Surveillance of women with a personal history of breast cancer by tumour subtype.

AIM: To determine if the rate and timing of a second breast cancer event (SBCE) in women with a personal history of breast cancer varies by disease subtype or breast imaging method. MATERIALS AND METHODS: A retrospective review was performed of women with a SBCE from January 2006 to December 2010 at a single institution. Data analysed included oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status of the primary and second breast cancers; mammographic and ultrasound (US) features from SBCE; and the time interval between both events. RESULTS: Of 207 patients diagnosed with a SBCE, the median age at first diagnosis was 50.6 years, range 24.8 to 80.2; at second diagnosis was 56.2 years, range 25.8 to 87.9. Eleven percent of SBCE were diagnosed >10 years after the primary cancer diagnosis. The median time between the first and second diagnosis for ER-positive patients was 2.7 years (range 0.7-17.4 years); and 1.9 years for ER-negative patients, (range 0.4-23.4 years; p<0.002). Patients with triple-negative breast cancer (TNBC) had a shorter time between diagnoses than others (p=0.0003). At 3, 5, and 10 years, 85%, 92%, and 97% of ER-negative and 54%, 81%, and 95% of ER-positive tumours, respectively, had recurred. ER-negative tumours and TNBC were more likely to be visible at US. CONCLUSION: There may be a role for customised imaging surveillance of women with a personal history of breast cancer (PHBC) after 10 years. Further studies are necessary to determine if US may be valuable in the surveillance of patients with ER-negative and TNBC tumours.

Is MRI helpful in assessing the distance of the tumour from the internal os in patients with cervical cancer below FIGO Stage IB2?

AIM: To determine the ability of magnetic resonance imaging (MRI) in detecting tumour-free margins from the internal os (IO). MATERIALS AND METHODS: A database search yielded 79 women with early-stage cervical cancer who underwent radical hysterectomy and preoperative MRI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MRI in assessment of ≤5 and >5 mm IO involvement were calculated with histopathological surgical specimen findings considered to be the reference standard. A main and subset analysis was performed. The subset analysis included only those patients who would have been considered for radical trachelectomy. RESULTS: For predicting a distance between the tumour and the IO of ≤5 mm, MRI had a sensitivity of 73%, a specificity of 98.3%, a PPV of 95%, a NPV of 88.1%, and an accuracy of 89.8% for the main analysis, and sensitivity of 81.8%, a specificity of 93.2% a PPV of 69.2% a NPV of 96.5% and an accuracy of 91.4% for the subset analysis. CONCLUSION: MRI has high specificity, NPV, and accuracy in detecting tumour from the IO, making MRI suitable for treatment planning in patients desiring trachelectomy to preserve fertility.

A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations.

BACKGROUND: Melanoma cell lines treated with decitabine show upregulation of cancer antigens, and interferon-α upregulates MHC Class I antigens in cancer cells, leading to enhanced T-cell recognition and T-cell mediated tumor apoptosis. We evaluated the synergy between the hypomethylating effects of decitabine and the immunomodulatory effects of interferon in a combination regimen administered to advanced melanoma patients in a phase 1 trial. METHODS: Patients with one prior systemic therapy were eligible. Using a modified 3 + 3 design, patients received escalating doses of decitabine and pegylated interferon α-2b (PEG-IFN) during every 28-day treatment cycle. Global DNA methylation was measured on days 1 and 5 of cycles 1 and 3. Cytokine profiling and quantification of T-cell subpopulations by FACS were performed at baseline and cycle 3. RESULTS: Seventeen patients were assigned to one of four dose levels. Decitabine 15 mg/m2/d + PEG-IFN 3 µg/kg was the maximum tolerated dose (MTD). Grade 3/4 cytopenias were seen across all dose levels: anemia (1), neutropenia (7), and thrombocytopenia (2). One patient remained progression-free for 37 weeks. The other 16 patients progressed at or before 12 weeks. Median overall survival was 39 weeks. Hypomethylation was seen at all dose levels. Due to treatment-induced lymphocytopenia, absolute changes in T-cell populations post-treatment were too small to be meaningfully interpreted. CONCLUSIONS: The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels.

