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1.
Ann Oncol ; 28(5): 1070-1077, 2017 05 01.
Article in English | MEDLINE | ID: mdl-28453704

ABSTRACT

Background: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers: NCT00513292, NCT00353483.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Breast Neoplasms/drug therapy , Trastuzumab/therapeutic use , Aged , Breast Neoplasms/genetics , Chemotherapy, Adjuvant , DNA Copy Number Variations , Female , Genetic Association Studies , Genome, Human , Germ-Line Mutation , Humans , INDEL Mutation , Middle Aged , Neoadjuvant Therapy , Polymorphism, Single Nucleotide , Receptor, ErbB-2/metabolism , Treatment Outcome
2.
Breast Cancer Res Treat ; 88(1): 9-16, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15538041

ABSTRACT

The objective of this study was to evaluate the different profiles of serum lipids resulting from the administration of selective estrogen receptor modulators (SERMs). Postmenopausal primary breast cancer patients (n = 197) with node-negative, hormone receptor-positive who were treated at our department or in other related medical institutions from April 1997 through March 2001 were given adjuvant therapy. The adjuvant therapy included 1 year's administration of tamoxifen (TAM) 20 mg or toremifene (TOR) 40 mg. The profiles of serum lipids such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and triglyceride (TG) were observed. After 1 year administration TC had significantly decreased (p < 0.001) both in the TAM group and the TOR group, but no significant difference was found between these groups (p = 0.249). HDL had significantly decreased in the TAM group (p < 0.001), while it had significantly increased in the TOR group (p < 0.001), and a significant difference was found between the groups (p < 0.001). TG had significantly increased in the TAM group (p < 0.001) but significantly decreased in the TOR group (p < 0.001). The medication was switched in those who still had abnormal lipid metabolism and given to them for another year. After 1 year from the crossover TC and HDL had increased to the levels of before administration (p < 0.001) and TG had decreased in those (n = 57) whose medication was switched from TAM to TOR. While TC had decreased and TG had increased in those (n = 23) whose medication was switched from TOR to TAM (p < 0.001). The above findings have suggested that TOR provides better profiles of lipid metabolism than TAM.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Lipids/blood , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Toremifene/therapeutic use , Administration, Oral , Aged , Aged, 80 and over , Breast Neoplasms/chemistry , Breast Neoplasms/surgery , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Chemotherapy, Adjuvant , Cross-Over Studies , Female , Humans , Middle Aged , Postmenopause , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis
5.
J Natl Cancer Inst ; 93(8): 583-96, 2001 Apr 18.
Article in English | MEDLINE | ID: mdl-11309435

ABSTRACT

BACKGROUND: Oncologic resection techniques affect outcome for colon cancer and rectal cancer, but standardized guidelines have not been adopted. The National Cancer Institute sponsored a panel of experts to systematically review current literature and to draft guidelines that provide uniform definitions, principles, and practices. METHODS: Methods were similar to those described by the American Society of Clinical Oncology in developing practice guidelines. Experts representing oncology and surgery met to review current literature on oncologic resection techniques for level of evidence (I-V, where I is the best evidence and V is the least compelling) and grade of recommendation (A-D, where A is based on the best evidence and D is based on the weakest evidence). Initial guidelines were drafted, reviewed, and accepted by consensus. RESULTS: For the following seven factors, the level of evidence was II, III, or IV, and the findings were generally consistent (grade B): anatomic definition of colon versus rectum, tumor-node-metastasis staging, radial margins, adjuvant R0 stage, inadvertent rectal perforation, distal and proximal rectal margins, and en bloc resection of adherent tumors. For another seven factors, the level of evidence was II, III, or IV, but findings were inconsistent (grade C): laparoscopic colectomy; colon lymphadenectomy; level of proximal vessel ligation, mesorectal excision, and extended lateral pelvic lymph node dissection (all three for rectal cancer); no-touch technique; and bowel washout. For the other four factors, there was little or no systematic empirical evidence (grade D): abdominal exploration, oophorectomy, extent of colon resection, and total length of rectum resected. CONCLUSIONS: The panel reports surgical guidelines and definitions based on the best available evidence. The availability of more standardized information in the future should allow for more grade A recommendations.


