The induction of preterm labor in rhesus macaques is determined by the strength of immune response to intrauterine infection.

Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli. PTL did not occur in LPS challenged rhesus macaques, while E. coli-infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli-infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E. coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.

Teprotumumab for Thyroid Eye Disease-related Strabismus.

PURPOSE: To assess and quantify teprotumumab's effect on thyroid eye disease-related strabismus by change in measured horizontal and vertical deviations and change in extraocular motility. METHODS: We reviewed a series of patients with thyroid eye disease-related strabismus treated with teprotumumab. Exclusion criteria included age under 18 years, strabismus of alternate etiology, or thyroid eye disease-related reconstructive surgery during the treatment course. Primary outcomes were absolute (prism diopters) and relative (%) differences in horizontal and vertical deviations in primary position at distance, as well as change in ductions of the more affected eye. Secondary outcomes included incidence and timing of strabismus surgery postteprotumumab. RESULTS: Thirty-one patients were included, with mean age 63 years and thyroid eye disease duration 10 months. After teprotumumab, there was 6 prism diopters (39%) mean reduction in vertical deviation ( p < 0.001), without significant change in mean horizontal deviation ( p = 0.75). Supraduction, abduction, adduction, and infraduction significantly improved in the more restricted eye ( p < 0.01, p < 0.01, p = 0.04, and p = 0.01, respectively). Thirty-five percent of patients underwent strabismus surgery posttreatment, at an average 10 months after last infusion. CONCLUSIONS: Teprotumumab produced a statistically significant reduction in vertical but not horizontal strabismus angles in primary position at distance. Extraocular motility in all 4 ductions also improved. A substantial minority of patients still required strabismus surgery following teprotumumab.

Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort.

BACKGROUND: The incidence of persistent clinical symptoms and risk factors in Post-Acute Sequelae of SARS-CoV-2 (PASC) in diverse US cohorts is unclear. While there are a disproportionate share of COVID-19 deaths in older patients, ethnic minorities, and socially disadvantaged populations in the USA, little information is available on the association of these factors and PASC. OBJECTIVE: To evaluate the association of demographic and clinical characteristics with development of PASC. DESIGN: Prospective observational cohort of hospitalized and high-risk outpatients, April 2020 to February 2021. PARTICIPANTS: One thousand thirty-eight adults with laboratory-confirmed symptomatic COVID-19 infection. MAIN MEASURES: Development of PASC determined by patient report of persistent symptoms on questionnaires conducted 60 or 90 days after COVID-19 infection or hospital discharge. Demographic and clinical factors associated with PASC. KEY RESULTS: Of 1,038 patients with longitudinal follow-up, 309 patients (29.8%) developed PASC. The most common persistent symptom was fatigue (31.4%) followed by shortness of breath (15.4%) in hospitalized patients and anosmia (15.9%) in outpatients. Hospitalization for COVID-19 (odds ratio [OR] 1.49, 95% [CI] 1.04-2.14), having diabetes (OR, 1.39; 95% CI 1.02-1.88), and higher BMI (OR, 1.02; 95% CI 1-1.04) were independently associated with PASC. Medicaid compared to commercial insurance (OR, 0.49; 95% CI 0.31-0.77) and having had an organ transplant (OR 0.44, 95% CI, 0.26-0.76) were inversely associated with PASC. Age, race/ethnicity, Social Vulnerability Index, and baseline functional status were not associated with developing PASC. CONCLUSIONS: Three in ten survivors with COVID-19 developed a subset of symptoms associated with PASC in our cohort. While ethnic minorities, older age, and social disadvantage are associated with worse acute COVID-19 infection and greater risk of death, our study found no association between these factors and PASC.

Obese- and allergic-related asthma phenotypes among children across the United States.

OBJECTIVES: Pediatric asthma is heterogeneous with phenotypes that reflect differing underlying inflammation and pathophysiology. Little is known about the national prevalence of certain obesity- and allergy-related asthma phenotypes or associated characteristics. We therefore assessed the national prevalence, risk factors, and caregiver-reported severity of four asthma phenotypes: not-allergic-not-obese, allergic-not-obese, obese-not-allergic, and allergic-and-obese. METHODS: We analyzed data from the 2007-2008 National Survey of Children's Health (NSCH) of 10-17 year-olds with caregiver-reported asthma. We described sociodemographic and health risk factors of each phenotype and then applied logistic and ordinal regression models to identify associated risk factors and level of severity of the phenotypes. RESULTS: Among 4427 children with asthma in this NSCH cohort, the association between race and phenotype was statistically significant (p < 0.0001); white children with asthma were most likely to have allergic-not-obese asthma while black and Hispanic children with asthma were most likely to have the obese-nonallergic phenotype (p < 0.001). Attention-deficit disorder/attention-deficit hyperactivity disorder was more likely to be present in allergic-not-obese children (odds ratio (OR) 1.50, confidence interval (CI) 1.14-1.98, p = 0.004). The phenotype with the highest risk for more severe compared to mild asthma was the obese-and-allergic asthma phenotype (OR 3.34, CI 2.23-5.01, p < 0.001). CONCLUSIONS: Allergic-not-obese asthma comprised half of our studied asthma phenotypes, while obesity-related asthma (with or without allergic components) comprised one-fifth of asthma phenotypes in this cohort representative of the US population. Children with both obese and allergic asthma are most likely to have severe asthma. Future management of childhood asthma might consider more tailoring of treatment and management plans based upon different childhood asthma phenotypes.

