Locally advanced breast cancer: is surgery necessary?

A retrospective analysis of the treatment of locally advanced breast cancer (LABC) was undertaken at Stanford Medical Center to assess the outcome of patients who did not undergo surgical removal of their tumors. Between 1981 and 1998, 64 patients with locally advanced breast cancer were treated with induction chemotherapy, radiation with or without breast surgery, and additional chemotherapy. Sixty-two (97%) patients received cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) induction chemotherapy. Induction chemotherapy was followed by local radiotherapy in 59 (92%) patients. Based on the clinical response to chemotherapy and patient preference, 44 (69%) patients received no local breast surgery. Radiotherapy was followed by an additional, non-doxorubicin-containing chemotherapy in all patients. The mean age of patients was 49 years. Of the 65 locally advanced breast cancers in 64 patients, 26 (41%) were stage IIIA, 35 (55%) were stage IIIB, and 4 (6%) were stage IV (supraclavicular lymph nodes only). Response to induction chemotherapy was seen in 59 patients (92%), with 29 (45%) achieving a complete clinical response and 30 (47%) a partial clinical response. With a mean follow-up of 51 months (range 7-187 months), 43 patients (67.2%) have no evidence of recurrent disease. Eight (12.5%) have recurred locally, and 21 (32.8%) have recurred with distant metastasis. Actuarial 5-year survival is 75%, disease-free survival is 58%, and local control rate is 87.5%. These data indicate that the routine inclusion of breast surgery in a combined modality treatment program for LABC does not appear necessary for the majority of patients who experience a response to induction chemotherapy.

Freehand iMRI-guided large-gauge core needle biopsy: a new minimally invasive technique for diagnosis of enhancing breast lesions.

The lack of reliable methods for minimally invasive biopsy of suspicious enhancing breast lesions has hindered the utilization of contrast-enhanced magnetic resonance imaging (MRI) for the detection and diagnosis of breast cancer. In this study, a freehand method was developed for large-gauge core needle biopsy (LCNB) guided by intraprocedural MRI (iMRI). Twenty-seven lesions in nineteen patients were biopsied using iMRI-guided LCNB without significant complications. Diagnostic tissue was obtained in all cases. Nineteen of the 27 lesions were subsequently surgically excised. Histopathologic analysis confirmed that iMRI-guided LCNB correctly distinguished benign lesions from malignancy in 18 of the 19 lesions. The histology revealed by core biopsy was partially discrepant with surgical biopsy in 2 of the other 19 lesions. Freehand iMRI-guided LCNB of enhancing breast lesions is promising. Larger studies are needed to determine the smallest lesion that can be sampled reliably and to precisely measure the accuracy of iMRI-guided LCNB as a minimally invasive tool to diagnose suspicious lesions found by breast MRI. J. Magn. Reson. Imaging 2001;13:896-902.

Radiofrequency ablation of breast cancer: first report of an emerging technology.

HYPOTHESIS: Radiofrequency (RF) energy applied to breast cancers will result in cancer cell death. DESIGN: Prospective nonrandomized interventional trial. SETTING: A university hospital tertiary care center. PATIENTS: Five women with locally advanced invasive breast cancer, aged 38 to 66 years, who were undergoing surgical resection of their tumor. One patient underwent preoperative chemotherapy and radiation therapy, 3 patients received preoperative chemotherapy, and 1 had no preoperative therapy. All patients completed the study. INTERVENTIONS: While patients were under general anesthesia and just before surgical resection, a 15-gauge insulated multiple-needle electrode was inserted into the tumor under sonographic guidance. Radiofrequency energy was applied at a low power by a preset protocol for a period of up to 30 minutes. Only a portion of the tumor was treated to evaluate the zone of RF ablation and the margin between ablated and nonablated tissue. Immediately after RF ablation, the tumor was surgically resected (4 mastectomies, 1 lumpectomy). Pathologic analysis included hematoxylin-eosin staining and enzyme histochemical analysis of cell viability with nicotinamide adenine dinucleotide-diaphorase (NADH-diaphorase) staining of snap-frozen tissue to assess immediate cell death. MAIN OUTCOME MEASURE: Cancer cell death as visualized on hematoxylin-eosin-stained paraffin section and NADH-diaphorase cell viability stains. RESULTS: There was evidence of cell death in all patients. Hematoxylin-eosin staining showed complete cell death in 2 patients. In 3 patients there was a heterogeneous pattern of necrotic and normal-appearing cells within the ablated tissue. The ablated zone extended around the RF electrode for a diameter of 0.8 to 1.8 cm. NADH-diaphorase cell viability stains of the ablated tissue showed complete cell death in 4 patients. The fifth patient had a single focus of viable cells (<1 mm) partially lining a cyst. There were no perioperative complications related to RF ablation. CONCLUSIONS: Intraoperative RF ablation results in invasive breast cancer cell death. Based on this initial report of the use of RF ablation in breast cancer, this technique merits further investigation as a percutaneous minimally invasive modality for the local treatment of breast cancer.