Thickness of superficial basal cell carcinoma (sBCC) predicts imiquimod efficacy: a proposal for a thickness-based definition of sBCC.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in the white population. It is an important driver of healthcare costs and causes significant morbidity. Topical imiquimod is a good noninvasive treatment alternative for surgical excision in superficial BCC (sBCC). However, there are currently no uniform histological definitions of sBCC. A definition based on tumour thickness might be a good alternative. OBJECTIVES: To determine whether tumour thickness in sBCC is a predictor of treatment failure. METHODS: We retrospectively examined 127 histological biopsy specimens of sBCC treated primarily with imiquimod five times a week for 6 weeks. Mean follow-up was 34 months (range 3-91). Recurrence was evaluated clinically with histological verification. RESULTS: Among nonrecurrent cases the median tumour thickness was 0·26 mm (range 0·09-0·61), while for recurrent cases the median tumour thickness was 0·57 mm (range 0·41-1·41, P < 0·0001). Among lesions ≤ 0·40 mm in thickness, none recurred, whereas for lesions > 0·40 mm the recurrence rate was 58% (P < 0·0001). CONCLUSIONS: We recommend the use of tumour thickness to define the superficial pattern in pathology reports for BCC as this can help to determine treatment response of sBCC to imiquimod.

Metaplastic sarcomatoid carcinoma of the breast appears more aggressive than other triple receptor-negative breast cancers.

Metaplastic sarcomatoid carcinoma (MSC) of the breast is usually triple receptor (ER, PR, and HER2) negative and is not currently recognized as being more aggressive than other triple receptor-negative breast cancers. We reviewed archival tissue sections from surgical resection specimens of 47 patients with MSC of the breast and evaluated the association between various clinicopathologic features and patient survival. We also evaluated the clinical outcome of MSC patients compared to a control group of patients with triple receptor-negative invasive breast carcinoma matched for patient age, clinical stage, tumor grade, treatment with chemotherapy, and treatment with radiation therapy. Factors independently associated with decreased disease-free survival among patients with stage I-III MSC of the breast were patient age > 50 years (P = 0.029) and the presence of nodal macrometastases (P = 0.003). In early-stage (stage I-II) MSC, decreased disease-free survival was observed for patients with a sarcomatoid component comprising ≥ 95% of the tumor (P = 0.032), but tumor size was the only independent adverse prognostic factor in early-stage patients (P = 0.043). Compared to a control group of triple receptor-negative patients, patients with stage I-III MSC had decreased disease-free survival (two-sided log rank, P = 0.018). Five-year disease-free survival was 44 ± 8% versus 74 ± 7% for patients with MSC versus triple receptor-negative breast cancer, respectively. We conclude that MSC of the breast appears more aggressive than other triple receptor-negative breast cancers.

A pilot study examining correlates of body image among women living with SCI.

STUDY DESIGN: Cross-sectional pilot study. OBJECTIVES: To explore correlates of body image among women with spinal cord injury (SCI), within the framework of Cash's cognitive behavioral model of body image. SETTING: Hamilton, Ontario, Canada. METHODS: Women with SCI (N=11, 64% with tetraplegia) reported their functional and appearance body image (Adult Body Satisfaction Questionnaire). A 3-day recall of leisure time physical activity (LTPA), three measures of body composition (that is, weight, waist circumference, body fat) and several demographic variables were assessed as potential correlates. RESULTS: Appearance satisfaction was negatively correlated with all three measures of body composition and positively correlated with years postinjury. Functional satisfaction was positively correlated with years postinjury, and negatively correlated with various LTPA variables. CONCLUSION: Functional and appearance body image may improve with time following SCI. Body composition may impact satisfaction with physical appearance for some women. The negative relationship between LTPA and functional satisfaction merits further examination, as functional dissatisfaction may motivate individuals to engage in certain types and intensities of LTPA. Correlates of body image differ between appearance and functional satisfaction. Future research should examine appearance and functional satisfaction separately among women with SCI.