The Negative Impact of Body Mass Index on the Tumor Microenvironment in Colon Cancer: Results of a Prospective Trial.

BACKGROUND: The association between tumor mismatch repair status and obesity in colon cancer is not well understood. The authors of this study hypothesized that mismatch repair deficiency in colon cancer may be associated with a lower Body Mass Index (BMI) and improved patient outcome due to an enhanced tumor immune microenvironment. METHODS: For this study, 70 patients were randomly selected from a prospective trial evaluating nodal ultrastaging for colon cancer. The mismatch repair status of tumors and immunomarker expression were correlated with clinicopathologic characteristics and evaluated for disease-free survival. RESULTS: Patients with mismatch repair-deficient tumors (n = 11) had a lower mean BMI than those with mismatch repair-proficient tumors (n = 59) (22.16 vs. 26.30 kg/m2, respectively; p = 0.029).The findings showed that CD3+ T cells were inversely associated with mismatch repair proficiency (p = 0.048). Mismatch repair-proficient tumors in nonobese patients (BMI < 30 kg/m2) versus obese patients had a higher density of CD8+ (p = 0.008) and FOXP3+ (p = 0.005) T cells. Multivariable analysis linked CD4+ (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.35-0.76), CD8+ (HR 0.67; 95% CI 0.50-0.89), and number of tumor-positive lymph nodes (HR 1.19; 95% CI 1.03-1.36) to disease-free survival for patients with mismatch repair-proficient tumors. CONCLUSIONS: Tumor mismatch repair status and obesity are correlated in patients with colon cancer. Increased intratumoral T cells in nonobese patients suggests an unexplored link between tumor mismatch repair and immunoprofile.

A quality initiative of postoperative radiographic imaging performed on mastectomy specimens to reduce histology cost and pathology report turnaround time.

Breast pathology relies on gross dissection for accurate diagnostic work, but challenges can necessitate submission of high tissue volumes resulting in excess labor, laboratory costs, and delays. To address these issues, a quality initiative was created through implementation of the Faxitron PathVision specimen radiography system as part of the breast gross dissection protocol; this report documents its impact on workflow and clinical care. Retrospective data from 459 patients who underwent simple or modified radical mastectomy at our institution between May 2012 and December 2014 were collected. Comparison was made between the mastectomy specimen control group before radiography use (233 patients, 340 breasts) and Faxitron group that underwent postoperative radiography (226 patients, 338 breasts). We observed a statistically significant decrease in mean number of blocks between control and Faxitron groups (47.0 vs 39.7 blocks; P<.0001), for calculated cost savings of US $146 per mastectomy. A statistically significant decrease in pathology report turnaround time was also observed (4.2 vs 3.8days; P=.038). Postoperative mastectomy specimen radiography has increased workflow efficiency and decreased histology costs and pathology report turnaround time. These findings may underestimate actual benefits and highlight the importance of quality improvement projects in anatomical pathology.

SNOT-22 subdomain outcomes following treatment for sinonasal malignancy: A prospective, multicenter study.

BACKGROUND: Patients with sinonasal malignancy (SNM) present with significant sinonasal quality of life (QOL) impairment. Global sinonasal QOL as measured by the 22-item Sinonasal Outcomes Test (SNOT-22) has been shown to improve with treatment. This study aims to characterize SNOT-22 subdomain outcomes in SNM. METHODS: Patients diagnosed with SNM were prospectively enrolled in a multi-center patient registry. SNOT-22 scores were collected at the time of diagnosis and through the post-treatment period for up to 5 years. Multivariable regression analysis was used to identify drivers of variation in SNOT-22 subdomains. RESULTS: Note that 234 patients were reviewed, with a mean follow-up of 22 months (3 months-64 months). Rhinologic, psychological, and sleep subdomains significantly improved versus baseline (all p < 0.05). Subanalysis of 40 patients with follow-up at all timepoints showed statistically significant improvement in rhinologic, extra-nasal, psychological, and sleep subdomains, with minimal clinically important difference met between 2 and 5 years in sleep and psychological subdomains. Adjuvant chemoradiation was associated with worse outcomes in rhinologic (adjusted odds ratio (5.22 [1.69-8.66])), extra-nasal (2.21 [0.22-4.17]) and ear/facial (5.53 [2.10-8.91]) subdomains. Pterygopalatine fossa involvement was associated with worse outcomes in rhinologic (3.22 [0.54-5.93]) and ear/facial (2.97 [0.32-5.65]) subdomains. Positive margins (5.74 [2.17-9.29]) and surgical approach-combined versus endoscopic (3.41 [0.78-6.05])-were associated with worse psychological outcomes. Adjuvant radiation (2.28 [0.18-4.40]) was associated with worse sleep outcomes. CONCLUSIONS: Sinonasal QOL improvements associated with treatment of SNM are driven by rhinologic, extra-nasal, psychological, and sleep subdomains.

