Differences in subtype distribution between screen-detected and symptomatic invasive breast cancer and their impact on survival

Purpose. Stage shift is considered a major reason for more favorable outcomes in patients with screen-detected breast cancer. However, even after adjusting for clinical stage, unresolved issues concerning the reasons for a survival benefit associated with screening programs remain. This study aims to evaluate differences in subtype distribution and outcomes among patients with screen-detected and symptomatic invasive breast cancer and assess whether variations in subtype distribution could explain differences in prognosis. Methods. Survival analysis was performed to estimate the likelihood of distant recurrence and death in 1132 patients. Subtypes were defined as luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-, and Ki67 low], luminal B (HER2-) (ER+ and/or PR+, HER2-, and Ki67 high), luminal B (HER2+) (ER+ and/or PR+ and HER2+), HER2 overexpressing (ER-, PR-, and HER2+), and triple negative (ER-, PR-, and HER2-). Results. Screen-detected cancers had favorable clinicopathological characteristics, such as smaller tumor size and a lower frequency of lymph node involvement. Women with screen-detected cancers had a survival advantage. Subtype distribution differed significantly among women with screen-detected and symptomatic cancer. Screen-detected cancers were more likely to be luminal A and less likely to be HER2 overexpressing or triple negative cancer compared with symptomatic cancers (luminal A 61.3 vs. 44.2%, HER2 overexpressing 4.0 vs. 8.0%, triple negative 8.0 vs. 15.9%). Node status, mode of detection, and subtype were independent prognostic factors in the multivariate analysis. Conclusions. Differences in subtype distribution between screen-detected and symptomatic cancer could partially explain differences in outcomes (AU)

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Differences in subtype distribution between screen-detected and symptomatic invasive breast cancer and their impact on survival.

PURPOSE: Stage shift is considered a major reason for more favorable outcomes in patients with screen-detected breast cancer. However, even after adjusting for clinical stage, unresolved issues concerning the reasons for a survival benefit associated with screening programs remain. This study aims to evaluate differences in subtype distribution and outcomes among patients with screen-detected and symptomatic invasive breast cancer and assess whether variations in subtype distribution could explain differences in prognosis. METHODS: Survival analysis was performed to estimate the likelihood of distant recurrence and death in 1132 patients. Subtypes were defined as luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-, and Ki67 low], luminal B (HER2-) (ER+ and/or PR+, HER2-, and Ki67 high), luminal B (HER2+) (ER+ and/or PR+ and HER2+), HER2 overexpressing (ER-, PR-, and HER2+), and triple negative (ER-, PR-, and HER2-). RESULTS: Screen-detected cancers had favorable clinicopathological characteristics, such as smaller tumor size and a lower frequency of lymph node involvement. Women with screen-detected cancers had a survival advantage. Subtype distribution differed significantly among women with screen-detected and symptomatic cancer. Screen-detected cancers were more likely to be luminal A and less likely to be HER2 overexpressing or triple negative cancer compared with symptomatic cancers (luminal A 61.3 vs. 44.2%, HER2 overexpressing 4.0 vs. 8.0%, triple negative 8.0 vs. 15.9%). Node status, mode of detection, and subtype were independent prognostic factors in the multivariate analysis. CONCLUSIONS: Differences in subtype distribution between screen-detected and symptomatic cancer could partially explain differences in outcomes.

Applicability of lectin histochemistry in a test system with in ovo treatment for detecting androgenic and antiandrogenic effects of chemicals in Japanese quail (Coturnix japonica).

