Gene expression profiling to predict the risk of locoregional recurrence in breast cancer: a pooled analysis.

The 70-gene signature (MammaPrint) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment. Given the strong association between locoregional and distant recurrence, we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence (LRR). 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherlands Cancer Institute between 1984 and 2006 were included. Adjuvant treatment consisted of radiotherapy, chemotherapy, and/or endocrine therapy as indicated by guidelines used at the time. All patients were included in various 70-gene signature validation studies. After a median follow-up of 8.96 years with 87 LRRs, patients with a high-risk 70-gene signature (n = 492) had an LRR risk of 12.6% (95% CI 9.7-15.8) at 10 years, compared to 6.1% (95% CI 4.1-8.5) for low-risk patients (n = 561; P < 0.001). Adjusting the 70-gene signature in a competing risk model for the clinicopathological factors such as age, tumour size, grade, hormone receptor status, LVI, axillary lymph node involvement, surgical treatment, endocrine treatment, and chemotherapy resulted in a multivariable HR of 1.73 (95% CI 1.02-2.93; P = 0.042). Adding the signature to the model based on clinicopathological factors improved the discrimination, albeit non-significantly [C-index through 10 years changed from 0.731 (95% CI 0.682-0.782) to 0.741 (95% CI 0.693-0.790)]. Calibration of the prognostic models was excellent. The 70-gene signature is an independent prognostic factor for LRR. A significantly lower local recurrence risk was seen in patients with a low-risk 70-gene signature compared to those with high-risk 70-gene signature.

Functional parathyroid cyst and hypocalciuric hypercalcemia.

Parathyroid cysts are uncommon. They can be divided into functional and nonfunctional cysts depending on whether or not they are associated with hypercalcemia. Functioning cysts are very rare, with fewer than twenty reported cases. We report a case of functioning parathyroid cyst associated with hypocalciuric hypercalcemia. We have been unable to find a similar case previously reported in the literature.

Occurrence and prognosis of contralateral carcinoma of the breast.

Of the 4,554 patients who registered at The University of Texas M. D. Anderson Cancer Center, Houston, Texas from 1965 to 1988 with a diagnosis of carcinoma of the breast and who underwent surgical treatment of at least one carcinoma of the breast at this institution, 142 had either a history of a prior carcinoma of the breast (metachronous; n = 55) or a contralateral carcinoma of the breast detected within four months of registration (synchronous; n = 87). We retrospectively studied the records of these 142 patients and found that the occurrence of bilateral carcinoma of the breast was low (3.1 percent), the frequency of metachronous carcinoma of the breast remained relatively constant over time, the nodal status of the second carcinoma of the breast correlated with the method of discovery rather than the stage of the first carcinoma of the breast and survival rates from the second carcinoma of the breast were similar for metachronous and synchronous disease. These data support the role of vigilant surveillance of the contralateral breast with screening at the time of initial diagnosis and during follow-up evaluation. Because the likelihood of detecting a second carcinoma of the breast at an early stage is high, with subsequent good survival rates, the use of prophylactic mastectomy should be very selective and based on the emotional needs of the patient.

Functional parathyroid cyst and hypocalciuric hypercalcemia.

Parathyroid cysts are uncommon. They can be divided into functional and nonfunctional cysts depending on whether or not they are associated with hypercalcemia. Functioning cysts are very rare with less than twenty reported cases. We report a case of functioning parathyroid cyst associated with hypocalciuric hypercalcemia. We have been unable to find a similar case previously reported in the literature.

Extremity epithelioid sarcoma. Amputation vs local resection.

Amputation has traditionally been advised for extremity epithelioid sarcoma because of its pattern of innocuous presentation and relentless soft-tissue and nodal metastasis. To assess the role of amputation in extremity epithelioid sarcoma, we reviewed our experience with 42 patients treated between 1961 and 1986. On presentation with localized primary tumor (n = 18), nine of 11 patients who underwent wide local excision and four of six patients who underwent excisional biopsy were free of disease, and one patient who underwent amputation died. After presentation with localized recurrence (n = 12), four of six patients who underwent wide local excision and two patients who underwent excisional biopsy were free of disease; three other patients who underwent wide local excision had margins that tested positive on pathologic examination, of whom one was free of disease; one patient who underwent amputation died of disease. On presentation with regional metastasis (n = 12), only one of five patients who underwent wide local excision and one of seven patients who underwent amputation were free of disease. Primary amputation offered no apparent overall survival benefit to patients presenting with regional metastasis. The favorable outcome after local resections for localized disease indicates that wide local excision with margins that test negative on pathologic examination is preferable to radical amputation in these patients.

Macrophages and cancer.

The uncontrolled growth of metastases resistant to conventional therapeutic modalities is a major cause of death from cancer. Data from our laboratory and others indicate that metastases arise from the nonrandom spread of specialized malignant cells that preexist within a primary neoplasm. These metastases can be clonal in their origin, and different metastases can originate from different progenitor cells. In addition, metastatic cells can exhibit an increased rate of spontaneous mutation compared with benign nonmetastatic cells. These data provide an explanation for the clinical observation that multiple metastases can exhibit different sensitivities to the same therapeutic modalities. These findings suggest that the successful therapy of disseminated metastases will have to circumvent the problems of neoplastic heterogeneity and the development of resistance. Appropriately activated macrophages can fulfill these demanding criteria. Macrophages can be activated to become tumoricidal by interaction with phospholipid vesicles (liposomes) containing immunomodulators. Tumoricidal macrophages can recognize and destroy neoplastic cells in vitro and in vivo, leaving nonneoplastic cells uninjured. Although the exact mechanism(s) by which macrophages discriminate between tumorigenic and normal cells is unknown, it is independent of tumor cell characteristics such as immunogenicity, metastatic potential, and sensitivity to cytotoxic drugs. Moreover, macrophage destruction of tumor cells apparently is not associated with the development of tumor cell resistance. Macrophages are found in association with malignant tumors in a definable pattern, suggesting that the most direct way to achieve macrophage-mediated tumor regression is in situ macrophage activation. Intravenously administered liposomes are cleared from the circulation by phagocytic cells, including macrophages, so when liposomes containing immunomodulators are endocytosed, cytotoxic macrophages are generated in situ. The administration of such liposomes in certain protocols has been shown to bring about eradication of cancer metastases. Macrophage destruction of metastases in vivo is significant, provided that the total tumor burden at the start of treatment is minimal. For this reason, we have been investigating various methods to achieve maximal cytoreduction in metastases by modalities such as chemotherapy or radiotherapy prior to macrophage-directed therapy. It is important to note that even the destruction of 99.9% of cells in a metastasis measuring 1 cm2 would leave 10(6) cells to proliferate and kill the host. The ability of tumoricidal macrophages to distinguish neoplastic from bystander nonneoplastic cells presents an attractive possibility for treatment of the few tumor cells which escape destruction by conventional treatments. Macrophage-directed therapy has been studied in several human protocols, yielding important biological information about the use of liposome-encapsulated macrophage activators in cancer patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypoperfusion of the intestinal microcirculation without decreased cardiac output during live Escherichia coli sepsis in rats.

In order to determine the intestinal microvascular responses to normotensive, high cardiac output (CO) bacteremia, we measured vascular diameters and blood flow at different levels of the intestinal microcirculation during live E. coli bacteremia in male Sprague-Dawley rats (n = 16). Precollicular brainstem transection was used to allow study free of drug anesthesia. The microcirculation of a loop of small intestine (with intact neurovascular connections) was observed by in vivo video microscopy and optical Doppler velocimetry at a magnification of x1,500. Intraluminal microvessel diameters and red cell velocity were measured in successive branches until the vessel entered a villus. CO was measured by transpulmonary thermodilution. Intravenous infusion of 1 x 10(9) live E. coli caused a 20% increase in CO at 50 min and a 14% decrease in systemic vascular resistance. However, microvascular blood flow to the small intestine decreased by 27% at 1 hr and by 56% at 2 hr. Progressive arteriolar constriction (25-50%, P less than .05) occurred at all levels of the intestinal microcirculation. These data indicate that intestinal hypoperfusion caused by arteriolar constriction occurs during high CO bacteremia. This hypoperfusion could contribute to mucosal injury and intestinal mucosal barrier dysfunction during sepsis.

Value of diagnostic laparoscopy in young women with possible appendicitis.

Removal of a normal appendix because of suspected appendicitis occurs most frequently in women of reproductive age. We investigated the value of laparoscopy in the diagnostic evaluation for possible appendicitis in women of childbearing age. Fifty-one women were entered in a management protocol, which included diagnostic laparoscopy in instances with atypical features. Twenty patients underwent immediate appendectomy because of history and physical findings classical for appendicitis; 31 women with atypical history and physical findings underwent an initial diagnostic laparoscopy. In the group of patients who underwent immediate appendectomy because of classical presentation, five of the appendices removed were normal. At laparoscopy, appendicitis was diagnosed in five patients, another disease in 15 and no diagnostic abnormality was found in six. Five patients had a normal appendix removed, two because of questionable inflammation and three because of nonvisualization of the appendix. There were no false-negative examination results. Twenty-one patients required no further operative intervention after laparoscopy. The negative appendectomy rate remained unchanged (ten negative appendectomies of 30 performed). Definitive diagnoses of eight instances of pelvic inflammatory disease, six of ruptured ovarian cysts and one instance of ileitis of the small intestine were made earlier than would have been possible without diagnostic laparoscopy in this setting. Diagnostic laparoscopy permits earlier definitive diagnosis and prompt institution of appropriate therapy for disease of the female reproductive tract that simulates appendicitis. Caution is advised, however, when diagnostic laparoscopy is applied more frequently than right lower quadrant exploration in the management of probable appendicitis. The improvement in diagnostic accuracy may be offset by an increased number of negative appendectomies resulting from nonvisualization and false-positive inflammation.

Balloon dilatation of anastomotic strictures.

Our experience with balloon dilatation of postoperative anastomotic strictures is reported herein. Six patients with strictures not responsive or accessible to standard bougie techniques were selected for balloon dilatation. A guidewire was passed through the stricture with an endoscope (four patients) or with fluoroscopic guidance alone (two patients). Balloon catheters were then advanced over the guidewire and distended with a water-contrast mixture. Sufficient pressure was applied to efface the stricture indentation of the balloon. Since August 1984, we have performed 12 dilatations in these six patients. We dilated four strictures to 20 mm and two strictures to 15 mm. With the exception of stenosis due to edema caused by cancer or radiation, balloon dilatation is an effective treatment of tight upper gastrointestinal tract strictures that have not responded to standard dilatation techniques.

Screening before surgery for colon neoplasms with a flexible sigmoidoscope by surgical residents.

The value of flexible sigmoidoscopy to screen for colorectal neoplasms was determined in asymptomatic patients. One hundred sixty men (mean age 61 +/- 10), who denied a change in bowel habits or blood in their stools and who had guaiac-negative stools, had flexible sigmoidoscopic examinations performed by surgical residents with little previous endoscopy experience, while a staff surgeon continuously viewed the resident's progress through a teaching scope. Forty-nine benign neoplastic polyps were removed from 21% of the patients. The examination was well tolerated in 93% of these patients who received no medications. Resident endoscopists who had performed more than 15 examinations were more likely to reach 50 cm (79%) than those with less experience. The authors conclude that surgical residents are able to safely and effectively screen for colorectal neoplasms with a flexible sigmoidoscope when supervised.