Evolving indications and long-term oncological outcomes of risk-reducing bilateral nipple-sparing mastectomy.

Background: Bilateral nipple-sparing mastectomy (NSM) is a technically feasible operation and is associated with excellent cosmetic outcomes. The aim of this study was to evaluate trends in patient characteristics, indications for surgery and long-term outcomes of bilateral NSM for breast cancer risk reduction over time. Methods: A review of a single-centre experience with bilateral NSM performed between 2001 and 2017 for breast cancer risk reduction in patients without breast cancer was performed. Trends in patient characteristics and indications for surgery were evaluated over four time intervals: 2001-2005, 2006-2009, 2010-2013 and 2014-2017. Statistical analysis was performed using χ2 tests. Results: Over the study period, 272 NSMs were performed in 136 patients; their median age was 41 years. The number of bilateral NSMs performed increased over time. The most common indication was a mutation in breast cancer-associated genes (104 patients, 76·5 per cent), which included BRCA1 (62 patients), BRCA2 (35), PTEN (2), TP53 (3) and ATM (2). Other indications were family history of breast cancer (19 patients, 14·0 per cent), lobular carcinoma in situ (10, 7·4 per cent) and a history of mantle irradiation (3, 2·2 per cent). The proportion of patients having a bilateral NSM for mutation in a breast cancer-associated gene increased over time (2001-2005: 2 of 12; 2006-2009: 9 of 17; 2010-2013: 34 of 41; 2014-2017: 61 of 66; P < 0·001). Mean follow-up was 53 months; no breast cancers were found during follow-up. Conclusion: The use of bilateral NSM for breast cancer risk reduction is increasing and the indications have evolved over the past 16 years. These excellent long-term oncological results suggest that bilateral NSM is a good option for surgical breast cancer risk reduction.

Primary gynecological neoplasms and clinical outcomes in patients diagnosed with breast carcinoma.

The purpose of this study was to quantify and describe nonmammary neoplasms (n-MN), particularly gynecological neoplasms, in a patient population previously diagnosed with breast cancer. Data were collected prospectively in our institutional review board-approved registry for patients diagnosed with infiltrating breast cancer or ductal carcinoma in situ. Patients who developed a second, n-MN were identified; neoplastic site, time to development after breast cancer, and clinical outcomes were recorded. FIGO stage was recorded for patients who developed a gynecological neoplasm. Synchronous bilateral breast cancer was defined as a second, contralateral diagnosis made within 12 months of the first and, similarly, synchronous n-MN were defined as those identified within 1 year of a breast cancer diagnosis. Outcome curves were generated using the method of Kaplan and Meier, and compared using the log-rank test. Of 4126 patients diagnosed with breast cancer, 3% developed a n-MN, the majority of which were nongynecological and asynchronous to the initial breast cancer diagnosis. Three percent of patients diagnosed with breast cancer were diagnosed with a second, n-MN. Among patients who developed a n-MN, most developed a nongynecological cancer more than 1 year after the initial breast cancer diagnosis, and their outcomes were significantly worse than those patients who did not develop a n-MN.

Tumour-derived mutated K-ras codon 12 expression in regional lymph nodes of stage II colorectal cancer patients is not associated with increased risk of cancer-related death.

This study examined the frequency of lymph node micrometastases detected by expression of mutant K-ras oncogene present in the respective primary tumour. The study population consisted of consecutive patients with stage II colorectal cancer (CRC) undergoing curative resection and with disease-free survival of 60 months or longer or CRC-related death. Of 27 patients found to have K-ras mutations at codon 12, 17 had genomic DNA suitable for PCR recovered from corresponding regional lymph node tissue. The same K-ras mutation was identified in the lymph nodes of 13 patients (76%), four of whom (30%) died of CRC recurrence within 5 years. A single patient in the negative group (25%) also died. Lymph node micrometastases detected by this technique thus show no relationship to mortality in stage II CRC. Further study of this technique is necessary before it can be used in the selection of patients for adjuvant chemotherapy.

Touch imprint cytological analysis of sentinel lymph nodes for detecting axillary metastases in patients with breast cancer.

