Citations

Abstract “I have noticed in operations of this kind, which I have seen performed by others upon the living, and in a number of excisions, which I have myself performed on the dead body, that most of the difficulty in the separation of the tumor has occurred in the region of these ligaments…. This difficulty, I believe, to be a very frequent source of that accident, which so commonly occurs in removal of goiter, I mean division of the recurrent laryngeal nerve.” Sir James Berry (1887)

Abstract BACKGROUND: Arm morbidity, the most reported comorbidity following axillary surgery for breast cancer, is of particular importance in young patients given the longer survivorship period and detrimental effects of arm-morbidity on body image and social-, home- and personal care functions. We assessed the incidence of arm-morbidity stratified by local therapy strategies in young women enrolled in the Young Women's Breast Cancer Study (YWS). PATIENTS AND METHODS: The YWS, a multicenter prospective cohort study, established to explore biological, medical and psychosocial issues in young breast cancer patients, enrolled 1302 women with stage 0-4 breast cancer ≤40 years of age from October 2006 to June 2016. For this analysis, we examined incidence of patient reported arm-swelling or decreased range of motion (ROM) 1-year after diagnosis using relevant items of the CARES-SF. Patients with stage 4 disease (n = 60), those for whom no information on arm-morbidity was available (n=198) and those with bilateral cancer with different local therapy strategies on each side (n=7), were excluded. We performed logistic regression analyses to identify risk factors for arm morbidity. RESULTS: Among 1037 patients (median age 37 years), 13% and 40% reported arm-swelling or decreased ROM, respectively, in the ipsilateral arm at 1-year. 52% (n=539) of patients underwent SLNB and 39% (n=407) ALND. The incidence of arm-swelling was 4% (11/280) in patients who underwent SLNB without RT, 8% (21/252) in patients who underwent SLNB with RT, 20% (13/66) in patients who underwent ALND without RT and 24% (84/337) in patients who received ALND with RT. The incidence of decreased ROM was 21% (59) in patients who underwent SLNB without RT, 34% (86) in patients who underwent SLNB with RT, 33% (22) in patients who underwent ALND without RT and 44% (148) in patients who received ALND with RT. Being overweight, uncomfortable financial status, T4 tumors, ALND and RT were independently associated with an increased risk of arm-swelling. Overweight, mastectomy and RT were independently associated with an increased risk of a decreased ROM Table 1). Results of the logistic regression analyses. Arm swelling at 1 year (n=137)Decreased ROM at 1 year (n=335) ORpORpBMI <18.50.70.620.70.4018.5-24.9ref ref 25-29.91.70.031.50.05≥301.10.791.10.70Financial comfort Comfortableref ref Uncomfortable0.60.020.90.67pT stage pT1ref ref pT21.20.621.50.13pT31.20.701.30.63pT44.40.032.20.29pN stage pN0ref ref pN11.10.851.70.08pN23.00.111.90.27pN33.20.112.70.16Surgery BCSref ref Mastectomy1.20.611.80.02Bilateral mastectomy1.10.841.60.06Axillary surgery SLNBref ref SLNB + ALND3<0.011.30.33ALND3.6<0.011.00.90RT Noref ref Yes1.80.052.4<0.01Note. In these analysis we also corrected for age, incidence year, employment status, stage of disease, reconstructive surgery, and chemotherapy treatment. . CONCLUSION: Patient reported outcomes reveal high rates of arm-swelling and decreased ROM 1 year after breast cancer diagnosis in a large prospective cohort of young breast cancer survivors. These findings suggest an opportunity for pre-operative education and early intervention for arm impairment in this population. Citation Format: Kuijer A, Dominici LS, Rosenberg SM, Hu J, Gelber S, Di Lascio S, Ruddy KJ, Wong J, Tamimi RM, Schapira L, Borges VF, Come SE, Sprunck-Harrild K, Partridge AH, King TA. Risk of arm morbidity after local therapy in young breast cancer survivors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-03.

SEEK and you may find cancer earlier Many cancers can be cured by surgery and/or systemic therapies when detected before they have metastasized. This clinical reality, coupled with the growing appreciation that cancer's rapid genetic evolution limits its response to drugs, have fueled interest in methodologies for earlier detection of the disease. Cohen et al. developed a noninvasive blood test, called CancerSEEK that can detect eight common human cancer types (see the Perspective by Kalinich and Haber). The test assesses eight circulating protein biomarkers and tumor-specific mutations in circulating DNA. In a study of 1000 patients previously diagnosed with cancer and 850 healthy control individuals, CancerSEEK detected cancer with a sensitivity of 69 to 98% (depending on cancer type) and 99% specificity. Science , this issue p. 926 ; see also p. 866

