Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Accurate axillary nodal staging can be achieved after neoadjuvant therapy for locally advanced breast cancer.

Lymph node status remains the most important prognostic indicator for breast cancer. Recent reports have established that the accuracy of assessing lymph node status is proportional to the number of nodes dissected. The accuracy of axillary staging following neoadjuvant chemotherapy has been cited as a technical concern due to limited node retrieval. The current study attempts to evaluate the ability to perform sentinel node biopsy (SNB) and formal axillary node dissection (AND) following neoadjuvant chemotherapy and to compare these results with non-neoadjuvant patients. One hundred sixteen consecutive patients undergoing SNB with simultaneous AND were retrospectively reviewed. Forty-two of these patients were treated with neoadjuvant chemotherapy prior to AND. Overall success rate in performing SNB in the neoadjuvant group was 95 per cent, and no false negatives have been noted to date. The overall SNB success rate in the non-neoadjuvant group was also 95 per cent with a false negative rate of 3 per cent. After AND in each group, a mean of 21 nodes were retrieved in the neoadjuvant group and 17.9 nodes in the non-neoadjuvant group (P = 0.018). In the neoadjuvant group, there were 19 node positive patients (42%) and 21 patients (28%) in the non-neoadjuvant group (P = 0.16). The mean number of positive nodes per patient was also similar between the two groups (2.9 in the neoadjuvant group vs 1.67 in the non-neoadjuvant group, P = 0.10). Following neoadjuvant therapy, accurate evaluation of the axilla is feasible. In this study, the mean number of nodes is significantly different in favor of the neoadjuvant group, but there is no significant difference in the number of node positive patients identified or in the mean number of positive nodes identified per patient. SNB is technically feasible with accuracy similar to that seen in patients with no history of neoadjuvant therapy. Neoadjuvant chemotherapy extends the use of breast-conserving therapy without sacrificing the ability to accurately stage the axilla either by use of standard axillary dissection or SNB.

Neoadjuvant chemotherapy for locally advanced breast cancer results in alterations in preoperative tumor marker status.

Neoadjuvant therapy followed by breast-conserving surgery has become an acceptable option for patients with locally advanced breast cancer. Although a distinct survival benefit has not been demonstrated using this approach, several questions have been raised following such therapy including its effects on receptor status and tumor markers. The current study retrospectively reviews estrogen receptor (ER), progesterone receptor (PR), and HER2-neu status in 55 consecutive patients treated by neoadjuvant chemotherapy. Preoperative and postoperative tumor markers were available for 43 of the 55 patients (78%). The pathologic complete tumor response rate (pCR) for this group was 19 per cent (8/43). Of those patients who did not achieve a pCR (n = 35), a change in tumor markers was seen in 25.7 per cent (9/35) of patients. When compared to a control group not undergoing neoadjuvant therapy, a significantly higher percent change in marker expression was noted in the neoadjuvant group (25.7% vs 5.9%, P = 0.046). ER, PR, and HER2-neu status remain important prognostic indicators for breast cancer. Tumor markers are useful in planning adjuvant therapy regimens. In this review, nearly 19 per cent of patients achieved a pCR. In patients not achieving a pCR, one in four patients had at least one change in tumor marker status. This study demonstrates the importance of establishing receptor and marker status prior to neoadjuvant therapy, as many patients will achieve a pCR and make tumor analysis impossible. Postoperative marker studies should be performed given the possibility of a change in status. The clinical relevance of this data will require further long-term follow-up. Until such data becomes available, caution should be considered when basing adjuvant therapy regimens on preoperative tumor marker studies alone.