BACKGROUND: Sentinel lymph node biopsy is a procedure that examines the first tumour-draining lymph node. Touch imprint cytology may provide a quick method for intraoperative screening of sentinel lymph nodes for the presence of metastases. METHODS: Touch imprint cytological analysis of sentinel lymph nodes was compared prospectively with the findings obtained on routine paraffin sections. Touch imprint slides from 55 patients with breast cancer were prepared during operation from multiple sections of sentinel lymph nodes, stained with haematoxylin and eosin. A cytopathologist blinded to the histological results interpreted the smears. RESULTS: The concordance between touch imprint and paraffin sections of sentinel lymph nodes was 98 per cent (54 of 55). When touch imprint analysis of sentinel lymph nodes was compared with paraffin sectioning of all lymph nodes from the axillary node dissection, the concordance was 95 per cent (52 of 55). The sensitivity and specificity of sentinel lymph node touch imprints in detecting metastases were 82 and 100 per cent respectively. The positive and negative predictive values were 100 and 93 per cent respectively. CONCLUSION: Touch imprint cytology is potentially useful for the intraoperative evaluation of sentinel lymph nodes in patients with breast cancer.

Predicting the likelihood of residual disease in women treated for ductal carcinoma in situ.

BACKGROUND: To identify women at risk for residual disease after excision of ductal carcinoma in situ (DCIS), we assessed the relationship between characteristics of the initial biopsy and the presence of residual DCIS at a subsequent operation. STUDY DESIGN: We identified 134 consecutive "paired" operations from 112 women who had undergone 2 or more operations for DCIS between February 1995 and December 1996. Cancer status of the margins, patient age and leading presentation, tumor subtype and grade, and the presence of multifocal-extensive disease were assessed as potential predictors. RESULTS: Residual DCIS was found in 60 patients (45%): in 2 of 12 patients (17%) with negative margins, in 11 of 36 (31%) with close margins (< 2 mm), in 30 of 52 (58%) with positive margins, and in 17 of 34 patients (50%) with margins of unknown status. Patients with positive or unknown margins were 7.7 and 8.3 times, respectively, more likely to have residual disease than patients with negative margins (95% CI 1.1-59.1; 1.1-66.4). Patients with clinical presentations were 8.0 times more likely to have residual disease than patients who presented with abnormal mammograms (95% CI 2.3-27.6). Multifocal-extensive DCIS was associated with residual disease (adjusted odds ratio [OR] = 7.7, 95% CI 2.9-20.5), as was comedo subtype (OR = 2.7, 95% CI 1.1-6.7). CONCLUSIONS: Positive or unknown biopsy margins, a clinical presentation, multifocal-extensive cancer, and the comedo subtype are associated with higher risk of residual DCIS.

Experience with lymphatic mapping in breast cancer using isosulfan blue dye.

Sentinel (first tumor-draining) lymph node (SLN) biopsy directed by the blue dye technique may be as accurate as complete axillary lymph node dissection (ALND) in determining whether breast cancer has metastasized to the lymph nodes and may have fewer surgical complications because it is less invasive. Breast cancer patients scheduled for ALND between February and June 1997 who did not have prior axillary surgery, prior radiation therapy, or preoperative chemotherapy were included. Isosulfan blue dye was injected around the primary tumor or the biopsy cavity just before ALND. Operations were performed in a tertiary breast center by two breast surgeons who did not have experience with the technique before this study. The results of blue stained nodes were compared to those of the ALND. Blue-stained nodes were identified in 35 of 40 patients (88%), and the results were concordant with ALND in 33 of 35 (94%), 7 patients were concordant for positive results and 26 for negative results. We identified SLNs in patients whose cancers were either in the medial or lateral halves of the breast. Average time for SLN dissection was 19 +/- 9 minutes, and there were no complications. The diagnostic accuracy of the isosulfan blue dye technique for SLN biopsy, 94%, is high enough to warrant further research. The lack of complications and the short time needed to perform the technique are attractive features. Broader experience with the technique is required to evaluate the reliability and reproducibility of this method.

Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group.

