N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression.

Our group previously demonstrated that M-protein light chain (LC) glycosylation can be detected on routine MASS-FIX testing. Glycosylation is increased in patients with immunoglobulin LC amyloidosis (AL) and rarely changes over the course of a patient's lifetime. To determine the rates of progression to AL and other plasma cell disorders (PCDs), we used residual serum samples from the Olmsted monoclonal gammopathy of undetermined significance (MGUS) screening cohort. Four-hundred and fourteen patients with known MGUS were tested by MASS-FIX, and 25 (6%) were found to have glycosylated LCs. With a median follow-up of surviving patients of 22.2 years, the 20-year progression rates to a malignant PCD were 67% (95% CI 29%, 84%) and 13% (95% CI 9%, 18%) for patients with and without glycosylated LCs, respectively. The risk of progression was independent of Mayo MGUS risk score. The respective rates of progression to AL at 20 years were 21% (95% CI 0.0%, 38%) and 3% (95% CI 0.6%, 5.5%). In summary, monoclonal LC glycosylation is a potent risk factor for progression to AL, myeloma, and other PCDs, an observation which could lead to earlier diagnoses and potentially reduced morbidity and mortality.

A brief bedside visual art intervention decreases anxiety and improves pain and mood in patients with haematologic malignancies.

Treatment of cancer-related symptoms represents a major challenge for physicians. The purpose of this pilot study was to determine whether a brief bedside visual art intervention (BVAI) facilitated by art educators improves mood, reduces pain and anxiety in patients with haematological malignancies. Thirty-one patients (21 women and 10 men) were invited to participate in a BVAI where the goal of the session was to teach art technique for ~30 min. Primary outcome measures included the change in visual analog scale, the State-Trait Anxiety Inventory and the Positive and Negative Affect Schedule scale, from baseline prior to and immediately post-BVAI. Total of 21 patients (19 women and two men) participated. A significant improvement in positive mood and pain scores (p = .003 and p = .017 respectively) as well as a decrease in negative mood and anxiety (p = .016 and p = .001 respectively) was observed. Patients perceived BVAI as overall positive (95%) and wished to participate in future art-based interventions (85%). This accessible experience, provided by artists within the community, may be considered as an adjunct to conventional treatments in patients with cancer-related mood symptoms and pain, and future studies with balanced gender participation may support the generalisability of these findings.

Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10-49 years old: a population-based study from the National Health and Nutrition Examination Survey.

We studied the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in younger individuals, age 10-49 years, using samples from the National Health and Nutritional Examination Survey (NHANES) III. NHANES prevalence rates were standardized to the 2000 US total population. Among 12 372 individuals (4073 blacks, 4146 Mexican-Americans, 3595 whites, and 558 others), MGUS was identified in 63 persons (0.34%, 95% CI 0.23-0.50). The prevalence of MGUS was significantly higher in blacks (0.88%, 95% CI 0.62-1.26) compared with whites (0.22%, 95% CI 0.11-0.45), P=0.001. The prevalence of MGUS in Mexican-Americans was at an intermediate level (0.41%, 95% CI 0.23-0.73). The disparity in prevalence of MGUS between blacks and whites was most striking in the 40-49 age-group; 3.26% (95% CI 2.04-5.18) versus 0.53% (95% CI 0.20-1.37), P=0.0013. There was a trend to earlier age of onset of MGUS in blacks compared with whites. MGUS was seen in only two persons in the 10-19 age-group (both Mexican-American), and in three persons in the 20-29-year age-group (all of whom were black). In persons less than 50 years of age, MGUS is significantly more prevalent, with up to 10 years earlier age of onset, in blacks compared with whites.

Incidence of symptomatic osteochondritis dissecans lesions of the knee: a population-based study in Olmsted County.