Loss of phosphatase and tensin homologue deleted on chromosome 10 and phosphorylation of mammalian target of rapamycin are associated with progesterone refractory endometrial hyperplasia.

The objective of our study was to evaluate the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p27, and mammalian target of rapamycin (mTOR) expressions in women with progesterone-responsive and refractory endometrial hyperplasia (EH) samples and to determine if these markers could be associated with response or used as potential targets for treatment. Thirty-eight matched pre- and posttreatment pairs of paraffin-embedded endometrial biopsies were obtained from patients with EH. Immunohistochemical analysis for PTEN, p27, and phospho-mTOR were performed on all samples. Median age at diagnosis was 49 years (20-79 years). Median treatment interval was 3 months (1-12 months). Sixteen patients (42.1%) had complete resolution of their hyperplasia (responders), and 22 (57.9%) had persistent hyperplasia (nonresponders) after treatment with progesterone. In the pretreatment samples, no markers were found to predict nonresponders. In posttreatment samples, loss of PTEN expression with phospho-mTOR expression was observed in more nonresponders than responders (40.9% vs 6.3%; P= 0.03). Phospho-mTOR overexpression was found in 63.6% of nonresponders. We found that persistent hyperplasia refractory to progesterone therapy was associated both with the loss of PTEN and with the loss of phosphorylation of mTOR. In select cases of non-responsive progesterone refractory EH, a rational target for treatment may involve the mTOR pathway.

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=<0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82 and 51% (P=0.03), and the 3-year PFS estimates were 63% and 27% (P=0.001), respectively. The 2-year treatment-related mortality was 8 and 23% and the incidence of grade 3 or 4 GvHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370.

OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.

More than looking good: impact on quality of life moderates the relationship between functional body image and physical activity in men with SCI.

STUDY DESIGN: Cross-sectional. OBJECTIVES: To examine the relationship between body image and leisure time physical activity (LTPA) among men with spinal cord injury (SCI). Specifically, to examine the moderating function of the perceived impact of body image on quality of life (QOL). SETTING: Ontario, Canada. METHODS: Men with SCI (N=50, 50% paraplegic) reported, (a) their functional and appearance body image (Adult Body Satisfaction Questionnaire), (b) their perceived impact of body image on QOL and (c) LTPA performed over the previous 3 days. RESULTS: Body image was in the 'normal' range compared with the general population. Linear regression analysis found a significant LTPA x body image impact on QOL interaction beta=0.39, P<0.05. Post hoc analysis showed that among individuals who reported a negative effect of body image on QOL, those who engaged in LTPA were less satisfied with their physical function than those who did not. For those who did not perceive their body image to negatively impact their QOL, there was generally no difference in functional body image between those who engaged in LTPA and those who did not. CONCLUSION: Appearance body image is not related to LTPA for men with SCI. It has been suggested that body dissatisfaction may motivate some individuals to engage in LTPA. However, for men living with SCI, functional body image may be associated with LTPA only when a negative effect on QOL is perceived. Future research should consider the moderating function of the perceived impact of body image on QOL when examining the relationship between LTPA and body image among men living with SCI.

Forensic isotope analysis to refine a hydrologic conceptual model.

Water resources in the arid southwestern United States are frequently the subject of conflict from competing private and public interests. Legal remedies may remove impasses, but the technical analysis of the problem often determines the future success of legal solutions. In Owens Valley, California, the source of water for the Los Angeles Aqueduct (LAA) is flow diverted from the Owens River and its tributaries and ground water from valley aquifers. Future management of ground water delivered to the LAA needs technical support regarding quantity available, interconnection of shallow and confined aquifers, impact on local springs, and rate of recharge. Ground water flow models and ground water composition are tools already in use, but these have large uncertainty for local interpretations. This study conducted targeted sampling of springs and wells to evaluate the hydrologic system to corroborate conceptual and numerical models. The effort included measurement of intrinsic isotopic composition at key locations in the aquifers. The stable isotopic data of boron (delta(11)B), sulfur (delta(34)S), oxygen (delta(18)O), hydrogen (delta D), and tritium ((3)H) supported by basic chemical data provided rules for characterizing the upper and the lower aquifer system, confirmed the interpretation of ground water flow near faults and flow barriers, and detected hydraulic connections between the LAA and the perennial springs at key locations along the unlined reach of the LAA. This study exemplifies the use of forensic isotopic approaches as independent checks on the consistency of interpretations of conceptual models of a ground water system and the numerical hydrologic simulations.