BACKGROUND: Despite widespread use of aminosalicylates as maintenance treatment for ulcerative colitis (UC), patients still report troublesome symptoms, often nocturnally. AIM: To compare the efficacy and safety of balsalazide (Colazide) with mesalazine (Asacol) in maintaining UC remission. METHODS: A randomized, double-blind comparison of balsalazide 3 g daily (1.04 g 5-ASA) and mesalazine 1.2 g daily for 12 months, in 99 (95 evaluable) patients in UC remission. RESULTS: Balsalazide patients experienced more asymptomatic nights (90% vs. 77%, P=0.0011) and days (58% vs. 50%, N.S.) during the first 3 months. Balsalazide patients experienced more symptom-free nights per week (6.4+/-1.7 vs. 4.7+/-2.8; P=0.0006) and fewer nights per week with blood on their stools or on the toilet paper, mucus with their stools or with sleep disturbance resulting from symptoms or lavatory visits (each P < 0.05). Fewer balsalazide patients relapsed within 3 months (10% vs. 28%; P=0.0354). Remission at 12 months was 58%, in both groups. Similar proportions of patients reported adverse events (61% balsalazide vs. 65% mesalazine). There were five serious adverse events (two balsalazide, three mesalazine) and four withdrawals due to unacceptable adverse events (three balsalazide, one mesalazine), of which one in each group was also a serious adverse event. CONCLUSIONS: Balsalazide 3 g/day and mesalazine 1.2 g/ day effectively maintain UC remission and are equally well tolerated over 12 months. At this dose balsalazide prevents more relapses during the first 3 months of treatment and controls nocturnal symptoms more effectively.

Randomised double blind controlled study of recurrence of gastric ulcer after treatment for eradication of Helicobacter pylori infection.

OBJECTIVE: To determine whether eradication of Helicobacter pylori infection reduces recurrence of benign gastric ulceration. DESIGN: Randomised, double blind, controlled study. Patients were randomised in a 1:2 ratio to either omeprazole 40 mg once daily for eight weeks or the same treatment plus amoxycillin 750 mg twice daily for weeks 7 and 8. A 12 month untreated follow up ensued. SETTING: Teaching and district general hospitals between 1991 and 1994. SUBJECTS: 107 patients with benign gastric ulcer associated with H pylori. MAIN OUTCOME MEASURES: Endoscopically confirmed relapse with gastric ulcer (analysed with life table methods), H pylori eradication, and healing of gastric ulcers (Mantel-Haenszel test). RESULTS: 172 patients were enrolled. Malignancy was diagnosed in 19; 24 were not infected with H pylori; four withdrew because of adverse events; and 18 failed to attend for start of treatment, leaving 107 patients eligible for analysis (35 omeprazole alone; 72 omeprazole plus amoxycillin). In the omeprazole/amoxycillin group 93% (67/72; 95% confidence interval 84% to 98%) of gastric ulcers healed and 83% (29/35; 66% to 94%) in the omeprazole group (P = 0.103). Eradication of H pylori was 58% (42/72; 46% to 70%) and 6% (2/35; 1% to 19%) (P < 0.001) and relapse after treatment was 22% (16/72) and 49% (17/35) (life table analysis, P < 0.001), in the two groups, respectively. The recurrence rates were 7% (3/44) after successful H pylori eradication and 48% (30/63) in those who continued to be infected (P < 0.001). CONCLUSIONS: Eradication of H pylori reduces relapse with gastric ulcer over one year. Eradication rates achieved with this regimen, however, are too low for it to be recommended for routine use.

Breast cancer evaluation and follow-up: a survey of The Ohio Chapter of The American College of Surgeons.

Preoperative evaluation and postoperative follow-up of breast cancer patients vary considerably. Recent literature suggests that routine surveillance studies for breast cancer patients can be reduced without compromising the outcome. The Ohio State Chapter of The American College of Surgeons Committee on Cancer sponsored a survey of its general surgeon fellows to determine their practice philosophies regarding these issues. The questions centered around breast cancer screening, evaluation and treatment, and follow-up. The fellows were also questioned as to their opinions regarding practice parameters and whether the State Chapter should take a role in this area. Of the 764 surveys sent out, 34.2% were appropriate for evaluation. For breast cancer screening, 96.1% believe yearly mammography is important. Newly diagnosed breast cancer patients are generally evaluated with history and physical exam, chest X-ray, complete blood cell count, and liver function tests. Bone scans are used by 38.6% of surgeons. Most patients with positive lymph nodes see a medical oncologist. About half of primary breast cancer treatment (44.7%) is by breast preservation. Essentially all surgeons follow their patients after treatment for breast cancer surveillance. Essentially all surgeons feel that physical exam and mammograms are important for post-treatment follow-up. Complete blood cell count, liver function studies, and chest X-rays are used less commonly but still by more than half of the surgeons. 44.4% of the surgeons have found difficulty with third-party payers covering the costs of surveillance studies. 87.7% of surgeons surveyed felt the State Chapter should become involved in establishing clinical guidelines or practice parameters.