Subject(s)
Colonic Neoplasms/surgery , Rectal Neoplasms/surgery , Humans , Surgical Procedures, Operative/standards
6.
Ann Surg Oncol ; 8(2): 163-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11258782

ABSTRACT

BACKGROUND: Sphincter-sparing alternatives to abdominoperineal resection (APR) in the treatment of rectal cancer often are underused out of concern for inadequate distal margins and local failure. The present study addresses whether sphincter-sparing techniques with distal margins < or = 1 cm adversely influence oncological outcome in patients given preoperative chemoradiotherapy. METHODS: Thirty-seven patients with rectal cancer < or = 8 cm from the anal verge were enrolled in the study. Preoperative external beam radiotherapy (5400 Gy) was administered together with continuous infusion of 5-fluorouracil (300 mg/m2/day). Surgical resection was performed in 36 patients with pathological assessment of tumor response and margins. Patients with sphincter-sparing resection and distal margins > 1 cm or < or = 1 cm and those who underwent APR were compared. RESULTS: Thirty-six patients completed preoperative chemoradiotherapy, with successful sphincter-preservation in 28 patients. At a median follow-up of 33 months, there were 12 recurrences overall, which included 11 distant failures and four pelvic failures. Disease-free survival (DFS) was not different between those who had an APR compared with sphincter-sparing resection with distal margins < or = 1 cm. DFS was worse (P < .02) when radial margins were < or = 3 mm compared with > 3 mm. CONCLUSIONS: Sphincter preservation is feasible in more than 75% of patients with tumors < or = 8 cm from the anal verge after preoperative chemoradiotherapy. Sphincter-sparing surgery with distal margins < or = 1 cm can be used without adversely influencing local recurrence or DFS. Limited radial margins (< or = 3 mm), however, are associated with increased disease recurrence.


Subject(s)
Adenocarcinoma/pathology , Colorectal Neoplasms/pathology , Adenocarcinoma/therapy , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/therapy , Feasibility Studies , Female , Humans , Lymph Node Excision , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Recurrence, Local/diagnosis , Neoplasm Staging/methods , Prognosis
7.
Swiss Surg ; 7(6): 252-5, 2001.
Article in English | MEDLINE | ID: mdl-11771443

ABSTRACT

The primary treatment of resectable CRC is surgical resection. Postoperative adjuvant therapies are recommended when lymph node metastases are found (stage III). There is evidence that about 20% of node negative CRC cases (stage II) are understaged, i.e., they are actually node positive (stage III). New intraoperative procedures (lymphatic mapping and sentinel node identification) that are able to detect occult macro- and micrometastases. Molecular assessment of nodal disease should improve the current staging criteria for colon cancer and could influence recommendation for adjuvant treatment.


Subject(s)
Colorectal Neoplasms/pathology , Sentinel Lymph Node Biopsy , Biomarkers, Tumor/analysis , Colorectal Neoplasms/surgery , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Neoplasm Staging , Polymerase Chain Reaction , Predictive Value of Tests , Prognosis
12.
Gan To Kagaku Ryoho ; 27(5): 763-6, 2000 May.
Article in Japanese | MEDLINE | ID: mdl-10832449

ABSTRACT

Two patients with malignancy-associated hypercalcemia from bone metastases of breast cancer, accompanied by consciousness disturbance, were treated by a combination therapy of pamidronate and salmon calcitonin. The cause of the hypercalcemia in both cases was thought to be expanded bone metastases, which induced a local osteolytic hypercalcemia (LOH). In the end, this regimen could not control the growth of the metastatic tumor, but it produced a more rapid and prolonged decrease in serum calcium level than a single agent, and resulted in lessened consciousness disturbance without adverse effects. Hypercalcemia is a life-threatening paraneoplastic syndrome which requires urgent medical treatment, since malignant hypercalcemia progresses very rapidly and induces several severe complications. In conclusion, this combination therapy was extremely effective for consciousness disturbance accompanying hypercalcemia due to widespread bone metastases of cancer.