Parathyroid localization with high-resolution ultrasound and technetium Tc 99m sestamibi.

HYPOTHESIS: High-resolution ultrasound and technetium Tc 99m sestamibi scanning can be used for preoperative localization of abnormal parathyroid glands in patients with hyperparathyroidism. DESIGN: Ultrasound and sestamibi scanning were performed in patients undergoing neck exploration for hyperparathyroidism. If the 2 scans agreed in identifying a single adenoma, and surgery confirmed the location of a single adenoma and an ipsilateral normal gland, a unilateral exploration was performed. SETTING: University tertiary care center. PATIENTS: Sixty-one consecutive patients undergoing surgery for hyperparathyroidism from September 1, 1994, through September 30, 1997. INTERVENTIONS: High-resolution ultrasound was performed in 59 patients and sestamibi scanning in 58 patients; all patients underwent neck exploration by a single surgeon. MAIN OUTCOME MEASURES: The results of preoperative ultrasound and sestamibi scanning were compared with operative and histological findings. RESULTS: All patients were cured of hypercalcemia. Specificity of ultrasound and sestamibi scanning was 98% and 99%, respectively; however, their sensitivity was only 57% and 54%, respectively. Both imaging modalities had lower sensitivities in the setting of multigland disease. If both imaging studies were considered as a single test, sensitivity for imaging in patients with primary hyperparathyroidism reached 78%. Our localization protocol allowed a unilateral approach in 43% of patients (23 of 53). CONCLUSIONS: These results confirm the value of preoperative localization in patients with hyperparathyroidism. A unilateral approach can be used with a high degree of success in cases when ultrasound and sestamibi scanning agree in the identification of a single adenoma confirmed by surgical exploration with the identification of a normal ipsilateral gland.

Perforated jejunal diverticula.

Jejunal diverticular (JD) perforation is an uncommon cause of acute abdominal pain in the elderly. From 1971 to 1994 we treated 13 such patients, 9 men and 4 women, with a mean age of 68 years. All patients experienced sudden onset of abdominal pain, nausea and vomiting, and leukocytosis (range of white blood cell counts, 14,000-21,000). On physical examination, three patients had localized peritonitis, were thought to have appendicitis, and underwent immediate laparotomy and segmental jejunal resection for perforated JD. The remaining 10 patients had abdominal tenderness without peritoneal signs. They were hospitalized and managed expectantly. All experienced worsening signs and symptoms and underwent exploratory laparotomy and resection of the involved jejunal segment 13 hours to 8 days after admission. Although 6 of 13 patients had had JD documented previously, in only 2 patients was perforated JD diagnosed preoperatively. In 8 of 13 patients peritoneal contamination was minimal and was contained within the leaves of the mesentery. Soilage was severe with abscess formation in 5 patients. The longer the delay in operative intervention, the greater the peritoneal soilage. The 3 patients undergoing immediate surgery had minimal contamination. Of the 10 patients initially observed, the mean interval before operation was 74 hours in the 5 patients with severe soilage versus 21 hours in those with minimal contamination. The postoperative course was uneventful in 11 patients. Two patients died. Surgical consultation was delayed (8 days, 12 days) in both patients, who had severe peritoneal contamination and died of sepsis. In conclusion, JD perforation is an uncommon and frequently overlooked cause of acute abdominal pain in elderly patients. Timely operative intervention and resection of the involved jejunum are the keys to a successful outcome. Because the presentation and physical findings of perforated JD can be highly variable, a history of preexisting JD should arouse suspicion for JD perforation as the etiology of acute abdominal pain in the elderly.

Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival.

IL-2Rs are expressed by T cells activated in response to foreign histocompatibility Ags but not by normal cells. This difference in IL-2R expression is exploited by blockade of IL-2Rs to achieve immunosuppression. High affinity IL-2Rs involve three subunits, IL-2R alpha, IL-2R beta, and IL-2R gamma. Murine Mik beta 1, a mAb that blocks IL-2 binding to IL-2R beta, was developed as an immunosuppressive agent. There was modest prolongation of cynomolgus cardiac allograft survival in animals treated with murine Mik beta 1 (mean survival 11.8 +/- 1.6 days compared with 8.2 +/- 0.4 days in untreated animals; p = 0.06). However, murine Mik beta 1 is ineffective in recruiting primate effector cells and is neutralized by monkey Abs directed toward the infused Ab. To circumvent these limitations, a humanized form of Mik beta 1, which is a largely human IgG1k Ab, except that murine hypervariable regions are retained, was developed. In vivo plasma survival of humanized Mik beta 1 was threefold longer than simultaneously administered murine Mik beta 1 (terminal t1/2, 104 +/- 10 h vs 37 +/- 2 h). Furthermore, humanized Mik beta 1 manifests Ab-dependent cellular cytotoxicity, an activity that is absent with the parental murine Mik beta 1. Graft survival was significantly prolonged by humanized Mik beta 1 treatment with survivals of 22, 22, 24, 27, 44, and > 300 days (p vs control < 0.01; p vs murine Mik beta 1 < 0.01). Survival was not prolonged further (p > 0.3) by the addition of humanized anti-Tac, which blocks interaction of IL-2 with IL-2R alpha subunits. There was no toxicity attributable to the use of Mik beta 1 Abs. Thus, humanized Mik beta 1 prolonged cardiac allograft survival in primates without toxicity and may be effective as an adjunct to standard immunosuppressive therapy.

Prolongation of graft survival in primate allograft transplantation by yttrium-90-labeled anti-Tac in conjunction with granulocyte colony-stimulating factor.

High-affinity IL-2 receptors are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac, a murine monoclonal antibody specific for the IL-2R alpha subunit, was used to inhibit organ allograft rejection. To enhance its effector function, anti-Tac was armed by chelation with yttrium-90, a pure beta-emitting radionuclide. Animals received no immunosuppression (n = 5, group I, controls), unmodified anti-Tac (n = 5, 1 mg/kg q.o.d., group II), or 90Y-anti-Tac (n = 5, 1.6 mCi/kg divided into four doses, group III). The animals in group IV (n = 4) were treated identically to those in group III with the exception that 5 micrograms/kg/dose of granulocyte colony-stimulating factor was administered intramuscularly on the days when the yttrium-90 was given and on postoperative days 12 through 35 in order to reduce hematopoietic toxicity. Mean graft survival +/- S.E.M. for the control group was 8.2 +/- 0.5 days as compared with 13.8 +/- 2.1 days (P < 0.05) for those monkeys treated with unmodified anti-Tac. Graft survival was further prolonged in animals of group III that received 90Y-anti-Tac, with a mean graft survival of 45.0 +/- 11.8 days; however, three of the five monkeys retained viable grafts within this group but died secondary to bone marrow suppression. In comparison, the monkeys in group IV that were treated with G-CSF in conjunction with 90Y-anti-Tac had a mean graft survival of 49.2 +/- 2.9 days. In contrast to group III there were no deaths in the group (IV) receiving G-CSF. Furthermore, animals in group IV had a reduced magnitude and shortened duration of irradiation-induced neutropenia when compared with that observed in group III animals that did not receive G-CSF. Thus, treatment with 90Y-anti-Tac in conjunction with G-CSF may have potential applications in organ transplantation and the treatment of IL-2 receptor-expressing neoplastic diseases.

Anti-Tac-H, a humanized antibody to the interleukin 2 receptor, prolongs primate cardiac allograft survival.