An update on breast cancer: evolving treatments and persistent questions.

This review describes recent advances in imaging technology and treatment options, and discusses the persistent questions about the best strategies for preventing, diagnosing and treating breast cancer. Possible clinical implications of new research on the causes of breast cancer are also examined. The evolution of breast cancer management over the past century is summarized.

Diabetic mastopathy: a clinicopathologic study in palpable and nonpalpable breast lesions.

Diabetic mastopathy is a distinct clinicopathologic entity with specific histopathologic characteristics which include keloidal fibrosis, epithelioid fibroblasts, widespread periductal/lobular lymphocytic infiltration, and widespread perivascular lymphocytic infiltration. We report the clinical and histopathologic breast tissue findings of 20 patients with diabetes mellitus as compared to 20 age-matched controls. The control patients also were matched for diseases other than diabetes mellitus. All patients with diabetes mellitus showed at least one of the histologic findings of diabetic mastopathy: 13 patients (65%) showed all four histopathologic characteristics; one patient showed three; one patient showed two; and five patients showed one feature. The 20 control patients did not demonstrate any of the four histopathologic features of diabetic mastopathy. We confirm previously reported findings of diabetic mastopathy presenting as palpable breast masses in insulin-dependent diabetics. However, we also suggest that diabetic mastopathy should be expanded to include the histopathologic findings characteristic in diabetic patients with nonpalpable mammographic abnormalities and breast tissue distant to the site of involvement by carcinoma.

Omeprazole 10 mg or 20 mg once daily in the prevention of recurrence of reflux oesophagitis. Solo Investigator Group.

This study determined the optimal maintenance dose of omeprazole in reflux oesophagitis. One hundred and ninety three patients rendered asymptomatic and healed after four or eight weeks omeprazole were randomised double blind to 10 mg omeprazole once daily (n = 60 evaluable), 20 mg omeprazole once daily (n = 68), or placebo (n = 62) for one year or until symptomatic relapse. Each omeprazole regimen was superior to placebo in preventing both symptomatic relapse (life table analysis, p < 0.001) and endoscopically verified relapse (p < 0.001). At 12 months, the life table endoscopic remission rates (proportions of patients without grade > or = 2 oesophagitis) were: 50% (95% confidence intervals 34 to 66%) with 10 mg omeprazole once daily, 74% (62 to 86%) with 20 mg omeprazole once daily, and 14% (2 to 26%) with placebo. At 12 months, the life table symptomatic remission rates (proportions of patients asymptomatic or with mild symptoms) were: 77% (64 to 89%) with 10 mg omeprazole once daily, 83% (73 to 93%) with 20 mg omeprazole once daily, and 34% (16 to 52%) with placebo. Both 10 mg and 20 mg omeprazole once daily were effective in prolonging the remission of reflux oesophagitis: 10 mg may be appropriate to start longterm treatment, though the existence of a dose response relation means that 20 mg once daily may be effective in patients for whom 10 mg once daily is suboptimal.

Age does not predict breast cancer outcome.