Subject(s)
Antineoplastic Agents/administration & dosage , Bone Neoplasms/secondary , Breast Neoplasms/pathology , Calcitonin/administration & dosage , Diphosphonates/administration & dosage , Hypercalcemia/drug therapy , Bone Neoplasms/complications , Breast Neoplasms/chemically induced , Consciousness Disorders/drug therapy , Consciousness Disorders/etiology , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Hypercalcemia/etiology , Middle Aged , Pamidronate
14.
Chem Senses ; 25(1): 21-9, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10667990

ABSTRACT

Olfactory discrimination of amino acids was investigated in brown bullhead catfish (Ameiurus nebulosus). Based on the magnitude of the observed food search activity of catfish conditioned to single amino acids, the tested compounds were classified as being detected by the catfish as equal to, similar to, or different from the conditioned stimulus. L-Proline (L-Pro)-conditioned brown bullhead catfish discriminated all amino acids from L-Pro, but catfish conditioned to L-valine (L-Val) and L-isoleucine (L-Ile) did not discriminate L-Val from L-Ile nor L-Ile from L-Val; however, all other amino acids tested were always discriminated from these two compounds. Catfish conditioned to L-alanine (L-Ala) discriminated basic, acidic and several neutral amino acids with long side-chains (LCNs) from L-Ala; however, they did not always discriminate L-Ala from all neutral amino acids with short side-chains (SCNs). The L-norleucine (L-nLeu)-conditioned fish responded to L-norvaline (L-nVal), L-methionine (L-Met) and L-Ala similarly to L-nLeu, indicating that these amino acids are detected as similar or identical to L-nLeu. L-nLeu was, however, discriminated from L-Ala in L-Ala-conditioned catfish. Interestingly, L-leucine (L-Leu) was discriminated from the conditioned stimuli, L-Ala, L-Ile and L-Val, indicating independent receptors for L-Leu. Although conditioned catfish discriminated other amino acids from L-arginine hydrochloride (L-Arg), in some tests they were unable to discriminate L-Arg from L-lysine hydrochloride (L-Lys). These results imply the existence of independent olfactory receptive pathways for: (i) L-Pro; (ii) basic amino acids (L-Arg and L-Lys); (iii) L-Leu; (iv) other neutral amino acids with branched side-chains (L-Ile and L-Val); (v) neutral amino acids with long linear side-chains (L-nLeu, L-nVal and L-Met); (vi) neutral amino acids with short side-chains; and (vii) amino acids with sulfhydryl groups (L-Cys and L-homoCys).


Subject(s)
Amino Acids , Discrimination Learning , Ictaluridae/physiology , Smell/physiology , Animals , Conditioning, Classical , Olfactory Pathways/surgery
15.
Surg Oncol ; 9(3): 127-34, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11356341

ABSTRACT

The conventional and accepted treatment for curative resection of colon cancer is laparotomy with hemicolectomy for right or left sided lesions. The technique of colon resection through an open laparotomy incision is well known. Over the past several years, laparoscopically assisted colectomy has been developed and studied, following the explosion of laparoscopic technology from the cholecystectomy experience and with acquisition of advanced general laparoscopic techniques. The right, left or sigmoid colon can be mobilized and regional lymphadenectomy performed using laparoscopic instruments and video-imaging equipment. The advantage of laparoscopic colectomy is the use of small abdominal port site and wound incisions which translate to reduced postoperative pain and analgesic requirement, earlier return of bowel function and normal physical activities, and shorter hospital stay without increasing health care costs. Laparoscopic colectomy compares favorably with open colectomy in terms of surgical morbidity and mortality. The laparoscopic approach has been shown to be technically and oncologically feasible with equivalent lymph node harvest from mesenteric lymphadenectomy and achieves adequate proximal and distal margins of colonic resection. Despite initial early anecdotal reports of port site cancer recurrence in laparoscopically assisted colectomy, port site recurrence is rare and its incidence is similar to incisional recurrences in conventional open colectomy. Recent prospective comparative studies have demonstrated equivalent patient survival and equivalent local or distant colon cancer recurrences for open versus laparoscopic curative resection of colon cancer.


