness of this procedure.Methods: During 2004 and 2005, 140 peritoneal washings were submitted for cytopathological examination in our institutions for staging of 36 ovarian, 101 endometrial and 3 synchronous ovarian/endometrial cancers.Results: The washings contained malignant cells in 39 cases (28%). 35 of these cases had high stage disease – not confined to the organ of origin (i.e. stage 2 or more for ovary and stage 3 or more for endometrial). The other 4 were stage 1C ovarian cancers where there was either rupture or tumour involvement of the capsule. In only 2 of the 39 positive cases the cancer was marginally upstaged by the positive washings – these were ovarian cancers upstaged from 2A /B to 2C.Discussion: These findings suggest that peritoneal washing cytology as a routine procedure for staging ovarian and endometrial cancer is of limited clinical value. A larger study is needed to determine whether this procedure should continue to be included in staging protocols for gynaecological cancer.

Human kallikrein 10, a predictive marker for breast cancer

Our laboratory is involved in identifying genes that can be used as early diagnostic or prognostic markers in breast cancer. We previously identified a gene (NES1) that is expressed in normal but not in transformed mammary epithelial cells (MECs). NES1 is located on chromosome 19q13.4 within the kallikrein locus and thus was designated as human kallikrein 10 (hK10), although we have been unable to detect any protease activity. Importantly, hK10 expression is decreased in a majority of breast cancer cell lines. Transfection of hK10 into hK10-negative breast cancer cells reduces the tumorigenicity. Using methylation-specific PCR and subsequent sequencing, we demonstrate a strong correlation between hypermethylation of hK10 and loss of mRNA expression. Further analysis showed that essentially 100% of normal breast specimens had hK10 expression, whereas 46% of ductal carcinoma in situ (DCIS) and the majority of infiltrating ductal carcinoma (IDC) samples lacked the hK10 mRNA. Importantly, hK10-negative DCIS diagnosed at the time of biopsy were subsequently diagnosed as IDC at the time of definitive surgery. It has been shown that hK10 protein expression is regulated by steroids. In addition to breast cancers, hK10 is downregulated in cervical cancer, prostate cancer and acute lymphocytic leukemia, whereas it is upregulated in ovarian cancers. These results point to the paradoxical role of hK10 in human cancers and underscore the importance of further studies of this kallikrein.

Phase II study of dose-dense sequential doxorubicin and docetaxel for patients with advanced operable and inoperable breast cancer

Rapid sequential delivery of doxorubicin 75 mg/m2 q 2 weeksx3 cycles followed by docetaxel 100 mg/m2 q 2 weeksx3 cycles, with filgrastim support was evaluated in patients with inoperable and large operable breast cancers who were not initially candidates for breast conservation therapy. Postoperative CMF chemotherapy and/or radiation were administered based on surgical findings. Median age of the 39 enrolled patients was 47 (range 27-59), stage IIA (6 patients), IIB (14 patients), IIIA (10 patients), IIIB (9 patients), and 23 patients (59%) had clinical nodal involvement. The average bidimensional tumor size before treatment was 30 cm2. Clinical responses included 13 (33%) complete responses, 23 (59%) partial responses, 1 stable disease, and 2 progressive disease, for an overall response rate of 92%. Clinical response rate was 11/13(85%) in HER2/neu positive patients compared to 25/26 (96%) in tumors that did not express HER2/neu. Twenty patients (51%) underwent breast conservation surgery. Pathologic tumor response at the time of definitive surgery included 4 pathologic CR (pCR, 10%), 4 microscopic invasion (pINV), and 14 (36%) pathologically negative axillary nodes. pCR was not observed in any HER2/neu positive patients. 5/39 patients were unable to complete all cycles of docetaxel and 8 patients required dose reduction of docetaxel due to development of grade 3-4 mucositis and hand-foot syndrome. This observation prompted a protocol change requiring 3 weeks between doxorubicin and docetaxel. Primary chemotherapy with dose-dense doxorubicin and docetaxel given sequentially is well tolerated and allows a high rate of breast sparing in patients with large breast cancers.

Thyroglossal duct cyst’s inflammation. When do we operate?

Thyroglossal duct cyst (TGDC) disease, one of the most common developmental neck lesion in the pediatric population, often presents as infected neck mass. The authors reviewed their experience in the management of inflamed TGDC cases, in order to suggest the most efficient approach of these patients regarding the ideal type and time of surgical intervention. The medical records of all the patients with the diagnosis of TGDC treated at our department from 1988 to 2003 were reviewed. Data collected included age, gender, preoperative inflammation, treatment and time of definitive surgery. The outcome of the operation was graded as successful, recurrence, or postoperative infection. Eighty-nine (89) patients with histologically confirmed TGDC were treated at our department. Mean age at operation was 6.0 years (range, 9 months-14 years). Male to female ratio was 1.2:1. All patients underwent Sistrunk operation and the mean follow-up was 3 years. Fifty-four (54) patients (60.6%) presented with an inflamed TGDC. Among them, 24 patients were operated immediately after diagnosis at the phase of acute inflammation, and 30 patients after antibiotic administration and resolution of inflammation. The overall recurrence incidence was 6.7%. Recurrence was noted in 6 of 24 (25%) patients operated during the acute phase of inflammation and none in patients operated after resolution of inflammation (P = 0.0052) or with no preoperative inflammation (P = 0.0002). Postoperative wound infection was noted in seven cases but none of them developed recurrence of the disease. The presence of inflammation at the time of surgery is an important risk factor for relapse. We suggest that in the inflamed cases of TGDC disease, the initial treatment should be antibiotic administration and after resolution of the inflammation, surgical management should follow.

