Population-based analysis of the impact and generalizability of the NSABP-B24 study on endocrine therapy for patients with ductal carcinoma in situ of the breast.

BACKGROUND: In 1999, the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B24 trial demonstrated that tamoxifen reduced relapse risk in women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) and radiotherapy (RT). In 2002, Allred's subgroup analysis showed that tamoxifen mainly benefitted estrogen receptor (ER)-positive disease. This study evaluates the impact and generalizability of these trial findings at the population level. PATIENTS AND METHODS: From 1989 to 2009, 2061 women with DCIS underwent BCS + RT in British Columbia. The following cohorts were analyzed: (1) pre-NSABP-B24 era (1989-1998, N = 417); (2) post-NSABP-B24 era (2000-2009, N = 1548). Cohort 2 was further divided into pre- and post-Allred eras. RESULTS: Endocrine therapy (ET) was used in 404/2061 (20%) patients. Median age of patients treated with compared with without ET, was 53 versus 57 years, (P < 0.0005). One of 417 (0.2%) versus 399/1548 (26%) patients took ET before versus after NSABP-B24. Among the post-Allred era cohort treated with ET (N = 227), tumors were ER-positive in 65%, ER-negative in 1%, and ER-unknown in 33%; whereas of those treated without ET (N = 801), ER was positive in 43%, negative in 15%, and unknown in 42% (P < 0.0005). On multivariable analysis of the post-NSABP-B24 era, ET was associated with improved event-free survival (EFS) (hazard ratio 0.6; P = 0.02); 5-year EFS were 96.9% with ET versus 94.5% without ET. CONCLUSIONS: ET use in DCIS patients treated with BCS + RT increased significantly after the NSABP-B24 study. ER+ disease and younger age were associated with increased ET use. ET was associated with improved EFS, confirming the generalizability of trial data at a population level.

Breast carcinoma--rare types: review of the literature.

Invasive breast cancer is a heterogeneous disease in its presentation, pathological classification and clinical course. However, there are more than a dozen variants which are less common but still very well defined by the World Health Organization (WHO) classification. The rarity of many of these neoplasms does not allow large or randomized studies to define the optimal treatment. Many of the descriptions of these cancers are from case reports and small series. Our review brings updated information on 16 epithelial subtypes as classified by the WHO system with a very concise histopathology description and parameters helpful in the clinic. The aim of our review is to provide a tool for breast cancer caregivers which will enable a better understanding of the disease and its optimal approach to therapy. This may also stand as a clinical framework for a future understanding of these rarer breast cancers when gene analysis work is reported.

Refinement of breast cancer classification by molecular characterization of histological special types.

Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC NOS), whereas about 25% are defined as histological 'special types'. These special-type breast cancers are categorized into at least 17 discrete pathological entities; however, whether these also constitute discrete molecular entities remains to be determined. Current therapy decision-making is increasingly governed by the molecular classification of breast cancer (luminal, basal-like, HER2+). The molecular classification is derived from mainly IDC NOS and it is unknown whether this classification applies to all histological subtypes. We aimed to refine the breast cancer classification systems by analysing a series of 11 histological special types [invasive lobular carcinoma (ILC), tubular, mucinous A, mucinous B, neuroendocrine, apocrine, IDC with osteoclastic giant cells, micropapillary, adenoid cystic, metaplastic, and medullary carcinoma] using immunohistochemistry and genome-wide gene expression profiling. Hierarchical clustering analysis confirmed that some histological special types constitute discrete entities, such as micropapillary carcinoma, but also revealed that others, including tubular and lobular carcinoma, are very similar at the transcriptome level. When classified by expression profiling, IDC NOS and ILC contain all molecular breast cancer types (ie luminal, basal-like, HER2+), whereas histological special-type cancers, apart from apocrine carcinoma, are homogeneous and only belong to one molecular subtype. Our analysis also revealed that some special types associated with a good prognosis, such as medullary and adenoid cystic carcinomas, display a poor prognosis basal-like transcriptome, providing strong circumstantial evidence that basal-like cancers constitute a heterogeneous group. Taken together, our results imply that the correct classification of breast cancers of special histological type will allow a more accurate prognostication of breast cancer patients and facilitate the identification of optimal therapeutic strategies.

Glycogen-rich clear cell carcinoma of the breast. A clinicopathologic study of 21 cases.