Subject(s)
Colectomy/methods , Colonic Neoplasms/surgery , Laparoscopy/methods , Colectomy/adverse effects , Colectomy/economics , Colectomy/psychology , Colonic Neoplasms/mortality , Feasibility Studies , Health Care Costs/statistics & numerical data , Humans , Laparoscopy/adverse effects , Laparoscopy/economics , Laparoscopy/psychology , Length of Stay/economics , Length of Stay/statistics & numerical data , Lymph Node Excision/methods , Morbidity , Quality of Life , Survival Analysis , Treatment Outcome
16.
J Clin Oncol ; 17(8): 2403-11, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10561303

ABSTRACT

PURPOSE: Patients with local-regional gastric carcinoma have a low rate of curative resection (R0) because of the advanced stage at diagnosis and suboptimal clinical staging. This study was designed to improve clinical staging with the use of laparoscopy and endoscopic ultrasonography (EUS) and to improve R0 resection rates and tolerance by delivering all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. PATIENTS AND METHODS: All patients with histologic proof of localized adenocarcinoma of the stomach underwent a staging laparoscopy before registration. EUS was performed when feasible. The intention was to administer up to five courses of preoperative chemotherapy consisting of fluorouracil (500 mg/m(2)/d as a continuous infusion on days 1 through 5 and as a bolus on days 12 and 19), interferon alfa-2b (3 million units subcutaneously three times a week for 3 weeks), and cisplatin (15 mg/m(2)/d as a bolus on days 1 through 5). After chemotherapy, surgery was attempted to remove the primary and regional lymph nodes. Clinical response and EUS staging were correlated with surgical pathology. The feasibility of this approach, resection rates, patient survival, and patterns of failure also were assessed. RESULTS: All 30 patients enrolled were assessed for toxicity, response, and survival. Nineteen men and 11 women were enrolled. The median number of courses delivered per patient was three (range, one to five courses). Fourteen patients (47%) received all five preoperative courses of chemotherapy. The overall clinical response rate was 34%. Twenty-nine patients (97%) underwent attempted resection. Twenty-five (83%) had an R0 resection. Two patients (7%) had no evidence of carcinoma in the surgical specimen, and three had only microscopic carcinoma (>/= 90% necrosis). Posttreatment EUS findings did not correlate well with surgical pathology. The median duration of follow-up was 30 months (range, 5 months to 65+ months). The median survival time for 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 months to 65+ months). There were no cases of grade 4 toxicity. CONCLUSION: It is feasible to administer prolonged preoperative therapy in patients with potentially resectable gastric carcinoma. Enhanced staging with laparoscopy and EUS helped in proper selection of patients and better characterization of the stage.


Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Drug Administration Schedule , Endosonography , Feasibility Studies , Female , Fluorouracil/administration & dosage , Humans , Interferon alpha-2 , Interferon-alpha/administration & dosage , Laparoscopy , Male , Middle Aged , Neoplasm Staging , Preoperative Care , Recombinant Proteins , Stomach Neoplasms/mortality , Stomach Neoplasms/surgery , Survival Analysis
17.
Anat Embryol (Berl) ; 200(5): 487-94, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10526017

ABSTRACT

The grass goby is a mud-burrowing fish with a rich retinal vasculature appropriate to its hypoxic habitat. NADPH-diaphorase histochemistry was performed on retinal sections and wholemounts to reveal cells that contain nitric oxide synthase and so may be presumed to synthesise nitric oxide, a gaseous intercellular messenger with many roles including vasodilation. Structures that were consistently stained by this method included cone ellipsoids, horizontal cells, Müller cells and their processes, large displaced ganglion cells in the inner nuclear layer (identified by their axons), large interstitial ganglion cells in the inner plexiform layer, and capillary endothelial cells. In wholemounts, horizontal cells were seen to form a regular pattern, contacting each other at their dendritic terminals. Some cells in the ganglion cell layer were weakly stained, but stained bipolar and amacrine cells were not seen. The diaphorase-positive large ganglion cells all formed large, sparsely branched dendritic trees, arborizing near the scleral border of the inner plexiform layer. The displaced and interstitial cells seemed to belong to distinct morphological types, the interstitial cells having smaller somata and trees. Analysis of their spatial distributions in one representative retina confirmed this: the displaced cells formed a highly regular mosaic with a mean spacing (nearest-neighbour distance) of 303 microm, whereas the interstitial cells formed a separate mosaic, almost as regular but with a smaller mean spacing of 193 microm, rising to 217 microm in a sample that excluded the area retinae temporalis. Spatial correlogram analysis showed that these two mosaics were spatially independent. Nitric oxide probably has many roles in the retina. The presence of its synthetic enzyme in Müller cells, which communicate with retinal blood vessels, is consistent with a role in the control of retinal blood flow. Its function in large, mosaic-forming retinal ganglion cells is unknown.


