On the origin of finger enslaving: control with referent coordinates and effects of visual feedback.

When a person tries to press with a finger, other fingers of the hand produce force unintentionally. We explored this phenomenon of enslaving during unintentional force drifts in the course of continuous force production by pairs of fingers of a hand. Healthy subjects performed accurate force production tasks by finger pairs Index-Middle, Middle-Ring, and Ring-Little with continuous visual feedback on the combined force of the instructed (master) fingers or of the noninstructed (enslaved) fingers. The feedback scale was adjusted to ensure that the subjects did not know the difference between these two, randomly presented, conditions. Across all finger pairs, enslaved force showed a drift upward under feedback on the master finger force, and master force showed a drift downward under feedback on the enslaved finger force. The subjects were unaware of the force drifts, which could reach over 50% of the initial force magnitude over 15 s. Across all conditions, the index of enslaving increased by ∼50% over the trial duration. The initial moment of force magnitude in pronation-supination was not a consistent predictor of the force drift magnitude. These results falsify the hypothesis that the counter-directional force drifts reflected drifts in the moment of force. They suggest that during continuous force production, enslaving increases with time, possibly due to the spread of excitation over cortical finger representations or other mechanisms, such as increased synchronization of firing of α-motoneurons innervating different compartments of extrinsic flexors. These changes in enslaving, interpreted at the level of control with referent coordinates for the fingers, can contribute to a variety of phenomena, including unintentional force drifts.NEW & NOTEWORTHY We report a consistent slow increase in finger enslaving (force production by noninstructed fingers) when visual feedback was presented on the force produced by either two instructed fingers or two noninstructed fingers of the hand. In contrast, force drifts could be in opposite directions depending on the visual feedback. We interpret enslaving and its drifts at the level of control with referent coordinates for the involved muscles, possibly reflecting spread of cortical excitation.

Which prediction models best identify additional axillary disease after a positive sentinel node biopsy for breast cancer?

To determine which web-based model best identifies women at low risk of further axillary disease after a positive sentinel lymph node (SLN+) biopsy. 673 women with T1-2cN0M0 SNB+ breast cancer who underwent completion axillary dissection (AxD) were identified. A subgroup not eligible to avoid AxD as part of the Z0011 study was defined (Z0011 exclusion group). Predicted risk of further axillary disease was generated using seven web-based models. "Low risk" was defined as a ≤10% risk of further axillary disease. False negative ("low risk" prediction but AxD+) rates (FNRs), area under the receiver operating characteristic curve (AUC), and Brier score were determined for each model. 6 of 7 models identified "low risk" patients but FNRs ranged from 14 to 30%. The Stanford and Memorial Sloan-Kettering (MSKCC) models had the best FNRs. FNRs were lower with SLN micrometastasis (7-15%) and higher in the Z0011 exclusion group (21-41%). All models under-predicted further nodal disease in low risk patients and over-predicted in higher-risk patients. The Stanford and MSKCC models were able to identify women with SLN micrometastasis with a ≤10% FNR. Models were not able to accurately identify low risk women from a cohort that would have been excluded from Z0011.

Limited M1 disease: a significant prognostic factor for stage IV breast cancer.

PURPOSE: The prognosis of patients with breast cancer presenting with distant metastasis can vary depending on disease extent. This study evaluates a definition of limited M1 disease in association with survival in a cohort of women presenting with metastatic breast cancer. METHODS: The study cohort comprised 692 women referred to the BC Cancer Agency between 1996 and 2005 with M1 breast cancer at presentation. Limited M1 disease was defined as <5 metastatic lesions confined to one anatomic subsite. Extensive M1 disease was defined as ≥ 5 lesions or disease in more than one subsite. Clinicopathologic and treatment characteristics and overall survival (OS) were compared between subjects with limited (n = 233) versus extensive (n = 459) M1 disease. Multivariable analysis was performed by Cox regression modeling. RESULTS: Median follow-up time was 1.9 years. Five-year Kaplan-Meier OS was significantly higher in patients with limited compared to extensive M1 disease (29.7 vs. 13.1 %, p < 0.001). In the multivariable Cox regression analysis, limited M1 disease was significantly associated with OS (hazard ratio 0.51, 95 % confidence interval 0.40-0.66, p < 0.001). The only patient subsets with limited M1 disease with poor 5-year OS <15 % were patients with Eastern Cooperative Oncology Group performance status of ≥ 2 or estrogen receptor-negative status. CONCLUSIONS: Limited M1 disease, defined as <5 metastatic lesions confined to one anatomic subsite, is a relevant favorable prognostic factor in patients with stage IV breast cancer. This definition may be used in conjunction with other clinicopathologic factors to select patients for more aggressive systemic and locoregional treatments.

Finger interdependence and unintentional force drifts: Lessons from manipulations of visual feedback.