High-affinity interleukin 2 receptors (IL-2Rs) are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac-M, a murine monoclonal antibody specific for the IL-2R alpha chain, was used to inhibit organ allograft rejection. However, the use of murine anti-Tac as an immunosuppressive agent was limited by neutralization by human anti-murine antibodies and by weak recruitment of effector functions. To circumvent these difficulties, a humanized antibody to the IL-2R, anti-Tac-H, was prepared. This molecule is human with the exception of the hypervariable segments, which are retained from the mouse. In vivo survival of anti-Tac-H is 2.5-fold longer than simultaneously administered anti-Tac-M (terminal t1/2, 103 hr vs. 38 hr). In addition, anti-Tac-H is less immunogenic than anti-Tac-M when administered to cynomolgus monkeys undergoing heterotopic cardiac allografting. Specifically, all monkeys treated with anti-Tac-M developed measurable anti-anti-Tac-M levels by day 15 (mean onset, 11 days). In contrast, none of the animals receiving anti-Tac-H produced measurable antibodies to this monoclonal antibody before day 33. Finally, there was a prolongation of graft survival in the cynomolgus heterotopic cardiac allograft model in animals receiving anti-Tac. In animals that received anti-Tac-M, the allograft survival was prolonged compared to that of the control group (mean survival, 14 +/- 1.98 days compared to 9.2 +/- 0.48 days; P less than 0.025). Graft survival was further prolonged by anti-Tac-H with a mean survival of 20.0 +/- 0.55 days (compared to controls, P less than 0.001; compared to anti-Tac-M, P less than 0.02). There was no toxicity attributable to the administration of either form of anti-Tac. Thus, anti-Tac-H significantly prolonged allograft survival in primates, without toxic side effects, and may be of value as an adjunct to standard immunosuppressive therapy in humans.

Disseminated cutaneous herpes zoster following cardiac surgery.

Our case report describes disseminated cutaneous Herpes Zoster in the early post-operative period following cardiac surgery with cardiopulmonary bypass. This has not been reported previously in the absence of immunosuppressive therapy. Despite associated neurologic and respiratory impairment, our patient was treated successfully with intravenous Acyclovir and subsequently discharged.

Controlled reperfusion following regional ischemia.

The ability to reverse acute coronary occlusion with fibrinolytic agents and percutaneous transluminal angioplasty has increased interest in the revascularization of ischemic myocardium. This study defines changes in global ventricular function, mass, and compliance during acute coronary occlusion and following reperfusion with blood in the beating and arrested heart. In 17 dogs on cardiopulmonary bypass, the proximal left anterior descending coronary artery was occluded for 45 minutes. In 12 dogs, flow was reestablished by releasing the coronary snare in the beating heart. In the other 5 dogs, the snare was released during a continuous 10-minute infusion of blood potassium cardioplegia in the arrested heart. Coronary occlusion resulted in significant decreases in stroke work index and left ventricular (LV) mass, but compliance was unchanged. Reperfusion in the beating heart increased LV mass compared with the values measured before ischemia (104 +/- 5 versus 95 +/- 5 gm; p less than 0.05) and decreased LV compliance (39 +/- 4 versus 53 +/- 4 ml at LV end-diastolic pressure of 8 mm Hg; p less than 0.05). In contrast, with blood cardioplegia-based reperfusion in the arrested heart, LV mass and LV compliance remained unchanged from control values. We conclude that revascularization of acutely ischemic myocardium in the beating heart further impairs LV function by increasing LV mass and decreasing compliance. This damage can be avoided by reperfusion with blood cardioplegia in the arrested heart.

Experiments on the abiotic amplification of optical activity.

Our earlier experiments are briefly reviewed, involving the abiotic generation of optical activity by exposure of DL-amino acids to various "chiral" physical forces. The enantiomeric enrichments so obtained were low, however, and additional experiments were undertaken with the objective of abiotically enhancing such small enantiomeric excesses. D not equal to L Mixtures of leucine N-carboxy anhydride gave enantiomerically enriched polymers on partial polymerization, while valine NCA mixtures behaved oppositely. Leucine polymers were also found to hydrolyze stereoselectively, providing for additional enantiomeric enhancement. A repetitive sequence of partial polymerization-hydrolysis steps is suggested as a possible mechanism for the abiotic genesis of optically enriched polypeptides on the primitive Earth.