The aim of the current study was to examine whether analysis of the appearance of specific lectin-positive substances in the quail embryonic cloacal gland would be useful for evaluating the androgenic and antiandrogenic effects of chemicals. Fertilized Japanese quail eggs were injected with 0 to 75 µg of cyproterone acetate (CA), an antiandrogenic compound, on d 12 of incubation (d 12), followed by injection of 0 to 300 µg of testosterone propionate (TP) on d 13. Experimental groups consisted of a control group (corn oil injections on d 12 and 13), a TP-L group [corn oil and a low dose (L; 30 µg) of TP], a TP-H group [corn oil and a high dose (H; 300 µg) of TP], a CA-L + TP-H group [a low dose (L;7.5 µg) of CA + TP-H], and a CA-H + TP-H group [a high dose (H; 75 µg) of CA + TP-H]. The cloacal tissues were collected on d 16, processed into paraffin sections, and stained using 14 different biotinylated lectins. The Vicia villosa (VVA) lectin most strongly stained the developing cloacal glandular cells in TP-H. Western blotting analysis showed 1 VVA-positive band of approximately 75 kDa. The ratio of VVA-positive areas per unit square examined microscopically by image analysis was significantly greater in the TP-H group than in the control group in both males and females. The ratio was significantly decreased in the CA-L + TP-H and CA-H + TP-H groups compared with the TP-H group in both males and females. Furthermore, the ratio was smaller in females than in males within a TP-L or TP-H treatment group. These results suggest that lectin histochemistry on quail embryonic cloaca using VVA is useful for evaluating the androgenic and antiandrogenic effects of chemical compounds.

Bombyx mori Ras proteins BmRas1, BmRas2 and BmRas3 are neither farnesylated nor palmitoylated but are geranylgeranylated.

The lipid modifications which occur on Bombyx mori Ras proteins BmRas1, BmRas2 and BmRas3 were studied by metabolic labelling in an insect cell-free protein synthesis system and in a baculovirus expression system, using specific inhibitors of protein prenylation and protein palmitoylation. In addition, the subcellular localization of BmRas proteins was examined using EGFP fusion proteins of constitutively active forms of BmRas proteins transiently expressed in Sf9 cells. As a result, it was revealed that the three B. mori Ras proteins BmRas1, BmRas2 and BmRas3 are neither farnesylated nor palmitoylated but are geranylgeranylated for localization to the plasma membrane of insect cells. Thus, the mechanism of membrane binding of insect Ras proteins is quite different from that reported for mammalian Ras proteins.

Sensitive embryonic endpoints with in ovo treatment for detecting androgenic and anti-androgenic effects of chemicals in Japanese quail (Coturnix japonica).

The aim of the current study was to establish the sensitive embryonic endpoints and a test system for detecting androgenic and anti-androgenic potential of chemicals using an in ovo treatment assay in Japanese quail. In ovo injection with 0 to 75 microg of cyproterone acetate (CA) was performed on d 12 of incubation, followed by 0 to 300 microg of testosterone propionate (TP) injection on d 13 and histological examination on d 16. Experimental groups were composed of control (twice injected corn oil injections; on d 12 and d 13, respectively), TP-L (corn oil and 30 microg of TP), TP-H (corn oil and 300 microg of TP), CA-L + TP-H (7.5 microg of CA and 300 microg of TP), and CA-H+ TP-H (75 microg of CA and 300 microg of TP). Histological examinations were performed in the cloacal gland, liver, kidneys, testes, ovaries, uropygial gland, and bursa of Fabricius. The cloacal gland consists of many glandular units (tubular gland structures) lined by developed or undeveloped glandular cells. The developed glandular cells were tall in height and contained mucous substance in the cytoplasm. The glandular units containing developed glandular cells were termed as the developing glandular units. The developing glandular units were observed in the TP-H, CA-L + TP-H, and CA-H + TP-H groups, but not in the control and TP-L groups, in both males and females. The ratio of developing glandular units to the total number of glandular units was significantly greater in TP-H than control and TP-L and was significantly decreased in CA-L + TP-H and CA-H + TP-H compared with TP-H in both males and females. The ratio was significantly greater in males than in females of CA-L + TP-H. No significant structural differences were observed in the other organs. These results suggest that the most sensitive endpoint of androgenic effects in quail embryo appeared in the cloacal glands. The ratio of the developing glandular units could be used for evaluation of androgenic and anti-androgenic effects of compounds.

[Outcomes of bronchoplasty procedures for lung cancer].