Twenty-one glycogen-rich clear cell carcinomas of the breast were studied. There were 13 invasive carcinomas and 8 intraductal carcinomas. Ten of the invasive carcinomas contained an intraductal component. Three intraductal carcinomas were papillary carcinomas ("intracystic" papillary carcinoma), and the others showed a mixture of solid, micropapillary, and cribriform patterns of growth. Most of the invasive carcinomas had nested, corded, or sheet-like growth patterns, and all were grade 2 or 3 neoplasms. Among patients with invasive carcinoma, two had metastases to axillary lymph nodes and three died of tumor. One patient with intraductal papillary carcinoma experienced two local recurrences, with invasion in the second recurrence. Thirteen cases (62%) exhibited focal apocrine features. Based on this small series, the clear cell morphology did not appear to influence the clinical outcome once stage and grade were taken into account. Glycogen-rich clear cell carcinoma of the breast may be a variant of apocrine carcinoma.

Splenic pathology in immune thrombocytopenia.

Splenic pathology was analysed in 73 patients with immune thrombocytopenic purpura who underwent splenectomy for bleeding that had been resistant to adrenocorticosteroids. The mean splenic weight was 100 g. The only notable macroscopic feature was the prominence of Malpighian corpuscles in 15 cases. Microscopic examination showed formation of germinal centres in the lymphoid tissue of the white pulp in 40 cases, prominence of the histiocytes in the red pulp in 18 cases, and infiltration with neutrophils in the same area in 49 cases. Myeloid metaplasia throughout the splenic tissue was minimal in 58 cases, moderate in 15, and extreme in two. No distinguishing features were found in the spleen from patients who had not received previous immunosuppressive treatment (n = 3), those treated with prednisone (1 mg/kg/day) for a median of 14 days (n = 62), or those who had received the same dose of prednisone and additional azathioprine or cyclophosphamide (2 mg/kg/day) for a median of four weeks (n = 8). No correlation could be shown between histological features and the age of the patient or titre of antiplatelet antibodies. Similarly, no distinguishing features were found in patients with associated systemic lupus erythematosus (n = 8), hyperthyroidism (n = 6), immune haemolysis (n = 3), or recent viral illness (n = 3).

Evaluation of lymphocyte responsiveness to polyclonal activators during acute and chronic experimental Trypanosoma cruzi infection.

The responses of spleen cells from mice infected with Trypanosoma cruzi to T and B cell-specific mitogens were monitored during the acute and chronic stages of the infection. Responses to either T (phytohemagglutinin or concanavalin A) or B (endotoxic lipopolysaccharide) cell mitogens measured on days 5, 10, 15, and 20 postinfection, i.e., at different times during the acute period, were markedly reduced. Responses measured on days 54 and 90, i.e., during the chronic stage, did not differ significantly from those of normal mouse spleen cells. Proportions of T and B lymphocytes in the spleen were reduced and unaltered, respectively, during acute T. cruzi infection but were comparable to normal values during the chronic state. These results highlight a return of normal T and B lymphocyte responses during chronic experimental Chagas' disease and suggest that transition from the acute to the chronic phase of the infection may be immunologically regulated.

Virus-like infectious agent (VLIA) is a novel pathogenic mycoplasma: Mycoplasma incognitus.

The newly recognized pathogenic virus-like infectious agent (VLIA), originally reported in patients with AIDS but also known to be pathogenic in previously healthy non-AIDS patients and in non-human primates, was cultured in cell-free conditions using a modified SP-4 medium and classified as a member of the order Mycoplasmatales, class Mollicutes. The infectious microorganism is tentatively referred to as Mycoplasma incognitus. M. incognitus has the unique biochemical properties of utilizing glucose both aerobically and anaerobically, as well as having the ability to metabolize arginine. Among all known human mycoplasmas, these specific biochemical characteristics were found previously only in a rarely isolated species, M. fermentans. In comparison with M. fermentans, M. incognitus appears to be even more fastidious in cultivation requirements and fails to grow in all tested mycoplasma media other than modified SP-4 medium. In addition, M. incognitus grows much more slowly, has a smaller spherical particle size and occasional filamentous morphology, and forms only irregular and very small colonies with diffuse edges on agar plates. Antigenic analysis using polyclonal and monoclonal antibodies and DNA analysis of sequence homology and restriction enzyme mappings in M. incognitus, M. orale, M. hyorhinis, M. hominis, M. pneumoniae, M. fermentans, M. arginini, M. genitalium, M. salivarium, Ureaplasma urealyticum, and Acholeplasma laidlawii revealed that M. incognitus is distinct from other mycoplasmas, but is most closely related to M. fermentans.