OBJECTIVE: To determine whether age is a prognostic factor of breast cancer and should be used to make treatment recommendations, because younger patients are considered to have a poorer prognosis compared with that of older patients and, thus, often receive more aggressive therapy. DESIGN: A large group of patients with operable breast cancer, all of whom were followed up prospectively as part of two multicenter trials. SETTING: Case Western Reserve University, Cleveland, Ohio, was the primary hospital and study center, with 12 participating regional institutions. PATIENTS: All 1353 patients underwent uniform local-regional therapy that consisted of a modified radical mastectomy. Patients who were node negative were followed up, and patients who were node positive received systemic chemoendocrine therapy. MAIN OUTCOME MEASURES: Patients were followed up at regular intervals for either recurrence or death. RESULTS: Patients ranged in age from 22 to 75 years with a median age of 56 years. Younger patients had more estrogen receptor-negative tumors (P < .0001) and a greater number of positive lymph nodes (P < .0001). Of the 241 black patients in the study, a greater percentage were younger compared with white patients (P < .0001). Age was considered in a Cox's multivariate model, together with nodes, tumor diameter, estrogen receptor content, and race. Age was not a significant predictor of either disease-free (P = .33) or overall (P = .30) survival. Using mixture models with covariates, the estimated average hazards (where lambda indicates the force of mortality) of breast cancer deaths per year were similar (P, not significant) for patients 45 years old or younger (lambda = 0.061), older than 45 years but 65 years old or younger (lambda = 0.052), and older than 65 years (lambda = 0.061). CONCLUSIONS: In conclusion, younger patients as a group have more aggressive and advanced breast cancer at presentation compared with older patients. Considered in a multivariate model, together with other variables, age does not provide independent prognostic information and should not be used alone for management decisions.

Positron emission tomography and breast masses: comparison with clinical, mammographic, and pathological findings.

BACKGROUND: Positron emission tomography (PET) is a means of imaging tissue based upon its metabolic activity. Initial studies in the field of oncology suggest that PET may be useful for diagnosis, staging, and treatment of various tumors. METHODS: Twenty-eight patients with 37 breast lesions were studied with PET using [fluorine-18] 2-deoxy-2-fluoro-D-glucose (FDG) to assess which clinicopathological characteristics relate to FDG accumulation by the primary tumor. RESULTS: PET-FDG was found to successfully discriminate malignant from benign breast lesions (p = 0.02) and identify axillary lymph node metastases. FDG uptake by the primary tumor was found to be independent of age, menopausal status, race, tumor size, laterality, histologic differentiation, ploidy, DNA index, estrogen or progesterone receptor value, pathologic stage, and serum glucose. Higher tumor nuclear grade and S-phase were associated with more FDG accumulation by the primary tumor compared with normal breast tissue. PET-FDG correctly identified five malignant lesions that were indeterminant for cancer both on clinical breast examination and mammography and identified one occult cancer that was neither palpable nor apparent mammographically. PET-FDG correctly identified clinical occult axillary metastatic cancer in five patients. CONCLUSIONS: This study shows that PET-FDG imaging can distinguish malignant from benign breast lesions among a diverse group of patients and suggests that PET-FDG may not only allow for preoperative staging of patients but also provide information about prognosis. This study provides impetus for continued research into PET-FDG imaging of breast lesions, which could have a major impact on the treatment of breast cancer.

Does 40 mg omeprazole daily offer additional benefit over 20 mg daily in patients requiring more than 4 weeks of treatment for symptomatic reflux oesophagitis?

This study was designed to establish whether 40 mg omeprazole once daily exhibits sufficient additional efficacy over that of 20 mg omeprazole once daily in patients with symptomatic reflux oesophagitis requiring more than an initial 4-week course of 20 mg omeprazole once daily (o.m.) to warrant routine use of the higher dose. Three hundred and thirteen patients were randomized to receive either 20 mg omeprazole (4 weeks) then 20 mg (second 4 weeks if not both healed and symptom-free after 4 weeks), or 20 mg omeprazole (4 weeks) then 40 mg omeprazole o.m. (second 4 weeks). One hundred and twenty-seven patients were healed and symptom-free after 4 weeks and left the study at that point. Taking the second treatment period in isolation, the healing rate (64% vs. 45%, P < 0.02) and relief of heartburn (72% vs. 60%, P < 0.002) were greater among patients receiving 40 mg omeprazole o.m., demonstrating the existence of a dose-response relationship for omeprazole. However, on completion, there were no significant differences between the patients randomized to the 20/20 mg (healed 65%, asymptomatic 69%) or the 20/40 mg (healed 74%, asymptomatic 74%: both not significant differences compared with 20/20 mg) regimens. The magnitude of the difference in efficacy between 20 and 40 mg omeprazole in symptomatic reflux oesophagitis is insufficient to warrant the routine use of 40 mg in patients requiring more than 4 weeks' treatment with 20 mg omeprazole o.m.; continued treatment with 20 mg omeprazole for 4-8 weeks is the preferred option.

Evaluation of breast masses and axillary lymph nodes with [F-18] 2-deoxy-2-fluoro-D-glucose PET.

Twenty-eight patients with a total of 35 suspect breast masses underwent positron emission tomography (PET) with [fluorine-18] 2-deoxy-2-fluoro-D-glucose (FDG) in order to study the utility of this technique in the evaluation of breast cancer. FDG PET allowed discrimination between eight benign and 27 malignant breast masses, with a sensitivity of 96% and specificity of 100%. Among the malignancies, there was a significant correlation between normalized FDG uptake and nuclear grade (P = .006). In addition, the results of PET imaging were compared with results of axillary node dissection in 20 cases of breast cancer. PET allowed correct categorization of 10 of 10 axillae as negative (specificity = 100%). PET results were equivocal in one axilla and positive in the remaining nine of 10 axillae with positive dissection results (sensitivity = 90%). The authors conclude that FDG PET may give useful information on breast masses and axillary node status prior to surgery.

Primary tumor size. Relevance to breast cancer survival.

In view of current emphasis on identifying prognostic factors for patients with early breast cancer, we studied the importance of tumor size to survival among 1392 patients with primary operable breast cancer who were followed up prospectively. All patients had modified radical mastectomies. Nine hundred seventeen patients had negative nodes and did not receive postoperative adjuvant therapy. Four hundred seventy-five patients had node involvement and received combination chemoendocrine therapy. In a Cox's proportional hazards model, tumor size was a significant predictor of disease-free and overall survival when the number of positive nodes, estrogen receptor status, menopausal status, and race were considered. Among the node-negative group, tumor size explained considerable variation in disease-free and overall survival, varying from a 10-year disease-free and overall survival of 80% and 99% for patients with estrogen receptor-positive tumors measuring 1 cm or less to a 10-year disease-free and overall survival of 51% and 59% for patients with tumors larger than 5 cm.

Effect of tamoxifen on preneoplastic cell proliferation in N-nitroso-N-methylurea-induced mammary carcinogenesis.

N-Nitroso-N-methylurea (NMU) is an effective carcinogen for the induction of mammary carcinoma in the rat. Tamoxifen (TAM), used as a chemopreventive agent to reduce tumor incidence, has been well studied using this model. We have utilized the rat mammary carcinoma model to assess the effect of TAM on preneoplastic changes. Fifty-day-old virgin female Sprague-Dawley rats were randomized by weight and divided into the following five groups: Group 1, normal controls (n = 24); Group 2, TAM (n = 20); Group 3, NMU-short term (n = 24); Group 4, NMU-short term + TAM (n = 26); and Group 5, NMU-long term (n = 23). Seven weeks after the exposure to NMU, rats in Groups 1, 2, 3, and 4 were given injections of [3H]thymidine and sacrificed 4 h later for autoradiographic determination of thymidine labeling index (TLI). The rats from Group 5 were observed for 30 weeks after NMU exposure to confirm mammary tumor development. TLI in both terminal ducts and terminal end buds was modulated by treatment with TAM. Carcinogen administration induced higher TLI relative to the normal controls [18.3 +/- 1.8% (SD) versus 15.5 +/- 2.1%, P less than 0.001] in terminal end buds. The effect of carcinogen on TLI was also apparent in the terminal ducts (15.8 +/- 1.1% versus 9.5 +/- 1.1%, P less than 0.001). TAM administration was able to suppress both constitutive and NMU-induced TLI increases in terminal end buds (15.5 +/- 2.1% versus 2.8 +/- 1.1% and 18.3 +/- 1.8% versus 6.8 +/- 1.4%, respectively, P less than 0.001). Similar effects were observed in terminal ducts. In addition to its antiproliferative effect on nontransformed mammary tissue, TAM was effective in suppressing NMU-induced mammary tumor incidence and frequency. NMU-induced hyperproliferation is an intermediate stage in NMU carcinogenesis in the rat and is suppressed by TAM. Mammary epithelial hyperproliferation may provide a useful quantitative intermediate end point to evaluate chemopreventive efficacy.