OBJECTIVE: To (1) define population-based incidence of knee Osteochondritis dissecans (OCD) lesions using the population of Olmsted County, (2) examine trends over time, and (3) evaluate rate of surgical management over time. METHOD: Study population included 302 individuals who were diagnosed with knee OCD lesions between January 1, 1976 and December 31, 2014. Complete medical records were reviewed to extract injury and treatment details. Age- and gender-specific incidence rates were calculated and adjusted to the 2010 US population. Poisson regression analyses were performed to examine incidence and surgery trends by age, gender, and calendar period. RESULTS: Overall age- and gender-adjusted incidence annual incidence of knee OCD lesions was 6.09 per 100,000 person-years. The incidence was significantly higher (P < 0.001) in males (8.82, 95% CI 7.63 to 10.00 per 100,000) compared to females (3.32, 95% CI 2.61 to 4.04 per 100,000). Age- and gender-specific incidence was highest in both males and females in the 11-15 years old at 39.06 and 16.15 per 100,000, respectively. In males aged 11-15 years, OCD incidence increased significantly over the study period from 20.68 in 1976-1985 to 48.16 in 2006-2014 (per 100,000). CONCLUSIONS: Overall age- and gender-adjusted annual incidence of knee OCD lesions in the Olmsted Country Population was 6.09 per 100,000 person-years with a significantly higher incidence in males compared to females. The highest incidence for both males and females occurred between the ages 11-15 years. Trends indicate increasing OCD incidence in younger males and decreasing surgical management in females over the last decade.

Fluctuation Analysis: Dissecting Transcriptional Kinetics with Signal Theory.

Recent live-cell microscopy techniques now allow the visualization in multiple colors of RNAs as they are transcribed on genes of interest. Following the number of nascent RNAs over time at a single locus reveals complex fluctuations originating from the underlying transcriptional kinetics. We present here a technique based on concepts from signal theory-called fluctuation analysis-to analyze and interpret multicolor transcriptional time traces and extract the temporal signatures of the underlying mechanisms. The principle is to generate, from the time traces, a set of functions called correlation functions. We explain how to compute these functions practically from a set of experimental traces and how to interpret them through different theoretical and computational means. We also present the major difficulties and pitfalls one might encounter with this technique. This approach is capable of extracting mechanistic information hidden in transcriptional fluctuations at multiple timescales and has broad applications for understanding transcriptional kinetics.

Triceps insufficiency after the treatment of deep infection following total elbow replacement.

Treatment of an infected total elbow replacement (TER) is often successful in eradicating or suppressing the infection. However, the extensor mechanism may be compromised by both the infection and the surgery. The goal of this study was to assess triceps function in patients treated for deep infection complicating a TER. Between 1976 and 2007 a total of 217 TERs in 207 patients were treated for infection of a TER at our institution. Superficial infections and those that underwent resection arthroplasty were excluded, leaving 93 TERs. Triceps function was assessed by examination and a questionnaire. Outcome was measured using the Mayo Elbow Performance Score (MEPS). Triceps weakness was identified in 51 TERs (49 patients, 55%). At a mean follow-up of five years (0.8 to 34), the extensor mechanism was intact in 13 patients, with the remaining 38 having bone or soft-tissue loss. The mean MEPS was 70 points (5 to 100), with a mean functional score of 18 (0 to 25) of a possible 25 points. Infection following TER can often be eradicated; however, triceps weakness occurs in more than half of the patients and may represent a major functional problem.

Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.

Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.

Risk of acute leukemia and myelodysplastic syndromes in patients with monoclonal gammopathy of undetermined significance (MGUS): a population-based study of 17 315 patients.

The purpose of this study was to determine if there is an increased risk of acute leukemia and myelodysplastic syndromes (MDS) in persons with monoclonal gammopathy of undetermined significance (MGUS). We used a large population-based cohort of individuals systematically screened for the presence or absence of MGUS. MGUS status was then linked to the diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and MDS. A total of 17 315 patients age 50 and older (605 MGUS and 16 710 controls) with a cumulative 435 021 person-years of follow-up were studied. MGUS patients had a significantly higher risk of developing MDS compared with controls, hazard ratio 2.4 (95% CI 1.08, 5.32), P=0.031. There was no statistically significant increase in the risk of AML (RR 1.36 P=0.675), and no increased risk of developing ALL.

Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS.

We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain (HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5-3.7; P<0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1-3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.