Mycoplasma genitalium infection and host antibody immune response in patients infected by HIV, patients attending STD clinics and in healthy blood donors.

Prevalence of Mycoplasma genitalium in humans is still not clear. We have developed a sensitive and specific serological assay for M. genitalium using lipid-associated membrane proteins (LAMPs) as antigens. Antibodies to LAMPs from M. genitalium showed little cross-reactivity to LAMPs from antigenically similar M. pneumoniae. For validity testing, urines from 104 patients were tested by PCR for M. genitalium. All 15 PCR+ patients had M. genitalium-LAMPs antibodies. Moreover, none of 64 antibody-negative patients were PCR+. Serological study of 1800 patients of various diseased groups and healthy blood donors showed M. genitalium was primarily a sexually transmitted microbe that infected patients with AIDS (44.0%), intravenous drugs users with or without HIV infection (42.5%), and also HIV- patients attending STD clinics (42.6%). Only 5.5% HIV- healthy blood donors and 1.3% HIV+ hemophiliacs tested positive. M. genitalium has been associated with acute non-gonococcal urethritis in male patients. However, many sexually active men and women appear to be chronically infected or colonized by the microbe without apparent clinical symptoms and may continue to transmit the organism through sexual contacts.

Intralesional autotherapy of cutaneous leishmaniasis with buffy coat cells: cytological findings.

The skin lesions of five patient volunteers with dry-type cutaneous leishmaniasis were treated by intralesional injection of auto-leukocytes prepared from buffy coat of the patient's own blood. Giemsa stained, air-dried cytological smear preparations were prepared from scrapings taken from the margins of the lesions. The cellular interaction between the organism and the inflammatory response of the host was studied. All lesions showed clinical evidence of regression. The cytological findings suggested progressive degradation of the Leishman donovan (LD) bodies within the parasitophorous vacuoles of the activated macrophages. The parasiticidal effect appeared to be induced by synergistic action of the injected neutrophils and lymphocytes. Due to lack of placebo controls in this study the possibility that, healing might not be related to therapy can not be excluded. This study illustrates the potential for intralesional autotherapy with buffy coat in dry-type cutaneous leishmaniasis.

Serum binding of steroid tracers and its possible effects on direct steroid immunoassay.

We studied the serum protein binding of 3H-labelled progesterone, oestradiol and testosterone, and five 125I-labelled analogues of these steroids. All tracers investigated appeared to be bound by proteins in every serum sample tested. The addition of blocking agents caused a substantial reduction in serum protein binding of 3H-labelled steroids, but had relatively little effect on the binding of analogue steroid tracers. Use of analogue steroid tracers in conventional direct immunoassays for oestradiol and progesterone produced anomalous results for some patient samples when compared to extraction radioimmunoassays, but assays where tracer binding to serum constituents was prevented by adoption of two-step procedures appeared to avoid anomalous results. The results suggest that serum protein binding of steroid analogue tracers may be a source of interference in some direct steroid immunoassays.

Aggressive glomus tumor of the nasal region. Report of a case with multiple local recurrences.

We describe a locally aggressive glomus tumor that occurred in the nasal region of a 32-year-old woman. The neoplasm recurred six times over a period of 14 years following the initial excision. This aggressive behavior resulted in problems with the diagnosis of the neoplasm. Although grossly cystic, the tumor contained large areas with a solid growth pattern and exhibited an infiltrative margin. There was no cytological atypia, mitoses were scanty, and necrosis was absent. The neoplasm did not metastasize.

In vitro antimicrobial susceptibility testing for the newly identified AIDS-associated Mycoplasma. Mycoplasma fermentans (incognitus strain).

Mycoplasma fermentans (incognitus strain) has recently been recognized as a possible infectious pathogen in humans. This mycoplasma is associated with an acute fatal disease in previously healthy patients who do not have the acquired immunodeficiency syndrome. Many patients with the acquired immunodeficiency syndrome suffer a systemic infection with this microbe. Quantitative assay of antimicrobial susceptibility for M fermentans (incognitus strain) in cultures to representative antibiotics has revealed that the microbe is not sensitive to erythromycin, the most commonly used antibiotic for human mycoplasma infections. The testing shows that M fermentans (incognitus strain) is sensitive in vitro to the antibiotics tetracycline, doxycycline, chloramphenicol, clindamycin, lincomycin, and ciprofloxacin.