Subject(s)
NADPH Dehydrogenase/analysis , Neuroglia/chemistry , Neuroglia/cytology , Perciformes/anatomy & histology , Retina/chemistry , Retina/cytology , Retinal Ganglion Cells/chemistry , Retinal Ganglion Cells/cytology , Animals , Histocytochemistry
19.
Surgery ; 124(4): 757-61; discussion 761-2, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9780998

ABSTRACT

BACKGROUND: Sentinel lymph node (SLN) mapping by lymphoscintigraphy has changed the surgical management of regional lymph node metastases for melanoma. SLNs lying outside of traditional nodal basins are now being identified. Our hypothesis is that when preoperative lymphoscintigraphy identifies aberrant SLNs, these nodes should be excised and, if histologically positive, lymphadenectomy of the aberrant nodal basin should be performed. METHODS: Patients with melanomas 1 mm or larger Breslow thickness and clinical stage N0M0 underwent lymphoscintigraphy and excision with SLN biopsy. Preoperative lymphoscintigraphy, intraoperative gamma probe, and intraoperative injection of isosulfan blue were performed to identify the SLN. Aberrant SLNs were defined as epitrochlear, supraclavicular, or popliteal nodes for extremity lesions and intramuscular nodes for truncal and head and neck lesions. RESULTS: Thirty-two patients were entered into the protocol. Seven (22%) were found to have aberrant nodes. Five of 19 patients with extremity melanoma had an aberrant SLN; 2 of 13 patients with truncal and head and neck melanoma had an aberrant SLN. CONCLUSIONS: This study demonstrates that (1) aberrant SLNs are encountered with similar frequency for extremity and truncal lesions, (2) biopsy should be performed on aberrant SLNs with intraoperative lymph node mapping with the gamma probe and blue dye, and (3) lymphadenectomy of the aberrant region should be considered if the aberrant SLN is positive.


Subject(s)
Lymph Node Excision , Lymph Nodes/diagnostic imaging , Melanoma/surgery , Skin Neoplasms/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Lymphatic Metastasis , Male , Melanoma/diagnostic imaging , Melanoma/pathology , Middle Aged , Radionuclide Imaging , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/pathology
20.
Am J Surg ; 176(6): 554-8, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9926789

ABSTRACT

BACKGROUND: The appropriateness of laparoscopic colon resection (LCR) as treatment for malignancy has been questioned. METHODS: From 1992 to 1997, 91 patients were entered into a prospective study of LCR for cancer. Clinical, pathologic, and economic parameters of LCR were compared in a cohort of patients matched for age, tumor stage, and type of colectomy who underwent open colon resection (OCR) during the same time period. RESULTS: With a median follow-up of 26 months, there were no significant differences in survival rate for patients in the LCR, converted colon resection, and OCR groups. There were no port-site recurrences and the number of lymph nodes harvested was similar among the procedures. Hospital stay was significantly shorter if laparoscopic resection was successful. Total hospital costs were similar for LCR and OCR; however, the costs were significantly higher for converted colon resection. CONCLUSIONS: LCR is a sound oncologic procedure that can be performed with costs similar to OCR.


Subject(s)
Colectomy/methods , Colorectal Neoplasms/surgery , Laparoscopy/methods , Adult , Aged , Aged, 80 and over , Colectomy/economics , Cost-Benefit Analysis , Female , Follow-Up Studies , Humans , Laparoscopy/economics , Lymph Node Excision , Lymph Nodes/pathology , Male , Middle Aged , Prospective Studies , Recurrence , Survival Analysis , Treatment Outcome
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