High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) carries a 50% risk of progression to multiple myeloma (MM) or related malignancy within the first 5 years following diagnosis. The goal of this study was to determine if high levels of circulating plasma cells (PCs) are predictive of SMM transformation within the first 2-3 years from diagnosis. Ninety-one patients diagnosed with SMM at Mayo Clinic from January 1994 through January 2007, who had testing for circulating PCs using an immunofluorescent assay and adequate follow-up to ascertain disease progression, were studied. High level of circulating PCs was defined as absolute peripheral blood PCs >5 × 10(6)/l and/or >5% PCs per 100 cytoplasmic immunoglobulin (Ig)-positive peripheral blood mononuclear cells. Patients with high circulating PCs (14 of 91 patients, 15%) were significantly more likely to progress to active disease within 2 years compared with patients without high circulating PCs, 71% versus 24%, respectively, P=0.001. Corresponding rates for progression within 3 years were 86% versus 34%, respectively, P<0.001. Overall survival (OS) after both SMM diagnosis and MM diagnosis was also significantly different. High levels of circulating PCs identify SMM patients with an elevated risk of progression within the first 2-3 years following diagnosis.

The pattern of the fracture and displacement of the fragments predict the outcome in proximal humeral fractures.

Our aim was to determine the effect of the initial pattern of fracture and the displacement of fragments on the outcome of proximal humeral fractures treated conservatively. We followed 93 consecutive patients prospectively for one year. Final movement and strength were compared with those of the contralateral side. The final American Shoulder and Elbow Society score and the Disabilities of Arm, Shoulder and Hand and Short-Form 36 questionnaires were compared with those provided by the patient on the day of the injury. Radiographs and CT scans with three-dimensional reconstruction were obtained in all patients. The pattern of the fracture and the displacement of individual fragments were analysed and correlated with the final outcome. There were two cases of nonunion and six of avascular necrosis. The majority of the fractures (84 patients; 90%) followed one of the following four patterns: posteromedial (varus) impaction in 50 patients (54%), lateral (valgus) impaction in 13 (14%), isolated greater tuberosity in 15 (16%), and anteromedial impaction fracture in six (6%). Head orientation, impaction of the surgical neck and displacement of the tuberosity correlated strongly with the outcome. In fractures with posteromedial impaction, a poor outcome was noted as the articular surface displaced inferiorly increasing its distance from the acromion. A poorer outcome was noted as a fractured greater tuberosity displaced medially overlapping with the posterior articular surface. Lateral impaction fractures had a worse outcome than other patterns of fracture.

Quality of life after coloanal anastomosis and abdominoperineal resection for distal rectal cancers: sphincter preservation vs quality of life.

AIM: A permanent colostomy is considered to have an adverse impact on quality of life (QOL). However, functional outcomes following sphincter preservation also affect QOL. Our aim was to determine differences in QOL of patients undergoing coloanal anastomosis (CAA) or abdominoperineal resection (APR) for distal rectal cancer. METHOD: Eighty-five patients underwent CAA (72 with intestinal continuity and 13 with a stoma because of complications) and 83 patients underwent APR for a distal rectal cancer between 1995 and 2001 at a single institution and responded to our survey. QOL was evaluated using the EORTC QLQ-C30 and QLQ-CR38. RESULTS: Patients with CAA were younger than APR patients (mean age 57 vs 62 years, P < 0.001), but gender distribution, tumour stage and proportion of subjects receiving radiotherapy was not significantly different. Patients undergoing CAA had higher scores (better QOL) for physical functioning; lower scores (fewer symptoms) for fatigue, pain, financial difficulties, weight loss and chemotherapy side effects; and higher scores (more symptoms) for constipation and gastrointestinal symptoms compared with APR patients. CAA patients had higher scores (better QOL) for body image in men but not in women. Sexual functioning scores in men and women were lower (worse QOL) in CAA patients compared with APR patients. CONCLUSIONS: QOL after APR is comparable to sphincter preservation, although there are some differences that need to be considered. QOL and functional results should be taken into account with the oncological outcome when devising management strategy for distal rectal cancer.

Laparoscopic surgery for rectal cancer: short-term benefits and oncologic outcomes using more than one technique.