Sentinel lymph node biopsy after neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a developing alternative to axillary dissection and may prove to be accurate in the detection of micrometastases in lymph nodes of breast cancer patients. Limited studies exist in the use of SLNB after neoadjuvant therapy. This study was undertaken to determine the accuracy of SLNB after neoadjuvant chemotherapy. METHODS: Thirty-one patients with stage I or II breast cancer underwent SLNB after neoadjuvant chemotherapy. RESULTS: Lymphatic mapping was performed by radioisotope, blue dye, or both techniques. Sentinel nodes (SN) were identified in 29 patients (93.5%). The SN was positive in 11 patients (38.0%), and was the only positive node in 5 patients (45.5%). There were no false negative SN by hematoxyin and eosin stain or immunohistochemistry (IHC) studies. CONCLUSIONS: Sentinel node identification rate is similar to that in nonneoadjuvant studies. The sentinel node accurately predicted metastatic disease in the axilla. IHC studies failed to detect any additional micrometastases. This diagnostic technique may provide treatment guidance for patients after neoadjuvant therapy.

MRI: a role in clinical trials.

The diagnosis and treatment of breast cancer has evolved significantly over the last 20 years. Breast-conserving therapy is replacing the Halstedian concept of "en bloc" resection. Difficulties in detection, pre- and postoperative planning and follow up continue to challenge the clinician. Women at high risk present a significant clinical dilemma. MRI technology in many of these areas is providing more information about detection, tumor size, extent, and response to treatment. The careful and thoughtful inclusion of MRI in clinical trials may help continue the advancement of breast cancer care. J. Magn. Reson. Imaging 2001;13:837-841.

Long-term follow-up post-cryosurgery in a sheep breast model.

This study constitutes the advanced stage of an ongoing project for the development of cryosurgical devices and techniques for breast cryosurgery. The current study focuses on the long-term follow-up post-cryosurgery in a sheep breast model. Results of this study indicate that the cryotreatment site in a sheep breast model cannot be identified up to 5 months post-cryosurgery by means of ultrasound, mammography, or MRI. Histology findings of this study further indicate that there is no gross or microscopic difference between lesions that have been subject to one versus three freeze/thaw cycles. Under either cryosurgical protocol, there is a main cryoinjured region that has uniform destruction of epithelium and healing scar formation and a transition zone of damaged lobules without acini, surrounded by healthy tissues. The cryoinjured region at 5 months post-cryosurgery was found to be about half the diameter of the ultrasound-imaged frozen region during the cryoprocedure. This study shows that, in terms of recovery and regeneration, surgical excision appears to have an advantage over cryosurgery, which results in a more rapid healing process. Based on observations that the cryoinjured region is no smaller than the ultrasound-imaged ice-ball and that the typical thickness of the transition zone is up to 5 mm, a conservative use of the cryosurgical device developed for the current study in an ultrasound-monitored cryoprocedure requires at least 5 mm safety margins of the frozen region radius around the target region.

Gross damage accumulation on frozen rabbit liver due to mechanical stress at cryogenic temperatures.

The second phase of a pilot study dealing with the mechanical response of frozen biological tissues to external compressive load is presented. This stage deals with histological observations of the damage accompanying mechanically induced permanent deformation in frozen rabbit liver. no significant gross histological damage was observed in the liver samples due to either processing the tissue in the frozen state, due to slow cooling of the liver tissues down to -20 degrees C, or due to rapid cooling of the samples down to -196 degrees C. No histological changes were observed in tissue samples that were loaded within the elastic regime, that is, below the yield strength of the material. Therefore, it is concluded that histological changes due to mechanical stresses are associated with plastic (permanent) deformations. Histological observations indicate that linear cracks which appear to have no preferred orientation develop due to mechanical stress beyond the yield strength of the frozen tissue. These cracks accumulate until final failure of the frozen tissue, when the tissue sample collapses to rubble. Based on histological observations and concepts from solid mechanics, an interaction between crack formation and irregularities in the frozen medium is suggested. Significant sources for such irregularities, in an homogeneous tissue such as the liver, are blood vessels and bile ducts. These irregularities may either initiate crack formation or, on the other hand, may also arrest propagating cracks.