A sleeve lobectomy is an established general thoracic surgical procedure. To improve clinical outcomes following the procedure, we reviewed the records of 60 patients who underwent a bronchoplasty procedure in our department from 1992 to 2007. Induction chemotherapy was performed for 20, of whom 10 underwent radiotherapy as well. For all subjects, the postoperative mortality and morbidity rates were 1.7% and 33.3%, respectively. Induction therapy did not significantly affect those rates, though complications related to bronchial anastomoses occurred exclusively in subjects who received that therapy. The overall 5-year survival rate was 51.0%, while subjects with pN0 (67.9%) and pN1 (60.0%) disease, and those in stage I (79.1%) and stage II (59.9%) had better survival as compared with patients with pN2 (16.9%) disease, and those in stage III (21.8%) and stage IV (0%). Furthermore, the survival rate of yp-stage I and II patients was significantly greater than that of those in yp-stage III and IV (59.9% vs. 14.3%, p = 0.0158). We concluded that patients in stages I, II or with pN0-1 disease are good candidates for a bronchoplasty procedure, though induction therapy should be considered thereafter. In addition, due diligence for postoperative complications is necessary.

The effects of 2-methoxyoestrogen sulphamates on the in vitro and in vivo proliferation of breast cancer cells.

2-Methoxyoestrogen sulphamates are a new class of compounds, which inhibit breast cancer cell proliferation and are also potent inhibitors of steroid sulphatase (STS) activity. In the present study, we have used two cell proliferation assays (MTS and AB) to identify potent new compounds in this class. Similar IC(50) values were obtained using these assays with two of the most potent compounds identified being 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE) and 2-methoxyoestradiol-17beta-cyanomethyl-3-O-sulphamate (2-MeOE2CyMATE). Both compounds inhibited the proliferation of MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cells. Using the AB assay, which allows repeat measurements of cell proliferation without killing cells, both compounds were shown to inhibit cell proliferation in an irreversible manner. As STS may be involved in the removal of the sulphamoyl moiety of these compounds, which could reduce their potency, their ability to inhibit the proliferation of MCF-7 cells transfected with the cDNA for STS was also examined. Although the STS activity was 20-fold higher in these cells than in non-transfected MCF-7 cells, no decrease in the ability of these compounds to inhibit cell proliferation was detected. To test the efficacy of these compounds in vivo, nude mice were inoculated with MCF-7 cells in Matrigel and stimulated to grow with oestradiol. Three weeks after the oral administration of 2-MeOE2bisMATE or 2-MeOE2CyMATE (20mg/kg/day, 5 days/week) tumour volumes had regressed by 52% and 22%, respectively. Both compounds also inhibited liver and tumour STS activity by >90%. The potent anti-proliferative effects of these compounds, and their ability to inhibit tumour growth and STS activity in vivo, indicates that they are suitable for development as novel therapeutic agents, which should be active against a wide range of cancers.

Amino acid residues involved in interaction with tyramine in the Bombyx mori tyramine receptor.

To identify amino acid residues interacting with tyramine (TA) in the Bombyx mori TA (BmTA) receptor, several mutant receptors were expressed in HEK-293 cells and examined for their abilities to bind TA and to attenuate forskolin-stimulated cAMP production in response to TA. The D134A BmTA receptor showed no specific [3H]TA binding and no TA-attenuation of cAMP levels. Although the S218A and S222A BmTA receptors showed no specific [3H]TA binding, they still had the ability to mediate the attenuation of cAMP levels in response to the high concentration (100 microM) of TA. The double mutation of Ser218 and Ser222 to Ala, however, led to the loss of TA-attenuation of cAMP levels. The present study thus confirms that at least three amino acid residues play key roles in interaction with TA in the BmTA receptor.

Local correction of a transverse loop colostomy prolapse by means of a stapler device.

Prolapse is a common complication in patients with a transverse loop colostomy. In most cases, the prolapse can be managed conservatively awaiting time for closure eventually. However, loop stoma may also be intentionally permanent or the patient may be too fragile to have the colostomy closed and in these cases a laparotomy is required for correction of the prolapse. A simple method allowing local correction of the prolapsed loop stoma is described.