Sinus histiocytosis with massive lymphadenopathy. Report of a case associated with necrosis.

We describe a case of a 21-year-old man who had a generalized lymphadenopathy and arthritis. Inguinal and cervical lymph nodes showed changes typical of sinus histiocytosis with massive lymphadenopathy. Extensive coagulative necrosis of the intrasinusal histiocytes is described, a feature which, to our knowledge, is unreported previously.

Detection and isolation of Mycoplasma fermentans from urine of human immunodeficiency virus type 1-infected patients.

Mycoplasma fermentans (incognitus strain) has been linked with acquired immunodeficiency syndrome-associated nephropathy. Ten (23%) of 43 urine sediment specimens from 40 human immunodeficiency virus (HIV)-positive patients at different stages of acquired immunodeficiency syndrome disease tested positive in the polymerase chain reaction using a primer pair found in the insertion sequences specific to M fermentans. Mycoplasma fermentans was isolated from two HIV-positive patients' urine sediment specimens and on a repeated basis from one. All three culture-positive urine sediment specimens tested positive in the polymerase chain reaction. Fifty urine sediment specimens from age-matched HIV-negative healthy controls tested negative for M fermentans by polymerase chain reaction. Mycoplasma fermentans was not isolated from any of the control urine sediment specimens. Our results show a high prevalence of M fermentans in urine sediment specimens from HIV-positive patients but not from urine sediment specimens of HIV-negative healthy controls.

In vitro induction of suppressor cells by plasma of rats with Trypanosoma brucei rhodesiense infection.

Mitogenic responses of B and T lymphocytes from spleens of rats infected with Trypanosoma brucei rhodesiense were suppressed. Plasma from infected rats suppressed the mitogenic responses of B and T lymphocytes from spleens of normal uninfected rats. Removal of immune complexes from plasma of infected rats significantly reduced the suppressive effect of the plasma on splenic lymphocytes of normal uninfected rats. Normal thymus cells treated with plasma from infected rats and added to cultures of normal spleen lymphocytes inhibited the mitogenic responses of B and T lymphocytes. We suggest that the interaction of immune complexes and Fc or C3b receptors of T lymphocytes resulted in the in vitro induction or activation of T suppressor lymphocytes.

Reversal of immunosuppression induced with plasma of malarious rats by supplemented complement.

Suppression of antibody producing splenic lymphocytes by plasma from rats infected with Plasmodium chabaudi malaria was confirmed. Suppressive activity was found in plasma drawn on the sixth, seventh and eighth day of infection. It was temporally associated with anemia, elevated levels of soluble immune complex, reduced titers of lytic complement and elevated titers of immunoconglutinin (IK) in the plasma. Heat inactivation of the plasma to destroy complement and removal of IK by absorption did not reduce the suppressive activity. Incubating the plasma-treated lymphocytes with normal rat complement largely, but not completely, reversed the suppressive action. Soluble immune complexes prepared from bovine serum albumin (BSA) and antiBSA (BSA-antiBSA) alexinated complex (BSA-antiBSA-C') and immunoconglutinated complex (BSA-antiBSA-C'-IK) each suppressed the capacity of splenic lymphocytes from rats immunized with sheep blood cells to produce hemolytic Jerne plaques. Incubating the complex-treated cells with fresh complement largely reversed the suppressive activity. It is suggested that the suppressed responses of lymphocytes from malarious animals to antigens or mitogens, reported by others, may have been in part induced by complexes in blood of the animals, and that antibody producing cells might also have been suppressed. Since suppressive activity was not influenced by complement inactivation, but was reversed when plasma-treated cells were incubated with fresh complement, it is suggested that the hypocomplementemic state of suppressive plasma may have contributed to immunosuppression.

Complement reversal of immunosuppression induced with plasma of rats infected with Trypanosoma brucei rhodesiense.