A compact cryosurgical apparatus for minimally invasive procedures.

A new liquid-nitrogen-based apparatus for minimally invasive cryosurgery is presented. The cryoprobe was designed for application to breast tumors; however, it can be used for the treatment of other tumors. The cryoprobe has three major components, a cryoneedle, a thermal insulation shell, and a protective tube, which may be assembled as part of the operation. This special assembly keeps destruction to surrounding tissues due to cryoprobe penetration minimal, and allows accurate localization of the cryoprobe tip by means of stereotactic or needle-localization techniques. An alternative cryoprobe consists of a cryoneedle and a thermal insulation shell, which are rigidly connected. The liquid nitrogen supply system has two major components, an air-pressure source and a liquid nitrogen container, which are physically separated. This special configuration allows placement of the liquid nitrogen container adjacent to the cryotreated tissue and decreases the length of the cryoprobe feeding tube. In turn, heat losses to the surroundings are reduced, and therefore coolant consumption is reduced. The short feeding tube allows safe operation at low pressures. The small size of the apparatus makes it attractive for cryosurgical operations. It has been evaluated in gelatin solutions and in porcine skeletal muscle and liver. In-vivo results do not differ significantly from those obtained in gelatin solutions with regard to the dimensions of frozen regions. Using a three cryoprobe configuration, a frozen region with an average diameter of 50 mm and a length of 75 mm was obtained within 11 minutes. The thermal efficiency of that procedure was found to be 43%.

An experimental study of the mechanical response of frozen biological tissues at cryogenic temperatures.

An experimental study of the mechanical response of frozen soft biological tissues to applied compressive stresses is presented. This study is related to the mechanical stresses that develop due to the contraction of frozen tissues in cryopreservation as well as in cryosurgical procedures. The main concept in this study is that the stresses associated with the constrained contraction of the frozen tissue, i.e., due to temperature variations within the frozen tissue, can be simulated by an external mechanical load which is applied to the frozen tissue while the tissue is maintained at a uniform temperature. A new apparatus for measuring compressive stresses and strains of frozen biological tissues in cryogenic temperature range is presented. A new technique for processing the fresh biological tissue into a cylindrical frozen sample for mechanical testing is introduced. Results of compression tests on rabbit liver, kidney, and brain are presented and are compared with available data from the literature on sea ice and single ice crystals. An unusual response of frozen biological tissues to compressive stress was observed: after the initial, roughly linear elastic portion there was a series of sudden stress drops at constant strain, each followed by a linear increase of stress with strain to the next drop. This phenomenon, which is attributed to the accumulation of microcracks, broadly resembles plastic deformation, and thus provides some support for simple mechanical models invoked in theoretical studies.

Malfunctioning peritoneal dialysis catheter repaired by laparoscopic surgery.

OBJECTIVES: To review peritoneal dialysis catheter failures and to describe a technique of repairing malpositioned catheters. DESIGN: Two prospective case reports utilizing this technique are reported. SETTING: A tertiary care hospital. PATIENTS: Two patients on chronic peritoneal dialysis with malfunctioning catheters. INTERVENTION: Both patients underwent reposition of their malpositioned continuous ambulatory peritoneal dialysis catheters by laparoscopic suture technique. MAIN OUTCOME MEASURES: Outcome was measured by the successful return of adequate peritoneal dialysis. RESULTS: Both case studies show correction of malpositioned catheters with the return of successful peritoneal dialysis. CONCLUSION: The repositioning and suture application of malpositioned Tenckhoff catheters by laparoscopic surgery is a viable technique that can salvage the majority of malpositioned catheters and save the patients additional hospital time and recovery.

Laparoscopic removal of a displaced ventriculoperitoneal shunt.

Detached catheters in the peritoneal cavity are among the complications following implantation of ventriculoperitoneal shunts. We present one case and discuss the value of a laparoscopic approach to retrieve this foreign body. Laparoscopic removal of these catheters is an effective and safe procedure and can be used in these ill patients, avoiding the possible complications of a laparotomy.