Many-electron dynamics of a Xe atom in strong and superstrong laser fields.

We report on detailed investigations of ionization dynamics of a Xe atom exposed to intense 800-nm pulses of 20-fs duration in the extensive intensity range from 10(13)-10(18) W/cm(2). Ion yields of Xe+-Xe20+ were observed as a function of laser intensity and compared with the results from a single active electron based Ammosov-Delone-Krainov model. Unexpected ionization probabilities for lower charge states and no interplay between the inner and outer shells by screening are inferred. Suppression of nonsequential ionization towards higher intensity and few optical cycle regimes is also proved.

Energetic protons from a few-micron metallic foil evaporated by an intense laser pulse.

With detailed experimental studies and hydrodynamics and particle-in-cell simulations we investigate the role of the prepulse in laser proton acceleration. The prepulse or pedestal (amplified spontaneous emission) can completely evaporate the irradiated region of a sufficiently thin foil; therefore, the main part of the laser pulse interacts with an underdense plasma. The multiparametric particle-in-cell simulations demonstrate that the main pulse generates the quasistatic magnetic field, which in its turn produces the long-lived charge separation electrostatic field, accelerating the ions.

Pathophysiology and prevention of loop stomal prolapse in the transverse colon.

We investigated both pathogenesis and prevention of loop transverse stomal prolapse. Seven patients with reducible prolapsed stoma were studied under fluoroscopy after staining the prolapsed stoma and the colon by barium medium while prolapsing or reducing the stoma with or without the stomal wall pressed on to the abdominal wall of fascial plane. All prolapses occurred in the distal limbs of the loop stoma with the distal transverse colons redundant. The prolapse started around the mucocutaneous suture with the stoma inflated and the colon in it depressed and proceeded in accordance with an addition of abdominal pressure, but did not occur by pressing of the stomal wall. Prolapse of transverse loop stoma occurs when redundant colon invades the stoma with an abdominal pressure. Stomal prolapse might be prevented by fixation of the colon to the fascia.

[The present status of Japanese psychopathology. A summary of the World Congress of Psychiatry in Yokohama]. / Die gegenwärtige Situation der japanischen Psychopathologie. Ein Rückblick auf den Weltkongress der Psychiatrie in Yokohama.

The last World Congress of Psychiatry took place in Yokohama, Japan. It gave the opportunity for presenting specifically Japanese approaches to psychopathology to the international psychiatric community. This paper reports on prominent trends in Japanese psychopathological research, which has close ties to German psychopathology

Bladder and male sexual functions after autonomic nerve-sparing TME with or without lateral node dissection for rectal cancer.

BACKGROUND: We evaluated to what extent lateral lymph node dissection (LND) interferes with bladder and male sexual functions after radical rectal excision with adoption of careful total autonomic nerve preservation. METHODS: The study comprised 77 patients resected for mid-rectal or lower rectal cancer. Bladder and male sexual functions were studied by means of a questionnaire more than one year after surgery. Outcomes were compared between patients who received lateral LND (group 1, 65 patients) and those who did not (group 2, 12 patients). RESULTS: Only minor disturbances of bladder function were reported in 10 patients (15%) of group 1, and in 3 patients (25%) of group 2. Ten out of 37 preoperatively sexually active patients (27%) in group 1 males and one of 5 patients (20%) in group 2 males had partial or total impotency after surgery and retrograde ejaculation occurred in 3 of 27 patients (11%) and one of 4 patients (25%), respectively. Erectile impotency occurred less frequently when patients were operated during the period 1993-1996 than during 1988-1992 (11% vs. 42%, p<0.05). The age was significantly greater among patients who had loss of ejaculation. CONCLUSIONS: If lateral lymph node dissection should be used with the aim of improving radicality in rectal excision for cancer, it should be combined with careful nerve-preserving technique--which may reduce the risk of bladder and male sexual dysfunctions.

B96Bom encodes a Bombyx mori tyramine receptor negatively coupled to adenylate cyclase.

