Comparison of PD-L1 (22C3) Expression in Paired Primary and Metastatic Breast Carcinoma.

INTRODUCTION: PD-L1 immunohistochemistry (IHC) is being used as a predictive marker of the benefit derived from immunotherapy in several cancer types, including breast cancer. However, the insight gleaned of the prognostic and predictive value of PD-L1 status and its correlation with molecular characteristics during breast cancer progression remains limited. METHODS: We performed an PD-L1 (22C3) assay in pre-treatment primary and metastatic tumor sections from 33 patients with breast carcinoma, matched for post neoadjuvant chemotherapy (p-NACT). PD-L1 expression was evaluated using 3 scoring methods: immune cell (IC) and tumor cell (TC) with a 1% as the cutoff value, and combined positive scores (CPS) with a 1 as the cutoff value. Twenty-two samples from 11 patients had successful fluorescence in situ hybridization (FISH)-based molecular data available for analysis. RESULTS: In the 33 pre-treatment primary tumors, PD-L1 IC, TC, and CPS showed positive correlation with stromal tumor infiltrate lymphocytes (sTIL), histological grade 3, and triple negative breast carcinoma (TNBC). In the matched metastatic tumors, only PD-L1 IC showed a positive correlation with sTIL. The primary tumors showed a higher PD-L1 expression than the matched metastatic tumors by IC and CPS. Negative to positive conversion by CPS was identified in the metastatic tumors from lung, pleura and liver. p-NACT tumors also showed a trend of lower PD-L1 expression compared to the pre-treatment tumors. Six patients had matched samples for molecular and PD-L1 comparison, and none of them showed consistent gene alterations or PD-L1 expression among the primary, p-NACT and metastatic tumors. CONCLUSION: Our study showed a decrease in PD-L1 expression and disconnected molecular features during breast cancer progression. Repeating PD-L1 IHC testing could be considered in some specific metastatic sites if primary tumors were negative. Further studies are needed to identify other predictive factors for immune checkpoint inhibitor (ICI) therapy in patients with breast carcinoma.

Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content.

1. The oral sedative potencies of cannabis herb, crude ethanolic and petroleum-ether fractions, were assayed against delta'-trans-tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h. 2. The THC contents of the extracts were determined chemically by gas-liquid chromatography analysis and the B/C ratio (biological activity divided by chemical activity) calculated for each. The B/C values for cannabis herb, which contained THC but no CBD, was 4.47 and for ethanolic and petroleum-ether extracts, 5.26 and 4.39, respectively. 3. The sedative potency expressed as SDA50, the dose required to give 50% effect over 6 h, was 1.06 (0.98 to 1.15) mg/kg for THC; 4.72 (4.22 to 5.27) mg/kg for cannabidiol and 1.26 (1.22 to 1.80) mg/kg for chlorpromazine. 4. An infusion of cannabis herb made with boiling water was shown to have sedative activity of very low potency. 5. When the cannabinoids were completely extracted from a sample of herb with petroleum-ether the aqueous and ethanolic extracts of the marc had some sedative activity; but the 70% ethanolic fraction had none. 6. The sedative activity of THC, cannabis herb and a water soluble fraction is blocked by aspirin, a cyclo-oxygenase inhibitor, and restored by prostaglandin E2 (PGE2). 7. The sedative effect of chlorpromazine is not blocked by aspirin.

The effect of conditions influencing endogenous prostaglandins on the activity of delta'-tetrahydrocannabinol in mice.

1 The cataleptic effect of delta'-tetrahydrocannabinol (THC) depends upon the availability of the precursors of prostaglandins and the response is reduced in mice maintained on a diet deficient in arachidonic acid (AA) and restored by exogenous AA given intraperitoneally, or by feeding a normal diet. 2 In yeast-induced fever, which is accompanied by an increase in the synthesis of prostaglandins, THC shows an enhanced cataleptic effect. 3 Exposure to cold which results in depletion of prostaglandins reduces the effect of THC.

The oral activity of delta'-tetrahydrocannabinol and its dependence on prostaglandin E2.

1 delta'-trans-Tetrahydrocannabinol (THC) is more active orally in mice than previously thought, as cataleptic responses occur at doses from 0.06 mg/kg upwards, with peak activity at 2 to 4 h after dosing. These doses and peaks correspond well with the effects in man. 2 Comparison with chlorpromazine in mice shows that chlorpromazine and THC are equipotent as cataleptics during the first 2 h after dosing; thereafter the THC activity increases to a peak when it is 5.67 times as active as chlorpromazine. 3 The cataleptic effect of THC is abolished by aspirin, indomethacine, diffunisal and phenylbutazone which inhibit the biosynthesis of prostaglandins and is restored by exogenous prostaglandin E2 (PGE2) but not PGE1 and PGF2 alpha. This suggests that the effect of THC depends upon the presence of PGE2. 4 In contrast, the cataleptic effect of chlorpromazine is not affected by pretreatment with aspirin. 5 THC is very much less active intraperitoneally than orally; our results suggest this is not due to poor absorption or extraction into fat depots. 6 Cannabidiol has no cataleptic effect.