Closure of large postradiation vesicovaginal fistula with rectus abdominis myofascial flap.

We report the case of a patient who developed a large radiation-induced vesicovaginal fistula. She also had a paucity of the omentum due to previous laparotomy and adhesions. We were able to treat this patient successfully with a pedicled myofascial rectus abdominis flap.

Complications of indwelling central venous catheters in bone marrow transplant recipients.

Complications associated with indwelling central venous catheters in patients undergoing bone marrow transplantation are presented. The study group was comprised of 123 patients who underwent transplantation from 1982 to 1988 in whom 139 catheters were placed. One hundred and fifteen of 139 catheters placed had a triple lumen, while 24 had a dual lumen. Percutaneous placement through the subclavian vein was used in 127 of 139 catheters with a low complication rate. Catheters remained in place for 65.0 +/- 55.5 days (mean +/- standard deviation). One hundred and eight catheters remained functional during the course of treatment for these patients and lasted until elective removal or until the patient died. Thirty-one catheters were removed because of a complication. Infection was the most common complication, occurring in 22 catheters. Seven infected catheters were salvaged with antibiotic therapy. Coagulase negative staphylococcus was the most frequent organism identified. Mechanical problems causing catheter malfunction, migration, thrombosis and cuff erosion occurred in 19 catheters; 15 were removed. We concluded that double and triple lumen Silastic (silicone rubber) catheters provide relatively safe and effective access for bone marrow transplant recipients. The triple lumen catheter provides an additional venous access port that facilitates intensive care. The duration of catheter function is sufficient in most patients for therapy during and after bone marrow transplantation. Infection is the most common complication; our results indicate that catheters can be maintained and salvaged in some patients with septicemia. Noninfectious complications are less frequent, although catheters with persistent mechanical problems are less likely to be salvaged.

The management of aortoenteric and paraprosthetic fistulae.

Aortoenteric and aortic paraprosthetic fistulae are devastating complications. Most authors recommend total excision of the graft and revascularization of the lower extremities by extra-anatomic bypass. We reviewed the University of Pittsburgh experience with these fistulae in 15 patients between 1977 and 1987. There were 9 aortoenteric fistulae (AEF) and 6 paraprosthetic fistulae (PPF). Seven of the 9 AEF had no abscess surrounding the graft, but communication of the intestine with the aortic anastomosis. One patient died during operation. Six patients underwent a local repair or in situ replacement of the graft. All 6 of those patients survived operation without limb loss. Two of the 9 patients with AEF had evidence of graft infection and underwent total excision of the graft and extra-anatomic reconstruction. Both patients died, one of sepsis and one of aortic stump rupture. All 6 patients with PPF had clinical and operative evidence of overt graft infection and underwent total graft excision and extra-anatomic bypass. Two of these patients died secondary to sepsis. We conclude that AEF, without evidence of graft infection, were safely treated by local repair. Patients with PPF had infected grafts requiring graft removal with significant morbidity and mortality.

The triple-stapled colonic anastomosis.

This study reports the preliminary results of a new totally stapled end-to-end colonic anastomosis in 11 dogs. This "triple-stapled" end-to-end anastomosis was performed with one circular staple line and two linear staple lines, eliminating the need for a colotomy or purse-string suture. The fact that the anvil and anvil stem of a new circular stapling device (Premium EEA) can be detached from the frame of the instrument allows the anvil stem to be brought out through the proximal linear stapled colon. The trocar mounted on the main stem of the circular stapler allows the stem of the main device to be brought out through the distal staple line. Thus, a totally stapled colonic anastomosis is created after mating the anvil stem and main stem of the instrument. The new anastomosis was evaluated radiographically and at necropsy. The use of this technique resulted in no clinically detectable leaks, suggesting that it may facilitate the performance of anterior resections in humans.