The North American Consortium for the Study of End‐Stage Liver Disease's definition of acute‐on‐chronic liver failure (NACSELD‐ACLF) as two or more extrahepatic organ failures has been proposed as a simple bedside tool to assess the risk of mortality in hospitalized patients with cirrhosis. We validated the NACSELD‐ACLF's ability to predict 30‐day survival (defined as in‐hospital death or hospice discharge) in a separate multicenter prospectively enrolled cohort of both infected and uninfected hospitalized patients with cirrhosis. We used the NACSELD database of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 2,675). The cohort was randomly split 60%/40% into training (n = 1,605) and testing (n = 1,070) groups. Organ failures assessed were (1) shock, (2) hepatic encephalopathy (grade III/IV), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation). Patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 years and a diagnosis of alcohol‐induced cirrhosis (45%), and 1,079 patients had an infection during hospitalization. The mean Model for End‐Stage Liver Disease score was 19, and the median Child score was 10. No demographic differences were present between the two split groups. Multivariable modeling revealed that the NACSELD‐ACLF score, as determined by number of organ failures, was the strongest predictor of decreased survival after controlling for admission age, white blood cell count, serum albumin, Model for End‐Stage Liver Disease score, and presence of infection. The c‐statistics were 0.8073 for the training set and 0.8532 for the validation set. Conclusion: Although infection status remains an important predictor of death, NACSELD‐ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30‐day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (H epatology 2018;67:2367‐2374).

A β-escin-permeabilized canine tracheal smooth muscle preparation was used to test the hypothesis that cGMP decreases Ca2+sensitivity in airway smooth muscle primarily by inhibiting the membrane receptor-coupled mechanisms that regulate Ca2+sensitivity and not by inhibiting Ca2+/calmodulin activation of the contractile proteins. 8-Bromo-cGMP (100 μM) had no effect on the free Ca2+concentration-response curves generated in the absence of muscarinic receptor stimulation. In the presence of 100 μM ACh plus 10 μM GTP, 8-bromo-cGMP (100 μM) caused a rightward shift of the free Ca2+concentration-response curve, significantly increasing the EC50for free Ca2+from 0.35 ± 0.03 to 0.75 ± 0.06 μM; this effect of 8-bromo-cGMP was concentration dependent from 1 to 100 μM. 8-Bromo-cGMP (100 μM) decreased the level of regulatory myosin light chain (rMLC) phosphorylation for a given cytosolic Ca2+concentration but had no effect on the amount of isometric force produced for a given level of rMLC phosphorylation. These findings suggest that cGMP decreases Ca2+sensitivity in canine tracheal smooth muscle primarily by inhibiting the membrane receptor-coupled mechanisms that modulate the relationship between cytosolic Ca2+concentration and rMLC phosphorylation.

The mechanism of the direct relaxing effect of halothane on airway smooth muscle may involve a decrease in 1) cytosolic calcium concentration ([Ca2+]i) and/or 2) the force produced for a given [Ca2+]i (i.e., the “sensitivity” of the myofibrillar contractile system to Ca2+). This study was conducted to test the hypothesis that halothane reduces the sensitivity of the myofibrillar contractile system to Ca2+ during muscarinic receptor stimulation of canine tracheal smooth muscle. Isolated smooth muscle strips were mounted in a photometric superfusion system, stretched to their optimal length for force development, and loaded with the fluorescent Ca2+ indicator, fura 2, for simultaneous recording of fura 2 fluorescence and isometric force. Emission fluorescence intensities due to excitation at 340 (F340)- and 380 (F380)-nm wavelengths were measured and F340/F380 was used as an index of [Ca2+]i. After superfusion with Ca(2+)-free physiological salt solution (PSS) containing 1 or 100 microM acetylcholine (ACh), two consecutive cumulative concentration-response curves to CaCl2 (0.01–2.4 mM) were generated for each strip; one curve was generated in the presence of halothane. In strips stimulated with 1 (n = 6) or 100 (n = 6) microM ACh, the cumulative addition of CaCl2 to the Ca(2+)-free PSS caused concentration-dependent increases in both F340/F380 and force. In strips stimulated with 1 microM ACh, 2.4 +/- 0.3% halothane proportionally attenuated increases in both F340/F380 and force.(ABSTRACT TRUNCATED AT 250 WORDS)

This study used a beta-escin-permeabilized canine tracheal smooth muscle preparation to test the hypothesis that the volatile anesthetic halothane decreases myofilament Ca2+ sensitivity by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity and not by inhibiting Ca(2+)-calmodulin activation of the contractile proteins. Acetylcholine (ACh) caused a GTP-dependent increase in force at constant submaximal cytosolic Ca2+ concentration. ACh, guanosine-5'-O-(3-thiotriphosphate), and the protein kinase C agonist 12,13-phorbol dibutyrate each significantly decreased the concentration of free Ca2+ producing a half-maximal response from 0.77 +/- 0.09 microM (Ca2+ alone) to 0.16 +/- 0.01, 0.19 +/- 0.02, and 0.37 +/- 0.03 microM, respectively, demonstrating an increase in myofilament Ca2+ sensitivity. Halothane (0.92 +/- 0.12 mM) had no effect on the free Ca2+ concentration-response curves generated by Ca2+ alone. However, in the presence of 3 microM ACh plus 10 microM GTP to maximally activate muscarinic receptors, halothane significantly increased the EC50 for free Ca2+ from 0.17 +/- 0.01 microM to 0.38 +/- 0.03 microM. These findings suggest that halothane decreases myofilament Ca2+ sensitivity in beta-escin-permeabilized canine tracheal smooth muscle by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity.