Collaboration to Accelerate Proteogenomics Cancer Care: The Department of Veterans Affairs, Department of Defense, and the National Cancer Institute's Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) Network.

A tri-federal initiative arising out of the Cancer Moonshot has resulted in the formation of a program to utilize advanced genomic and proteomic expression platforms on high-quality human biospecimens in near-real-time in order to identify potentially actionable therapeutic molecular targets, study the relationship of molecular findings to cancer treatment outcomes, and accelerate novel clinical trials with biomarkers of prognostic and predictive value.

Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism.

Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers.

Localization of an ectopic parathyroid adenoma by double-phase technetium-99m-sestamibi scintigraphy.

Double-phase planar scintigraphy using 99mTc-MIBI has been introduced as a means to detect and localize parathyroid adenomas. Focal uptake on both early and delayed imaging is typical of these entities. We report a patient with persistent hypercalcemia following subtotal parathyroidectomy, who was found scintigraphically to have an ectopic parathyroid adenoma. Following initial detection within the mediastinum using planar scintigraphy, the adenoma was more precisely localized using SPECT imaging. This case suggests that double-phase parathyroid planar scintigraphy augmented with SPECT imaging, if needed, is cost-effective, and often necessary, in the assessment of primary hyperparathyroid patients before surgical reexploration.

Carcinoma of the esophagus. Prognostic significance of histologic type.

Previous investigators have reported that in patients with esophageal carcinoma tumor cell type affects prognosis. A retrospective analysis of 258 patients, from 1985 to 1991, undergoing curative esophagogastrectomy for adenocarcinoma (n = 134) or squamous cell carcinoma (n = 124) was performed to test the hypothesis that histologic cell type is an independent prognostic factor and to identify other predictors of survival after resection. The actuarial overall survival (p = 0.16) and disease-specific survival (p = 0.68) were similar for adenocarcinoma (median overall survival = 27 months) and squamous cell carcinoma (median overall survival = 22 months). Univariate analysis identified T stage, N stage, number of diseased nodes, tumor differentiation, tumor site, and blood transfusions as significant (p < 0.05) variables in predicting overall survival. The presence of Barrett's esophagus was not predictive of survival. Multivariate analysis demonstrated that T stage (p = 0.006), N stage (p = 0.01), and number of diseased lymph nodes (p = 0.03) were independent predictors of overall survival. This analysis demonstrated that histologic type is not an independent variable for overall survival in patients undergoing curative esophagogastrectomy for carcinoma of the esophagus and gastroesophageal junction. Outcome is most strongly influenced by extent of disease defined by T and N stage.

The use of computed tomography in the evaluation of mediastinal masses.

A retrospective analysis was conducted to ascertain whether computed tomography had increased diagnostic accuracy while decreasing the number of tests needed in the preoperative assessment of patients with mediastinal masses. A total of 42 patients were entered into the study: Fifteen patients were evaluated before the advent of computed tomography (No CT) and 27 patients had computed tomography during their evaluation (CT). The No CT group comprised 10 male and five female patients (2:1 ratio); the age range was 8 months to 61 years. The CT group included 15 male and 12 female patients (1.25:1.0 ratio), the age range being 21 to 70 years. In each group, both invasive and noninvasive studies were done. Although the CT group had 40 noninvasive tests, 27 were computed tomographic scans. The additional 13 noninvasive tests and the five invasive tests added no significant diagnostic information. In the No CT group, preoperative evaluation as to the cystic or solid nature of the mass was correct only four of 13 times (31%). In the CT group, 22 of 25 patients had accurate assessment as to the cystic or solid nature of the lesions (88%). In addition, extension of the mass into other structures, consistent with malignancy, was correctly diagnosed preoperatively in nine of the patients in the CT group. Two had extension of the mass at operation not preoperatively diagnosed (82% accuracy). None of the No CT group was given an assessment of possible mass extension preoperatively. The results suggest that mediastinal masses can be evaluated by computed tomography with a high degree of accuracy for predicting the nature, size, location, and involvement of other organs by the mass. The use of other tests before resection generally yields little additional information.

Sternal blood flow after median sternotomy and mobilization of the internal mammary arteries.

Although the internal mammary artery (IMA) is superior to the saphenous vein graft for bypassing certain coronary arterial obstructive lesions, such operations may predispose the patient to sternal infection or dehiscence--presumably as a result of sternal ischemia. This study was designed to measure sternal blood flow before and after median sternotomy and IMA mobilization in order to quantify the hemodynamic effects of these procedures. Rhesus primates were randomized into control, unilateral IMA-harvested, and bilateral IMA-harvested groups. After selective angiography enabled confirmation of IMA patency, 15 micron microscopheres, labeled with specific-spectra radioactive isotopes, were injected at baseline, after sternotomy, and after IMA harvesting. The sternal halves were subjected to gamma counting, and sternal circulation was accurately quantified. Our results showed that blood flow to the sternal halves in which the IMA was harvested decreased precipitously (from 4.5 to 0.8 ml/gm/min; p less than or equal to 0.001), although it remained unchanged in response to median sternotomy. This represented a 90% decrease in the mean rate of flow within the IMA-harvested sterna versus a stable flow rate for the unharvested sides. We conclude that mobilization of the internal mammary artery, as in coronary bypass procedures, significantly devascularizes the sternal half from which it was harvested.

Clinical evaluation of mastalgia.

OBJECTIVE: To describe an accurate and reproducible method to quantify a patient's subjective experience of breast pain. DESIGN: Prospective diary study. SETTING: Military tertiary care hospital. PATIENTS: Thirty female military health care beneficiaries from the Walter Reed Army Medical Center, Washington, DC, gynecology and general surgery clinics. MAIN OUTCOME MEASURES: Daily mastalgia was recorded using a visual analog scale and menstrual symptoms were measured using a daily questionnaire. These measures were correlated with results of a screening questionnaire completed prior to study entry. RESULTS: Patients identified as having cyclical mastalgia based on the screening questionnaire (n= 15) were found to have higher peak perimenstrual mastalgia according to their daily diaries than patients who did not meet diagnostic criteria (n=15) (5.3+/-0.7 vs 3.5+/-0.5, P<.001). Applying the same criteria used in the screening questionnaire to the diary data, 17 of 30 patients met diagnostic criteria for cyclical mastalgia. The ability of the screening questionnaire to predict the results of the prospective diary data was calculated, and positive and negative predictive values were 73% and 60%, respectively. Most patients with cyclical mastalgia also have other perimenstrual psychological and somatic complaints, although a subset of patients has high levels of mastalgia with minimal associated symptoms. CONCLUSIONS: Accurate assessment of mastalgia cannot be done with a retrospective questionnaire and requires prospective diary evaluation, owing to the variable and subjective nature of symptoms and recall bias. A daily visual analog scale provides reproducible results and is easy for patients to use.

Cyclical mastalgia: prevalence and impact in an outpatient breast clinic sample.

BACKGROUND: A descriptive study was conducted to examine prevalence of premenstrual breast symptoms, impact of cyclical mastalgia on various activities, and associated patterns of health care utilization among breast clinic outpatients. STUDY DESIGN: Patients (n = 231, age < 55 years) completed a questionnaire about lifetime and current premenstrual breast discomfort (cyclical mastalgia). RESULTS: Seventy-nine percent reported having regularly experienced cyclical breast symptoms; 48% have asked a health care provider about their mastalgia. Young women (< or = 35 years) were more than three times as likely to have had a mammogram (75%) if they regularly experienced cyclical mastalgia than if they did not (24%; p < 0.05). Current moderate to severe mastalgia lasting 5 days or more monthly was reported by 30% of women. This "clinical" level of mastalgia interferes with usual sexual activity for 33%, with physical activity for 29%, with social activity for 15%, and with work for 15% of these women. CONCLUSIONS: Reported prevalences of mastalgia obtained in this sample are higher than those reported in British studies; possible reasons for these differences are discussed. Cyclical mastalgia is a common problem sometimes severe enough to interfere with normal activity levels, and it is related to excessive use of mammography among young women. Although largely ignored both scientifically and clinically in the United States, this condition merits further biopsychosocial investigation.

Diagnosis and management of the autonomously functioning thyroid nodule: the Walter Reed Army Medical Center experience, 1975-1996.

In order to characterize the clinical and laboratory features of autonomously functioning thyroid nodules (AFTNs), and to assess optimal diagnosis and management of patients with this disorder, we performed a retrospective analysis of 49 such patients over a 22-year period encompassing January 1975 to November 1996. The following data were analyzed: thyroid hormone levels, thyroid scintiscan, radioiodine uptake, fine-needle aspiration biopsy, triiodothyronine (T3) suppression testing, thyrotropin-releasing hormone (TRH) stimulation test, and thyroid ultrasound. Clinical outcomes assessed included persistent hyperthyroidism, hypothyroidism, and nodule shrinkage after treatment, or in patients followed without definitive therapy, nodule growth, spontaneous degeneration, and progression to hyperthyroidism. Biochemical hyperthyroidism, often subclinical, was found in 73.5% of patients at presentation and in an additional 24.4% of patients during subsequent follow-up. The introduction of sensitive thyrotropin (TSH) testing during the period of study resulted in a decrease in the use of the T3-suppression test and TRH stimulation test from 100% and 20%, respectively, in the period from 1976-1980, to 4% each in the period from 1991-1996. T3-thyrotoxicosis occurred in 12.2% of patients. Thyrotoxicosis at any time during the course of follow-up was positively correlated with nodule size at diagnosis. Definitive therapy, used in 42.8% of patients, consisted of radioiodine ablation (38.1%) or thyroidectomy (61.9%). No patient had recurrence of thyrotoxicosis after definitive therapy, but 25% became hypothyroid. During follow-up for a mean of 30.9 months, nodules enlarged in 25% of patients overall, or 33% of patients not receiving definitive therapy. Cystic degeneration was documented in 26.5% of patients, although this change rarely reversed subclinical hyperthyroidism. The diagnosis of an AFTN requires a demonstration of TSH-independent nodular hyperfunction. The introduction of sensitive TSH assays has simplified the evaluation of AFTN patients and revealed a high prevalence of subclinical thyroid hyperfunction in this disorder. In view of current increased awareness of adverse consequences associated with subclinical hyperthyroidism and the rarity of spontaneous resolution of hyperthyroidism in AFTN patients (despite a propensity for spontaneous hemorrhage), definitive therapy is recommended. Both radioiodine and hemithyroidectomy have high cure rates and a low posttreatment incidence of hypothyroidism.

Decision making on surgical palliation based on patient outcome data.

BACKGROUND: Strategies for the effective application of palliative procedures are infrequently standardized and incompletely understood. The effect on patient outcome as determined by elements such as resolution of chief complaints, quality of life, pain control, morbidity of therapy, and resource utilization should predominate decisions regarding surgical palliative care. METHODS: Articles published between 1990 and 1996 on the surgical palliation of cancer were identified by a MEDLINE search and reviewed for designated parameters considered important for good palliative care. RESULTS: A total of 348 citations were included. Entries considered these fundamental elements: cost (2%); pain control (12%); quality of life (17%); need to repeat the intervention (59%); morbidity and mortality (61 %); survival (64%); and physiologic response (69%). Established methods for quality of life and pain assessment were sporadically utilized. CONCLUSIONS: In the current surgical literature, there is uncommon reporting of the range of data required to recommend sound palliative surgical choices.

Functional relationship and gene ontology classification of breast cancer biomarkers.

Breast cancer is a complex disease that still imposes a significant healthcare burden on women worldwide. The etiology of breast cancer is not known but significant advances have been made in the area of early detection and treatment. The advent of advanced molecular biology techniques, mapping of the human genome and availability of high throughput genomic and proteomic strategies opens up new opportunities and will potentially lead to the discovery of novel biomarkers for early detection and prognostication of breast cancer. Currently, many biomarkers, particularly the hormonal and epidermal growth factor receptors, are being utilized for breast cancer prognosis. Unfortunately, none of the biomarkers in use have sufficient diagnostic, prognostic and/or predictive power across all categories and stages of breast cancer. It is recognized that more useful information can be generated if tumors are interrogated with multiple markers. But choosing the right combination of biomarkers is challenging, because 1) multiple pathways are involved, 2) up to 62 genes and their protein products are potentially involved in breast cancer-related mechanisms and 3) the more markers evaluated, the more the time and cost involved. This review summarizes the current literature on selected biomarkers for breast cancer, discusses the functional relationships, and groups the selected genes based on a Gene Ontology classification.

Transhiatal esophagectomy.

THE is a versatile procedure that has become indicated for a variety of disease processes over the past two decades; amongst these indications are to treat many benign and malignant esophageal diseases, as well as for use in restoring gastrointestinal continuity after extensive pharyngeal or laryngopharyngeal resections. Careful and meticulous handling, formation, and transposition of the gastric tube are essential to the development of a well-perfused neo-esophagus. Present studies indicate acceptable morbidity and mortality of THE compared with transthoracic resections for carcinoma of the esophagus. There appears to be no significant detriment in overall long-term survival when THE is used as primary resection therapy for malignant esophageal disease.

Desmoid tumors of the chest wall.

Desmoid tumors are rare soft tissue neoplasms derived from fascial or musculoaponeurotic structures. These tumors are histologically benign but may behave aggressively at the local level with multiple recurrences after complete resection being common. Chest wall desmoids account for approximately 20% of all patients with desmoid tumors. Patients with these lesions are often asymptomatic and thus commonly present with lesions greater than 10 cm in size. The treatment for these neoplasms remains margin negative surgical excision, and, given the often large size at presentation, may require extensive chest wall resection. When this is required, chest wall reconstruction with either prosthetic material and/or autologous tissue may be performed. There may be recurrence in as many as 75% of patients. Neither adjuvant radiotherapy or chemotherapy have been shown to reduce the rate of recurrence. Recurrence should also be treated with surgical resection because patients who undergo complete surgical resection of recurrence are as likely to remain disease free after resection as patients who present with primary disease.

The utility of a rapid parathyroid assay for uniglandular, multiglandular, and recurrent parathyroid disease.

The rapid parathyroid hormone assay (rPTH) is an effective tool in minimally invasive resections of parathyroid adenomas. However, there are relatively few reports examining its utility in the full spectrum of parathyroid disease. The purpose of this study was to examine the utility of the rapid parathyroid hormone assay in uniglandular, multiglandular, and recurrent hyperparathyroidism. A retrospective analysis of all patients undergoing parathyroid resection from June 2001 to March 2003 was undertaken. All patients underwent preoperative localization studies. Rapid parathyroid hormone (PTH) levels were drawn immediately prior to and 10 minutes following parathyroid resection. A decline of > or = 50 per cent rPTH qualified as a successful/complete resection. Additional intraoperative samples were drawn as needed for patients with multiglandular disease. Of 46 treated patients who were examined (average age, 54 years), 30 had single, 12 patients had multigland disease, and 4 had recurrent/persistent hyperparathyroidism. Thirty-seven patients had primary hyperparathyroidism (32 with single and 3 with double adenomas; 2 with hyperplasia), 4 patients had secondary hyperparathyroidism, and 5 tertiary hyperparathyroidism. All procedures were considered successful, as every patient exhibited a postresection decrement in rPTH exceeding 50 per cent (average decrement, 91%). Although 2 patients exhibited a postoperative PTH increase exceeding 50 per cent of the preoperative value, all remained asymptomatic and eucalcemic (median follow-up, 21.5 months). The rPTH assay is an effective tool in determining success of parathyroidectomy in patients with primary uni- and multiglandular as well as recurrent hyperparathyroidism. It can be used to achieve minimally invasive neck dissections or guide surgical decision-making in more complex cases.

Sentinel lymph node biopsy for breast cancer: the role of previous biopsy on patient eligibility.

Several reports have demonstrated the accurate prediction of axillary nodal status with radiolocalization and selective resection of sentinel lymph nodes (SLNs) in patients with breast cancer (BC). Because of concerns over lymphatic disruption, several authors have proposed that prior excisional breast biopsy is a contraindication for SLN biopsy. Clear unfiltered 99mtechnetium-sulfur colloid (1.0 mCi) was injected around the perimeter of the breast lesion (palpable and nonpalpable) or prior biopsy site. Resection of the radiolocalized SLN was then performed. Axillary lymph node dissection was performed immediately after SLN biopsy in the first 57 patients. Eighty-two BC patients underwent SLN biopsy. The SLN was localized in 98 per cent (80 of 82). The type of previously performed diagnostic biopsy or the location of the primary lesion did not influence the ability to localize the sentinel lymph node. In the 57 patients who had axillary lymph node dissection, metastatic disease was identified in 23 per cent (13 of 57). Axillary nodal status was accurately predicted in 98 per cent (56 of 57). Early experience with radiolocalization and selective resection of SLN in BC remains promising. By demonstrating the effective localization of the SLN regardless of the extent of prior biopsy, these data support expanding the number of patients potentially eligible for SLN biopsy.

Cyclical mastalgia: premenstrual syndrome or recurrent pain disorder?

Approximately 8-10% of premenopausal women experience moderate to severe perimenstrual breast pain or cyclical mastalgia, monthly. This mastalgia can occur regularly for years until menopause, can interfere with usual activities, and is associated with elevated utilization of mammography among young women. Although mastalgia is a well documented symptom in premenstrual syndrome (PMS), it is unknown whether PMS is necessarily present in women with cyclical mastalgia. The present study prospectively examined mastalgia and its relationship to PMS. Thirty-two premenopausal women reporting recent mastalgia completed breast pain and menstrual symptom scales daily for 3-6 months. Eleven women (34.4%) met criteria for clinically significant cyclical mastalgia, reporting an average of 10.2 days of moderate-severe mastalgia monthly. Five women (15.6%) met criteria for PMS. Mastalgia was not significantly associated with PMS: 82% of women with clinical cyclical mastalgia did not have PMS. Cyclical mastalgia, although by definition associated with the menstrual cycle, is not simply premenstrual syndrome, and merits further investigation as a recurrent pain disorder whose presentation, etiology, and effective treatment are likely to differ from those of PMS.

Utility of computed tomographic enteroclysis for the general surgeon(1).

Enteroclysis uses contrast fluid distention of the small bowel through a jejunal catheter with flouroscopic imaging to identify abnormalities. Computed tomograpic enteroclysis (CT-E) adds cross-sectional imaging to identify small bowel pathology to include masses, gastrointestinal bleeding of unknown origin, and partial obstruction. Computed tomography-enteroclysis is being used more frequently in the assessment of patients with possible small bowel pathology. This study examines the applicability of CT-E and its superiority over conventional enteroclysis.A retrospective chart review was used to examine all CT-E and enteroclysis studies performed at our institution during a 24-month period (August 1997 to August 1999). All patients that had received CT-E or enteroclysis were divided into 3 categories; group I: small bowel mass, group II: gastrointestinal bleeding, and group III: partial small bowel obstruction (pSBO). All patients included had received other radiological procedures based on the indication for examination to include esophagogastroduodenoscopy, colonoscopy, CT, abdominal x-rays, barium enema, and upper gastrointestinal with small bowel follow-through.Forty-nine studies were performed, with enteroclysis or CT-E, used in 46 patients. Median age was 62 years (M:F, 1:1). In group 1 (n = 10), no masses were noted, but all patients identified as having a mass on previous studies (n = 6) were determined not to have a mass by CT-E (n = 1) and enteroclysis (n = 5). In group II (n = 19), 1 small bowel source (jejujunal arteriovenous malformation) was identified through CT-E, and all other studies in both categories were negative/normal. In group III (n = 20), 5 pSBO were identified through CT-E that had not been previously described.Enteroclysis and CT-E are both effective at disproving the presence of small bowel masses discovered through less-specific radiological methods. In terms of gastrointestinal bleeding, CT-E is as effective as enteroclysis at identifying source of bleeding and may have an added role through its ability to better identify anatomic relationships. Computed tomography-enteroclysis was able to determine the presence of pSBO in 5 patients that previously had been undiagnosed. In conclusion, enteroclysis remains an effective radiological study for examination of the small bowel. Computed tomography-enteroclysis matches that effectiveness with the added benefit on high-resolution anatomic images that serve it well as an additional diagnostic tool for the General Surgeon in patients with difficult to diagnose small bowel pathology.

5-year qualitative results of isolated cryosurgical ablation for hepatic malignancy at Walter Reed Army Medical Center(1).

Cryosurgical ablation (CSA) is an established treatment for primary and metastatic liver malignancies. The study objective was to qualitatively define our patient CSA experience and compare it with the existing literature.A retrospective review was conducted of patients who underwent isolated CSA from September 1995 to April 2000. Data were collected on patient characteristics, tumor characteristics, sequential 12-hour laboratory data, transfusion requirements, and survival data. SPSS 9.0 (SPSS, Chicago, Illinois) was used for data analysis.Twenty-four patients (14 men, 10 women) were studied. Eighty-seven lesions (mean 3.8/patient) were treated. Six patients underwent treatment for primary liver tumors, whereas 16 were treated for metastatic disease. White blood cell count increased 1.7-fold, and platelet count decreased 2.0-fold. Aspartate aminotransferase and alanine aminotransferase increased significantly 42- and 29-fold, respectively. Seven out of 21 (33%) patients required blood transfusion. Our overall complication rate was 25%. Perioperative mortality was 0%. Kaplan-Meier survival analysis revealed an overall survival of 46% at a median follow-up of 33.7 +/- 6.8 months.CONCLUSIONS:Although isolated CSA of hepatic malignancies results in major and minor alterations in serologic parameters, they equate to little clinical significance. Blood product transfusions are necessary in 30% patients post-CSA. Significant perioperative complications occur in 25% of patients. Survival estimates suggest that nearly 50% of patients undergoing CSA can be expected to survive longer than 2 years post-CSA.

Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression.

Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.