Activity of cannabis in relation to its delta'-trans-tetrahydro-cannabinol content.

1 Conditions have been worked out for a reliable estimation of the cataleptic activity of delta'-trans-tetrahydrocannabinol (THC) after oral administration to mice, using the ring test over a period of 6 h. 2 By this method, the activity of cannabis herb and 5 crude fractions were measured against THC; at the same time the THC contents were determined chemically. 3 The B/C ratio (biological activity divided by chemical assay) was calculated for each. With cannabis herb the value was 3.3 and with extracts prepared with ethanol or 70% ethanol the values ranged from 3.2 to 7.1, indicating that in all samples the activity was much higher than would be expected from their THC content. 4. The cannabinoids were completely extracted from a sample of herb using petroleum spirit and the marc examined for a possible synergist. Surprisingly, it contained a powerful inhibitor of the action of THC, which could be restored by intraperitoneal prostaglandin E2 (3 microgram/kg). Some crude fractions had inhibitory activities about 10 times that of aspirin. 5 In contrast, the petroleum spirit extract (referred to in 4) had a surprisingly high B/C ratio of 23, indicating that a powerful synergist of THC activity is present. 6 The net effect of the herb and ethanol extracts is probably due to a balance of synergist and inhibitor.

Current concepts of the lethal midline granuloma syndrome.

"Lethal midline granuloma" is an unusual but devastating spectrum of lymphoproliferative disorders that is now thought to include four entities: idiopathic midline destructive disease, Wegener's granulomatosis, polymorphic reticulosis, and nasal lymphoma. These disorders must be considered in the differential diagnosis of any patient with chronic, nonspecific complaints localized to the upper airway. An aggressive diagnostic and therapeutic approach may significantly decrease morbidity and death resulting from these lesions.

Sleep apnea in mandibular hypoplasia.

Obstructive sleep apnea is an insidious and potentially life-threatening disorder that is probably more prevalent than has been previously diagnosed. Since there is generally some mechanism for relief of the respiratory obstruction, this is a very successfully treatable disorder. A strong index of suspicion should be held in cases of oronasal or pharyngeal abnormalities with a potential for respiratory obstruction. Loud snoring (particularly a recent change) and daytime hypersomnolence should alert us. In-hospital sleep monitoring and arterial gas measurements can provide a definitive diagnosis.

Music shifts frontal EEG in depressed adolescents.

Recent studies have found that positive affect is associated with greater relative left frontal EEG activation and negative affect is associated with greater relative right frontal EEG activation. Further, chronically depressed adults typically display stable right frontal EEG activation. The present study investigated the effects of music on mood state and right frontal EEG activation associated with chronic depression. Fourteen chronically depressed female adolescents listened to rock music for a 23-minute session. These adolescents were compared with a control sample of chronically depressed female adolescents who were simply asked to sit and relax their minds and their muscles for the same time period. EEG was recorded during baseline, music, and postmusic for three minutes each, and saliva samples were collected before and after the session to determine the effects of the music on stress hormone (cortisol) levels. No group differences or changes were noted for observed or reported mood state. However, cortisol levels decreased and relative right frontal activation was significantly attenuated during and after the music procedure. It was concluded that music had positive effects on the physiological and biochemical measures even though observed and self-reported mood did not change.

Targeting adolescent mothers with depressive symptoms for early intervention.

Infants of mothers with depressive symptoms show developmental delays if symptoms persist over the first 6 months of the infant's life, thus highlighting the importance of identifying those mothers for early intervention. In Study 1, mothers with depressive symptoms (n = 160) and mothers without depressive symptoms (n = 100) and their infants were monitored to identify variables from the first 3 months that predict which mothers would still be symptomatic at 6 months. A "dysregulation" profile was noted for the infants of depressed mothers, including lower Brazelton scores, more indeterminate sleep, and elevated norepinephrine, epinephrine, and dopamine levels at the neonatal period, and greater right frontal EEG activation, lower vagal tone, and negative interactions at the 3- and 6-month periods. A group of maternal variables from the neonatal and 3-month assessments accounted for 51% of the variance in the mothers' continuing depressive symptoms. These variables included greater right frontal EEG activation, lower vagal tone, and less positive interactions at 3 months, and elevated norepinephrine, serotonin, and cortisol levels at the neonatal stage. In Study 2, a similar sample of mothers with depressive symptoms (n = 160) and without depressive symptoms (n = 100) was recruited and followed to 3 months. Those symptomatic mothers who had values above (or below) the median (depending on the negative direction) on the predictor variables identified in Study 1 (taken from the first 3 months) were then randomly assigned to an intervention or a control group at 3 months. These groups were then compared with each other, as well as with the group without depressive symptoms, at 6 and 12 months. The intervention, conducted from 3 to 6 months, consisted of free day care for the infants and a rehab program (social, educational, and vocational) plus several mood induction interventions for the mothers, including relaxation therapy, music mood induction, massage therapy, and mother-infant interaction coaching. Although the mothers who received the intervention continued to have more depressive symptoms than did the nondepressed mothers, their interactions significantly improved and their biochemical values and vagal tone normalized. Their infants also showed more positive interations, better growth, fewer pediatric complications, and normalized biochemical values, and by 12 months their mental and motor scores were better than those of the infants in the control group.