We explored the phenomenon of unintentional finger force drift by using visual feedback on the force produced either by explicitly instructed (master) finger pairs or by non-instructed (enslaved) finger pairs. In particular, we drew contrasting predictions from two hypotheses: that force drifts represented consequences of drifts in effector referent coordinates at the level of individual fingers vs. at the level of finger modes (hypothetical variables accounting for the finger force interdependence). Subjects performed accurate force production with two fingers of a hand, index-ring or middle-little. They received visual feedback on the force produced either by the master fingers or by the other two, enslaved, fingers. The feedback scale was adjusted to ensure that the subjects did not know the difference between these two, randomly presented, conditions. Under feedback on the master finger force, enslaved force showed a consistent drift upward. Under feedback on the enslaved finger force, master force showed a consistent drift downward. The subjects were unaware of the force drifts, which could reach over 35% of the initial force magnitude. The data support the hypothesis on drifts in the referent coordinate at the level of individual digits, not finger modes, as the origin of unintentional force drifts. The consistent increase in the relative amount of force produced by the enslaved fingers suggests that the commonly used methods to quantify enslaving should include relatively brief force production tasks.

Fingerprints of CD8+ T cells on human pre-plasma and memory B cells.

Differentiation of B cells is a stringently controlled multi-step process, which is still incompletely understood. Here we identify and characterize a rare population of human B cells, which surprisingly carry CD8AB on their surface. Existence of such cells was demonstrated both in tonsils and in human apheresis material. Gene expression profiling and real time PCR detected however no CD8A or CD8B message in these cells. Instead, we found that surface CD8 was hijacked from activated CD8+ T cells by a transfer process that required direct cell-to-cell contact. A focused transcriptome analysis at single cell level allowed the dissection of the CD8 positive B cell population. We found that the affected cells are characteristically of the CD27+CD200- phenotype, and consist of two discrete late-stage subpopulations that carry signatures of activated memory B like cells, and early plasmablasts. Thus, there is only a restricted time window in the differentiation process during which B cells can intimately interact with CD8+ T cells. The findings point to a novel link between the T and B arms of the adaptive immune system, and suggest that CD8+ T cells have the capability to directly shape the global antibody repertoire.

Stage IIIC Endometrial Cancer: Relapse and Survival Outcomes in Women Treated With Pelvic or Extended Field Para-Aortic Nodal Radiation Therapy.

PURPOSE: The optimal radiation (RT) volume for node-positive endometrial cancer is controversial. This study evaluates clinical outcomes in patients with stage IIIC, N1 endometrial cancer who received RT to the pelvis (PV RT) or pelvis plus para-aortic nodes (PV-PAN RT). METHODS: Overall, there were 89 women with stage IIIC endometrial cancer. Of these, 57 women had N1-only disease, forming the study cohort. Clinicopathologic characteristics, recurrence rates, endometrial cancer-specific survival (ECSS), and overall survival (OS) were examined among patients treated with pelvic RT (n=23) compared with pelvic plus para-aortic RT (n=34). Multivariable analysis of ECSS and OS was performed using Cox regression modeling. RESULTS: Median follow-up was 5.1 years. Adjuvant chemotherapy was used in 51/57 (89%) of N1 cases. Women with N1 disease who received PV-PAN RT compared with PV RT experienced lower recurrence (26% vs. 52%, P=0.06) and higher survival rates (5 y ECSS 81.5% vs. 47.0%, P=0.04 and OS 79.1% vs. 47.0%, P=0.01). On multivariable analysis, RT volume was not significantly associated with OS, whereas chemotherapy was associated with improved ECSS and OS. CONCLUSIONS: RT conferred excellent local control, whereas chemotherapy was associated with improved survival in women with N1 endometrial cancer. Distant relapse remains the most common site of recurrence despite chemotherapy.

Can locoregional treatment of the primary tumor improve outcomes for women with stage IV breast cancer at diagnosis?

PURPOSE: To examine the effect of locoregional treatment (LRT) of the primary tumor on survival in patients with Stage IV breast cancer at diagnosis. METHODS AND MATERIALS: The study cohort comprised 733 women referred to the British Columbia Cancer Agency between 1996 and 2005 with newly diagnosed clinical or pathologic M1 breast cancer. Tumor and treatment characteristics, overall survival (OS), and locoregional progression-free survival were compared between patients treated with (n = 378) and without (n = 355) LRT of the primary disease. Multivariable analysis was performed with Cox regression modeling. RESULTS: The median follow-up time was 1.9 years. LRT consisted of surgery alone in 67% of patients, radiotherapy alone in 22%, and both in 11%. LRT was used more commonly in women with age <50 years, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, Stage T1-2 tumors, N0-1 disease, limited M1 burden, and asymptomatic M1 disease (all p < 0.05). Systemic therapy was used in 92% of patients who underwent LRT and 85% of patients who did not. In patients treated with LRT compared with those without LRT, the 5-year OS rates were 21% vs. 14% (p < 0.001), and the rates of locoregional progression-free survival were 72% vs. 46% (p < 0.001). Among 378 patients treated with LRT, the rates of 5-year OS were higher in patients with age <50, ECOG performance status 0-1, estrogen receptor-positive disease, clear surgical margins, single subsite, bone-only metastasis, and one to four metastatic lesions (all p < 0.003). On multivariable analysis, LRT was associated with improved OS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.94, p = 0.009). CONCLUSION: Locoregional treatment of the primary disease is associated with improved survival in some women with Stage IV breast cancer at diagnosis. Among those treated with LRT, the most favorable rates of survival were observed in subsets with young age, good performance status, estrogen receptor-positive disease, clear margins, and distant disease limited to one subsite, bone-only involvement, or fewer than five metastatic lesions.