A cDNA encoding a biogenic amine receptor (B96Bom) was isolated from silkworm (Bombyx mori) larvae, and the ligand response of the receptor stably expressed in HEK-293 cells was examined. Tyramine (TA) at 0.1-100 micro m reduced forskolin (10 micro m)-stimulated intracellular cAMP levels by approximately 40%. The inhibitory effect of TA at 1 micro m was abolished by yohimbine and chlorpromazine (each 10 micro m). Although octopamine (OA) also reduced the cAMP levels, the potency was at least two orders of magnitude lower than that of TA. Furthermore, unlabelled TA (IC50 = 5.2 nm) inhibited specific [3H]TA binding to the membranes of B96Bom-transfected HEK-293 cells more potently than did OA (IC50 = 1.4 micro m) and dopamine (IC50 = 1.7 micro m). Taken together with the result of phylogenetic analysis, these findings indicate that the B96Bom receptor is a B. mori TA receptor, which is negatively coupled to adenylate cyclase. The use of this expression system should facilitate physiological studies of TA receptors as well as structure-activity studies of TA receptor ligands.

Minimally invasive surgery for carcinoid tumors in the rectum.

Most carcinoid tumors of the rectum are confined to the submucosa with a size less than 1-2 cm and are usually suitable for local excision, as metastasis to the regional nodes is limited. Endoscopic excision of carcinoid tumors has been performed for this entity as a least invasive method but incomplete resection and/or unclear surgical margin and curability have been reported to occur in 24-42% of cases because of a limited resection up to the submucosal layer and burn effect. Transanal local excision has often been applied for rectal carcinoid tumor as a least invasive method among local excision procedures to accomplish full thickness excision for determining the curability. However, it is often difficult to obtain free access with a sufficient surgical field by the conventional method. Transanal endoscopic microsurgery (TEM) has appeared as a useful option to access a high tumor with fine visibility but special caution has to be taken for tumors sited above the peritoneal reflection. To facilitate full thickness excision even for high tumors, novel local excisional technique called minimally invasive transanal surgery (MITAS) has been developed and used for local removal of carcinoid tumors in the rectum. A specially designed anal retractor connected to the Octopus retractor holder with several novel techniques facilitated excisional procedures around the anus with a sufficient fixed surgical field and an ENDO-stapler allowed the simultaneous excision and anastomosis to be performed. The technique facilitated total excisional biopsy with less operative time and blood loss, and no mobility or mortality in 12 patients with rectal carcinoid tumors.

Induction and mechanism of apoptotic cell death by propofol in HL-60 cells.

BACKGROUND: Apoptosis (programmed cell death) occurs in various physiological and pathological conditions, exhibits a characteristic mechanism of intracellular sequential reaction and may be involved in determining clinical outcome. The antioxidant activity of propofol (2,6-diisopropylphenol) together with the stimulating effect of protein kinase C suggests that propofol might have the potential to modulate apoptosis. Thus, it is of both clinical interest and biomedical importance to investigate and clarify the effect and mechanism of propofol upon the intracellular reactions underlying apoptotic cell death. METHODS: The effect of propofol on apoptosis was investigated using cultured human promyelocytic leukemia HL-60 cells. This well-characterized cell line is useful for the study of apoptosis because the various biochemical steps occurring during apoptosis have been well documented. RESULTS: Treatment of HL-60 cells with propofol resulted in growth inhibition with the formation of apoptotic bodies in a concentration-dependent manner. DNA fragmentation and ladder formation was also observed in a concentration-dependent manner. Propofol treatment resulted in activation of caspase-3, -6, -8 and -9, thereby suggesting that cell surface death receptor activation of the caspase cascade mediates propofol-induced apoptosis with consequent formation of the cleaved product of Bid (a pro-apoptotic Bcl-2 family member protein) and activation of the mitochondrial pathway with cytosolic release of cytochrome c. CONCLUSION: Propofol may induce apoptosis, which is dependent on the mechanism that activates both the cell surface death receptor pathway and the mitochondrial pathway.