Polydrug-using adolescent mothers and their infants receiving early intervention.

This study investigated the effects of an intervention for polydrug-using adolescent mothers. The program included educational, vocational, and parenting classes; social and drug rehab; and day care for their infants while they attended school half-day. The drug-exposed infants were similar to the nonexposed infants on traditional birth measures, although they had inferior Brazelton Neonatal Behavioral Assessment Scale scores, including habituation, orientation, abnormal reflexes, general irritability, and regulatory capacity. The drug-exposed infants also spent less time in quiet sleep and more time crying and showing stress behaviors. Both the mothers and the infants in the drug groups demonstrated inferior interactions, and their dopamine and serotonin levels were significantly higher. As early as 3 months (following 3 months of intervention), the drug rehab mothers and their infants looked more like the nondrug group in their interactions; by 6 months, they looked similar on virtually every measure. At 12 months, the infants of drug rehab mothers (versus the drug control group) had superior Early Social Communication Scale scores and Bayley Mental scale scores, as well as significantly greater head circumference and fewer pediatric complications. The drug rehab mothers also improved on several lifestyle variables. They demonstrated a lower incidence of continued drug use and repeat pregnancy, and a greater number continued school, received a high school or general equivalency diploma, or were placed in a job. Thus, a relatively cost-effective high school based intervention had positive effects on both adolescent mothers who had used drugs and their infants.

PIP: The impact of an early childhood intervention program on polydrug-abusing US adolescent mothers and their infants was evaluated. The program, which was located in a vocational school attended by the mothers, included drug rehabilitation, social skills training, parenting classes, job training, and relaxation therapy. Outcomes in 126 drug-exposed mothers 16-21 years of age who participated in the program were compared to those recorded among non-drug-using adolescent mothers who participated in the program and drug-using control mothers who did not participate. All three groups were similar in terms of age, education, socioeconomic status, and ethnicity, but drug-abusing mothers had higher rates of depression and stress. At baseline, drug-exposed infants had lower scores on the measures of habituation, orientation, abnormal reflexes, general irritability, and regulatory capacity on the Neonatal Behavioral Assessment Scale. Drug-exposed infants spent less time sleeping and more time crying and showing stress behaviors. The drug groups also had lower Optimal Interaction Rating Scale scores for both mothers and infants. Their dopamine and serotonin levels were higher than those recorded among non-drug-using mothers and their cortisol levels were lower. However, after 6 months of participation in the intervention program, the drug-using mothers had Beck Depression Inventory scores and interaction ratings that approached those of non-drug-using mothers and exceeded those among drug-using controls. Similar trends were observed for infants' head circumference and scores on the Early Social Communication Scale and the Bayley Mental Status Scale. Moreover, drug-using adolescent mothers who participated in the program demonstrated a lower incidence of repeat pregnancy and continued drug use than those who were not enrolled in the program; moreover, they were more likely to receive their high school diploma and be placed in jobs. Interventions such as this have the potential to attenuate the developmental delays of infants of drug-exposed adolescents.

Living with serious mental illness: the desire for normalcy.

This article describes the desire for normalcy as experienced by 6 men and 13 women with serious mental illness based on secondary analysis of data from two previous qualitative studies. Original data were collected by structured and semi-structured interviews, and thematic analysis was done. Major categories of desire for normalcy are having normal things and experiences; doing meaningful activities; and being well, safe, free, and independent. Self-care actions to promote and maintain normalcy are identified, and finding are discussed in relation to Orem's self-care deficit theory of nursing. Implications for nursing theory, research, and practice are addressed.

Formal and informal care of people with psychiatric disorders: historical perspectives and current trends.

People with severe and persistent mental illness have a broad array of needs related to health and well being. In the present era of shrinking health care resources and managed care, it is not likely that the formal health care system can or will be sufficiently responsive to the needs of this population. To address adequately the care and treatment of individuals with serious mental illness, it is essential to identify and use all available resources, both in the formal health care system and within informal systems of care.

Social networks for women with serious mental illness.

Assessment of ways to work with situations as they exist, and capitalizing on positive factors or strengths within the client's life context, may enhance the nurse-client relationship, and the likelihood of positive outcomes. It is important to identify "natural helpers" and "natural community resources," such as churches and adult centers within the community and to assess the actual and potential contributions and needs of these resources.