BACKGROUND: Several minimally invasive techniques have now been described for rectal cancer resection. Current outcome data for these approaches from high volume, single institutions remain limited. Our aim was to review outcomes in patients undergoing minimally invasive surgery for rectal cancer at our institution in the current era. METHODS: A retrospective analysis was done to assess short-term benefits and oncologic outcomes in patients undergoing minimally invasive surgery for rectal cancer between 2004 and 2007. RESULTS: One-hundred consecutive patients (61 men, median age 62) with a median follow-up of 1.8 years were identified. Sixty-seven had hand-assisted laparoscopic surgery (HALS), while 33 were done laparoscopic-assisted (LA). Seventy-two patients underwent anterior resection, 27 an abdominal perineal resection, and 1 a total proctocolectomy. Tumor stage was stage 1 (21%), stage 2 (17%), stage 3 (56%), and stage 4 (6%). A median of 16 lymph nodes, a median 3.4 cm distal margin, and a 99% negative circumferential margin was achieved. The 3-year disease-free and overall survivals were 86.2 and 94.5%, respectively. Three cases required conversion. Median time to both diet and first bowel movement was 3 days, and median length of stay was 5 days. Length of stay, time to soft diet, incision length, and pain scores were less using a LA approach compared to HALS (P < 0.01). Overall morbidity was 26% with no mortality. CONCLUSION: Both minimally invasive techniques used achieved excellent oncologic results in patients with rectal cancer. The LA approach had slightly better short-term outcomes.

Nuclear physics: quantitative single-cell approaches to nuclear organization and gene expression.

The internal workings of the nucleus remain a mystery. A list of component parts exists, and in many cases their functional roles are known for events such as transcription, RNA processing, or nuclear export. Some of these components exhibit structural features in the nucleus, regions of concentration or bodies that have given rise to the concept of functional compartmentalization--that there are underlying organizational principles to be described. In contrast, a picture is emerging in which transcription appears to drive the assembly of the functional components required for gene expression, drawing from pools of excess factors. Unifying this seemingly dual nature requires a more rigorous approach, one in which components are tracked in time and space and correlated with onset of specific nuclear functions. In this chapter, we anticipate tools that will address these questions and provide the missing kinetics of nuclear function. These tools are based on analyzing the fluctuations inherent in the weak signals of endogenous nuclear processes and determining values for them. In this way, it will be possible eventually to provide a computational model describing the functional relationships of essential components.

Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system.

To determine if the serum free light chain (FLC) ratio has prognostic value in patients with symptomatic multiple myeloma (MM), baseline serum samples from a well-characterized cohort of 790 newly diagnosed MM patients were tested with the FLC assay. FLC ratio was calculated as kappa/lambda (reference range 0.26-1.65). On the basis of the distribution of values, a cutpoint kappa/lambda FLC ratio of <0.03 or >32 was chosen for further analysis. Overall survival was significantly inferior in patients with an abnormal FLC ratio of <0.03 or >32 (n=479) compared with those with an FLC ratio between 0.03 and 32 (n=311), with median survival of 30 versus 39 months, respectively. We incorporated abnormal FLC ratio with the International Staging System (ISS) risk factors (that is, albumin <3.5 g/dl and serum beta(2)-microglobulin >or=3.5 g/l), to create a risk stratification model with improved prognostic capabilities. Patients with 0, 1, 2 or 3 adverse risk factors had significantly different overall survival, with median survival times of 51, 39, 30 and 22 months, respectively (P<0.001). These findings suggest that the serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma, and can be incorporated into the ISS for improved risk stratification.

Ivor Lewis approach is superior to transhiatal approach in retrieval of lymph nodes at esophagectomy.

Lymph node involvement may impact postoperative therapeutic decision-making and prognosis in patients undergoing esophagectomy. This study evaluates which surgical approach yields the most lymph nodes. We undertook a retrospective chart review of esophagectomies performed by six surgeons from April 1994 to February 2004 using a prospective general thoracic surgery database at Mayo Clinic, Rochester, Minnesota, US. Lymph nodes were categorized into one of 17 regions per the American Joint Committee on Cancer, with the total number of lymph nodes, summed over each region, used as the primary outcome. A total of 517 esophagectomies were performed: 68 transhiatal, 392 Ivor Lewis, and 57 extended Ivor Lewis. A mean of 18.7 (SD 8.5) lymph nodes were retrieved with the Ivor Lewis approach as compared to 17.4 (SD 9.2) with the extended Ivor Lewis approach (P = 0.30). Since there was no statistical difference between the number of nodes collected in either Ivor Lewis approach, they were collapsed into one group for comparison with the transhiatal cases. Significantly more lymph nodes were collected with an Ivor Lewis approach (mean 18.5, SD 8.6) than with a transhiatal approach (mean 9.0, SD 5.0, P < 0.001). As expected, more thoracic lymph nodes were retrieved with the Ivor Lewis approach [mean 12.4 (SD 7.0) vs. 4.7 (SD 5.3), P < 0.001]. The Ivor Lewis approach was also superior for retrieval of abdominal nodes [mean 6.1 (SD 5.6) versus 4.3 (SD 4.4), P = 0.01]. More lymph nodes are obtained at esophagectomy with an Ivor Lewis than a transhiatal approach.

Postoperative hematoma following inguinal herniorrhaphy: patient characteristics leading to increased risk.

BACKGROUND: Although relatively infrequent, groin hematoma following inguinal herniorrhaphy is a morbid complication with major ramifications of mesh infection and hernia recurrence. We have sensed an increasing frequency of this complication in our tertiary referral practice and sought to determine whether or not significant risk factors could be identified. METHODS: In this matched case-control study (1995-2003), we identified 53 patients with groin hematomas and paired them with 106 age- and gender-matched controls. Patient and procedure characteristics were analyzed using chi-square and both univariate and multivariable, conditional logistic regression analysis. RESULTS: The 53 patients developing groin hematoma following inguinal hernia repair (mean age=65, range 22-87, 90% male) were well matched with 106 controls (mean age=65, range 22-87, 90% male). There was no significant difference in the location (left, right, bilateral), type (direct, indirect, pantaloon, first repair, or recurrent), or technique of hernia repair (Bassini, Lichtenstein, mesh plug, endoscopic, or McVay) between groups. While univariate analysis identified Coumadin usage (P<0.001, hazard ratio 19.1), valvular disease (P<0.001, hazard ratio 10.9), atrial fibrillation (P=0.02, hazard ratio 4.2), vascular disease (P=0.04, hazard ratio 2.2), blood abnormalities (P=0.02, hazard ratio 3.2), and previous bleeding episodes (P=0.02, hazard ratio 4.9) as significant factors, only preoperative Coumadin usage was important in multivariate analysis. CONCLUSION: The crucial risk factor for groin hematoma developing in patients undergoing inguinal hernia repair is preoperative need for Coumadin therapy. Although the perioperative management of anticoagulation in patients undergoing inguinal herniorrhaphy is not clearly defined, meticulous management of patients requiring Coumadin therapy seems prudent.

Results at up to 20 years after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Ileal pouch-anal anastomosis (IPAA) is performed routinely for chronic ulcerative colitis. METHODS: Using data from a prospective database and annual standardized questionnaires, functional outcome, complications and quality of life (QoL) after IPAA were assessed. RESULTS: Some 1885 IPAA operations were performed for chronic ulcerative colitis over a 20-year period (mean follow-up 11 years). The mean age at the time of IPAA was 34.1 years, increasing from 31.2 years (1981-1985) to 36.3 years (1996-2000). The overall rate of pouch success at 5, 10, 15 and 20 years was 96.3, 93.3, 92.4 and 92.1 per cent respectively. Mean daytime stool frequency increased from 5.7 at 1 year to 6.4 at 20 years (P < 0.001), and also increased at night (from 1.5 to 2.0; P < 0.001). The incidence of frequent daytime faecal incontinence increased from 5 to 11 per cent during the day (P < 0.001) and from 12 to 21 per cent at night (P < 0.001). QoL remained unchanged and 92 per cent remained in the same employment. Seventy-six patients were eventually diagnosed with indeterminate colitis and 47 with Crohn's disease. CONCLUSION: IPAA is a reliable surgical procedure for patients requiring proctocolectomy for chronic ulcerative colitis and indeterminate colitis. The clinical and functional outcomes are excellent and stable for 20 years after operation.

The "Median" Method for the Reduction of Noise and Trigger Jitter on Waveform Data.

The "median" method for the reduction of the effect of noise and trigger jitter on waveform data is described. The effectiveness of this method was examined using simulations and experiments and, for typical jitter and noise observed in electrical pulse metrology, is shown to provide reconstructed waveforms with transition durations that accurately match those of the input signal. Also, for aberrations, an upper bound on the error in the amplitude of the aberration is provided.