Minimally invasive transanal surgery for localized rectal carcinoid tumors.

Local excision is often fully justified for rectal carcinoid tumors. However insufficient surgical field and difficult access to proximal tumors have been drawbacks in performing pre-existing local excision procedures. A novel local excisional technique called minimally invasive transanal surgery (MITAS) has been experimented for local removal of carcinoid tumors in the rectum. A specially designed anal retractor connected to the Octopus retractor holder was used and an ENDO-stapler allowed the simultaneous excision and anastomosis to be performed. Eight patients with carcinoid tumors in the rectum (4 tumors in the upper rectum) underwent MITAS. Median distance from anal verge to proximal tumor was 6.5 cm (range, 5-12 cm). The median diameter of the tumor was 9 mm. Median operative time was 18.5 minutes and blood loss was minimal. No analgesics were needed postoperatively, and there was no morbidity or mortality. Full-thickness excision of the rectum was accomplished and the tumors confined in the submucosa were demonstrated histologically to be with free surgical margins. No recurrences have been observed with a median follow-up period of 39 months. The technique facilitates total excisional biopsy for rectal carcinoid tumors and reduces operative time, blood loss and complications.

[Subglottic granuloma with extubating mini-trach II: report of a case].

A case of subglottic granuloma after extubating Mini-trach II is described. The patient went aorto-coronary bypass and Mini-trach II was inserted for suction of sputum. Mini-trach II was extubated 6 days after insertion. The patient complained of dyspnea 3 months later. Examination showed subglottic granuloma. First, we burned the granuloma by laser under local anesthesia. Because the visual field was not good due to vocal cord movement, we failed to resect the granuloma completely. Therefore, we performed laryngo microsurgery under general anesthesia and resected the granuloma perfectly. The patient is in good health without signs of recurrence 6 months after granuloma removal. When we used Mini-trach II, the most important issues are insertion to the cricothyroid membrane, preventing infection, and careful follow-up after removing the Mini-trach II.

Does perifascial rectal excision (i.e. TME) when combined with the autonomic nerve-sparing technique interfere with operative radicality?

OBJECTIVE: The lymphatic drainage from the rectum was studied to evaluate if the autonomic nerve sparing dissection may interfere with the operative radicality and might result in metastatic lymph nodes being overlooked and left in situ. PATIENTS AND METHODS: 50 consecutive patients had an extended extrafascial rectal excision resection for cancer. In 19 of the 50 patients activated carbon particles (CH40) were injected preoperatively into the rectum. The autonomic nerves with surrounding connective tissue were serially dissected from the resected specimen, carefully sliced at 5-mm intervals and collected for histological study. Lymph nodes along the axial and lateral drainage routes were examined, and the inclusion of CH40 in the nodes was microscopically studied according to the site of CH40 injection. RESULTS: Lymph nodes within the connective tissue along the dissected autonomic nerves were demonstrated in 47 of the 50 cases. Two of 50 cases had positive nodes along preaortic plexus or pelvic plexus, and a case with nodal involvement along the pelvic plexus had poor prognosis in spite of nerve excision. CH40 when injected into the rectum above the peritoneal reflection was demonstrated in the vast majority of the axial nodes, while in only one lymph node along the preaortic plexus when injected in the rectum above the peritoneal reflection. On the other hand when injected in the rectum below the peritoneal reflection, CH40 was demonstrated both in axial and lateral nodes as well as in lymph nodes along bilateral pelvic plexuses, right hypogastric nerve, superior hypogastric plexus, preaortic plexus and mesenteric plexus as well. CONCLUSIONS: When located above the peritoneal reflection a rectal carcinoma will spread preferentially along the upper axial route, while a carcinoma located below the peritoneal reflection will also spread laterally and along the autonomic nerves. It was inferred that lymphatic flow along the autonomic nerves came up from the rectum below the peritoneal reflection mainly through a so-called lateral ligament but its clinical significance was negligible. Therefore doing TME with autonomic nerve preservation does not imply a less radical surgery from the point of lymphatic spread.