PEG insertion at the time of definitive surgery for oral malignancy

PEG insertion at the time of definitive surgery for oral malignancy

Genome-wide array comparative genomic hybridization analysis reveals distinct amplifications in osteosarcoma.

BackgroundOsteosarcoma is a highly malignant bone neoplasm of children and young adults. It is characterized by extremely complex karyotypes and high frequency of chromosomal amplifications. Currently, only the histological response (degree of necrosis) to therapy represent gold standard for predicting the outcome in a patient with non-metastatic osteosarcoma at the time of definitive surgery. Patients with lower degree of necrosis have a higher risk of relapse and poor outcome even after chemotherapy and complete resection of the primary tumor. Therefore, a better understanding of the underlying molecular genetic events leading to tumor initiation and progression could result in the identification of potential diagnostic and therapeutic targets.MethodsWe used a genome-wide screening method – array based comparative genomic hybridization (array-CGH) to identify DNA copy number changes in 48 patients with osteosarcoma. We applied fluorescence in situ hybridization (FISH) to validate some of amplified clones in this study.ResultsClones showing gains (79%) were more frequent than losses (66%). High-level amplifications and homozygous deletions constitute 28.6% and 3.8% of tumor genome respectively. High-level amplifications were present in 238 clones, of which about 37% of them showed recurrent amplification. Most frequently amplified clones were mapped to 1p36.32 (PRDM16), 6p21.1 (CDC5L, HSPCB, NFKBIE), 8q24, 12q14.3 (IFNG), 16p13 (MGRN1), and 17p11.2 (PMP22 MYCD, SOX1,ELAC27). We validated some of the amplified clones by FISH from 6p12-p21, 8q23-q24, and 17p11.2 amplicons. Homozygous deletions were noted for 32 clones and only 7 clones showed in more than one case. These 7 clones were mapped to 1q25.1 (4 cases), 3p14.1 (4 cases), 13q12.2 (2 cases), 4p15.1 (2 cases), 6q12 (2 cases), 6q12 (2 cases) and 6q16.3 (2 cases).ConclusionsThis study clearly demonstrates the utility of array CGH in defining high-resolution DNA copy number changes and refining amplifications. The resolution of array CGH technology combined with human genome database suggested the possible target genes present in the gained or lost clones.

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy in stage II and III breast cancer patients: Preliminary results of a phase II and pharmacogenomic study

The purpose of this study is to evaluate the efficacy and safety of a biweekly neoadjuvant docetaxel/gemcitabine regimen in patients with histologically confirmed stage II and III breast cancer. In addition, a cDNA microarray study attempted to correlate pretreatment gene-expression profile with clinical and pathologic responses. Docetaxel 65 mg/m 2 was given in a 60-minute intravenous infusion followed by gemcitabine 2,500 mg/m 2 in a 30-minute intravenous infusion every 2 weeks for six cycles; prophylaxis with growth factors was allowed. Four cycles of standard AC (doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2every 21 days) was routinely delivered to all patients postsurgery. Thirty patients are accrued on-study so far. The overall response rate for 24 evaluable patients was 79% (95% confidence interval, 9.7 to 53.5) with six complete responses and 13 partial responses. One patient (4%) out of 23 achieved a pathologic complete response in the breast at the time of definitive surgery. Breast conservation procedure was possible in 14 patients (61%). A total of 161 cycles has been delivered. Grade 1/2 alopecia and a mild grade 1/2 LDH increase were the most frequently reported adverse events (78% and 55% of cycles, respectively). Grade 3/4 neutropenia was reported in 18 cycles (11%). These preliminary results show that biweekly docetaxel and gemcitabine is an optimal regimen as neoadjuvant treatment of stage II and III breast cancer. In spite of the large tumor size, breast conservation was possible in 61% of the patients. In general, toxicity was very manageable.

Swallowing function and tracheotomy dependence after combined-modality treatment including free tissue transfer for advanced-stage oropharyngeal cancer.

There are many treatments available for advanced oropharyngeal cancer. Organ-sparing protocols reserve surgery for salvage and are thought to provide adequate rehabilitation. Surgical resection with free tissue transfer may also provide adequate functional rehabilitation. The objective was to describe swallowing status and time to decannulation in a series of patients treated with combined-modality therapy that included free flap reconstruction. Retrospective chart review. Patient data were obtained from medical records of 20 patients with stage III or IV oropharyngeal carcinoma, who were consecutively treated with surgical tumor extirpation, free flap reconstruction, and postoperative irradiation at a tertiary academic center from 1985 to 2002. The following variables were identified: patient and tumor characteristics, free flap type, irradiation data, and airway and swallowing status before and after treatment. One patient underwent total laryngopharyngectomy, and the remaining 19 patients underwent tracheotomy at the time of definitive surgery. Free flap reconstructions included 1 ulnar and 15 radial forearm fasciocutaneous flaps and 4 fibula osteocutaneous flaps. Postoperatively, all 19 tracheotomized patients had successful decannulation. Average time to decannulation was 15 days (range, 3-42 d). After surgery and before irradiation, 13 patients initiated oral intake, on average, at 19.5 days (range, 7-28 d); 6 patients required no additional supplementation. By 4 months after surgery, having completed radiation therapy, 10 patients were consuming all nutrition orally; the other 10 patients still required tube-feed supplementation, although 6 of these patients were also eating by mouth. Combined-modality treatment that includes free flap reconstruction for advanced-stage oropharyngeal cancer may provide reasonable functional rehabilitation with respect to postoperative airway and swallowing.