Suppression of antibody production by splenic lymphocytes from rats immunized with sheep red blood cells (SRBC) after incubation with plasma from rats infected with Trypanosoma brucei rhodesiense was confirmed. Suppressive activity became evident in plasma after the sixth day of infection and was manifested by reduction in the number of hemolytic Jerne plaques produced by the treated cells. The activity was temporally associated with increased amounts of soluble immune complex (SIC) reduced titers of lytic complement, elevated titers of immunoconglutinin (IK) and anemia. Treatment of suppressive plasma with hemolysin sensitized SRBC alexinated with horse complement to reduce IK did not reduce suppressive activity, and the activity appeared to have been enhanced when the plasma was heated to inactivate the remaining complement (C'). When fresh rat C' was added to the treated cells, the suppression was largely, though not completely, reversed. Treatment of spleen cells with SIC prepared in vitro from bovine serum albumin (BSA) and rabbit antiBSA also suppressed the plaque forming capacity of the cells. Complexes of BSA-antiBSA-C' and complexes of BSA-antiBSA-C'-IK were equally suppressive. Again, addition of fresh C' to cells treated with these complexes largely, though not completely, reversed the suppressive effect on the cells. From the results it is suggested that immunosuppression associated with experimental T. b. rhodesiense infection may be in part a suppression of the capacity of induced lymphocytes to produce antibody. It is possible that the suppression was mediated by SIC present in the plasma of the infected rats and this effect was probably enhanced by reduced levels of complement in the suppressive plasma.

Immune complexes and immunoconglutinin interactions associated with altered lymphocyte activity in Plasmodium chabaudi infections.

Fresh plasma from rats infected with Plasmodium chabaudi, incubated with splenic lymphocytes from rats immunized 5 days previously with sheep blood cells, suppressed the capacity of the spleen cells to produce antibody against the sheep cells as was indicated by reductions in the numbers of hemolytic Jerne plaques formed by the treated cells. The effect was maximal in plasma of rats drawn on the 7th day of infection at a time the rats experienced a hemolytic crisis. Serologic studies indicated that the active plasma contained elevated titers of antibody against fibrinogen products, antibody against the soluble serum antigens elaborated during blood infections and antibody against the third component of fixed complement (C3) or immunoconglutinin. Titers of lytic complement were reduced and amounts of soluble immune complex precipitated with polyethylene glycol 6000 were elevated. The active plasma may have affected the antibody producing cells by one or both of two mechanisms. Soluble antigen-antibody complexes could have interacted with Fc receptors of activated lymphocytes to alter their function. Alternatively, the complexes may have fixed complement and interacted with receptors for fixed C3 on the lymphocyte membrane. Such cells, being coated with the antigen for immunoconglutinin, could be altered by immunoconglutination. Inasmuch as the immune complexes in the active plasma were generated in vivo, it would seem unlikely that the plasma would contain significant amounts of complex that had not fixed complement. With immunoconglutinin present in the plasma, alteration of the cells by immunoconglutination seems a more likely possibility.

Immunoconglutinin and suppression of an induced immune response by plasma from rats infected with Trypanosoma brucei rhodesiense.

Fresh plasma from rats infected with Trypanosoma brucei rhodesiense, incubated with splenic lymphocytes from rats previously immunized with sheep blood cells, suppressed the capacity of the splenic lymphocytes to produce antibody as was indicated by reductions in the numbers of hemolytic Jerne plaques produced by the treated cells. The effect was maximal in plasma samples drawn on the sixth to eighth day of infection when they contained elevated amounts of soluble immune complex, high titers of immunoconglutinin (IK), and reduced titers of lytic complement. We suggest that the active plasma may have affected the antibody-producing cells by one or both of two mechanisms. Soluble antigen-antibody complexes may have interacted with Fc receptors of activated lymphocytes to suppress antibody production. Alternatively, complement-fixing soluble immune complexes may have reacted with C3b receptors of the lymphocytes. These lymphocytes coated with the antigen for IK could then be injured by immunoconglutination.

Pericellular lacunae in the diagnosis of metastatic carcinoma in effusions: is this a useful sign?

The presence of pericellular lacunae has been cited as a useful criterion in distinguishing between benign and malignant effusions from body cavities. This study assessed the presence of pericellular lacunae in 75 specimens of malignant and 38 specimens of benign effusions. In a large number of cases, lacunae could not be assessed reliably because of technical and artifactual reasons. Pericellular lacunae were detected around the majority of the cell clusters in only 4 of the malignant and 2 of the benign cases. In our material, pericellular lacunae were not a useful criterion for the diagnosis of malignancy in body cavity fluids.