Geochemical tracers to evaluate hydrogeologic controls on river salinization.

The salinization of rivers, as indicated by salinity increases in the downstream direction, is characteristic of arid and semiarid regions throughout the world. Historically, salinity increases have been attributed to various mechanisms, including (1) evaporation and concentration during reservoir storage, irrigation, and subsequent reuse; (2) displacement of shallow saline ground water during irrigation; (3) erosion and dissolution of natural deposits; and/or (4) inflow of deep saline and/or geothermal ground water (ground water with elevated water temperature). In this study, investigation of salinity issues focused on identification of relative salinity contributions from anthropogenic and natural sources in the Lower Rio Grande in the New Mexico-Texas border region. Based on the conceptual model of the system, the various sources of water and, therefore, salinity to the Lower Rio Grande were identified, and a sampling plan was designed to characterize these sources. Analysis results for boron (delta(11)B), sulfur (delta(34)S), oxygen (delta(18)O), hydrogen (delta(2)H), and strontium ((87)Sr/(86)Sr) isotopes, as well as basic chemical data, confirmed the hypothesis that the dominant salinity contributions are from deep ground water inflow to the Rio Grande. The stable isotopic ratios identified the deep ground water inflow as distinctive, with characteristic isotopic signatures. These analyses indicate that it is not possible to reproduce the observed salinization by evapotranspiration and agricultural processes alone. This investigation further confirms that proper application of multiple isotopic and geochemical tracers can be used to identify and constrain multiple sources of solutes in complex river systems.

Displaced intraarticular fractures of the distal radius.

The treatment of intraarticular fractures of the distal radius has been dramatically altered over the past decade. Investigations into the pathomechanics of these injuries highlight the problems of arthritis, pain, swelling, weakness, limited range of motion and instability associated with nonanatomic reduction of both intraarticular fragments and their associated ligaments. Factors affecting the prognosis for these injuries include degree and location of articular involvement and the energy of the precipitating force as well as the anatomy of reduction. Operative treatment is reserved for displaced intraarticular fractures. Those extremely comminuted fractures are best fixed with distraction and external fixation. The operative approach to these fractures is dependent on the anatomy. Ligamentous instability, in particular with radial styloid fractures, must be sought and treated. Kirschner wires can be used as "joy sticks" to control unstable carpal bones or fracture fragments prior to fixation. Plates and screws are useful in the stabilization of volar and dorsal rim fractures. The use of intraoperative radiographs is emphasized. Postoperative early range of motion, when possible, greatly improves the long-term results.

The isolated digital cord in Dupuytren's contracture: anatomy and clinical significance.

This article describes the isolated occurrence of Dupuytren's pathologic fascial cords within digits of the hand. Thirty-seven cords were found in 32 patients with nearly half (45.6%) occurring in digits other than the small finger. Almost all patients (97.3%) had other clinical evidence of Dupuytren's disease. Cords were either single (83.8%) or double (16.2%) and originated from the periosteum at the base of the proximal phalanx in conjunction with adjacent ligaments and intrinsic tendons. They proceeded in an oblique direction to displace and then cross the neurovascular bundles before inserting on the bone and/or flexor tendon sheath of the middle phalanx. The average loss of extension of the proximal interphalangeal joint that resulted from these cords was 46 degrees, and surgical excision of the involved cords resulted in an average improvement of 24 degrees (53%).