University of Washington Quality of Life subdomain outcomes after treatment of sinonasal malignancy: A prospective, multicenter study.

PURPOSE: Sinonasal malignancies (SNMs) adversely impact patients' quality of life (QOL) and are frequently identified at an advanced stage. Because these tumors are rare, there are few studies that examine the specific QOL areas that are impacted. This knowledge would help improve the care of these patients. METHODS: In this prospective, multi-institutional study, 273 patients with SNMs who underwent definitive treatment with curative intent were evaluated. We used the University of Washington Quality of Life (UWQOL) instrument over 5 years from diagnosis to identify demographic, treatment, and disease-related factors that influence each of the 12 UWQOL subdomains from baseline to 5 -years post-treatment. RESULTS: Multivariate models found endoscopic resection predicted improved pain (vs. nonsurgical treatment CI 2.4, 19.4, p = 0.01) and appearance versus open (CI 27.0, 35.0, p < 0.001) or combined (CI 10.4, 17.1, p < 0.001). Pterygopalatine fossa involvement predicted worse swallow (CI -10.8, -2.4, p = 0.01) and pain (CI -17.0, -4.0, p < 0.001). Neck dissection predicted worse swallow (CI -14.8, -2.8, p < 0.001), taste (CI -31.7, -1.5, p = 0.02), and salivary symptoms (CI -28.4, -8.6, p < 0.001). Maxillary involvement predicted worse chewing (CI 9.8, 33.2; p < 0.001) and speech (CI -21.8, -5.4, p < 0.001) relative to other sites. Advanced T stage predicted worse anxiety (CI -13.0, -2.0, p = 0.03). CONCLUSIONS: Surgical approach, management of cervical disease, tumor extent, and site of involvement impacted variable UWQOL symptom areas. Endoscopic resection predicted better pain, appearance, and chewing compared with open. These results may aid in counseling patients regarding potential QOL expectations in their SNM treatment and recovery course.

Management of papillary lesions of the breast: can larger core needle biopsy samples identify patients who may avoid surgical excision?

BACKGROUND: The ability to distinguish benign from atypical/malignant papillary lesions on core needle biopsy is limited by the representative nature of the biopsy method, thus follow-up excision is usually recommended. We aimed to determine if larger samples of tissue obtained by core needle biopsy can more reliably predict the true benign nature of a papilloma. METHODS: We reviewed the pathology slides and medical records of 51 patients who were diagnosed with benign papillomas on core needle biopsy from 2000 to 2010, who subsequently underwent surgical excision. The characteristics of the core needle biopsy that were associated with retention of benign histology on excision were determined and analyzed. RESULTS: Atypical ductal hyperplasia and carcinoma were identified in 5.8 % (3/51) and 5.8 % (3/51) of papillary lesions, respectively, when excised. Patients whose lesions were diagnosed as benign on excision were significantly distinguished by the area (mm(2)) of tissue sampled by core needle biopsy (mean ± standard deviation (SD): 101.5 ± 106.5) compared with those with atypia or carcinoma on excision (mean ± SD: 41.7 ± 24.0, P = 0.003). All biopsies performed with 12-gauge or larger needles retained benign features on excision. Core needle biopsy tissue samples consisting of ≥7 cores, or measuring >96 mm(2) in aggregate, had a negative predictive value for atypia/malignancy of 100 %. CONCLUSIONS: Larger tissue samples significantly improved the predictive value of benign histology on core needle biopsy. A papilloma sampled by a 12-gauge or larger needle, ≥7 cores, or >96 mm(2) retained its benign features upon excision.

Perceived Cognitive Deficits in Patients With Symptomatic SARS-CoV-2 and Their Association With Post-COVID-19 Condition.

Importance: Neuropsychiatric symptoms are common in acute SARS-CoV-2 infection and in post-COVID-19 condition (PCC; colloquially known as long COVID), but the association between early presenting neuropsychiatric symptoms and PCC is unknown. Objective: To describe the characteristics of patients with perceived cognitive deficits within the first 4 weeks of SARS-CoV-2 infection and the association of those deficits with PCC symptoms. Design, Setting, and Participants: This prospective cohort study was conducted from April 2020 to February 2021, with follow-up of 60 to 90 days. The cohort consisted of adults enrolled in the University of California, Los Angeles, SARS-CoV-2 Ambulatory Program who had a laboratory-confirmed symptomatic SARS-CoV-2 infection and were either hospitalized in a University of California, Los Angeles, hospital or one of 20 local health care facilities, or were outpatients referred by a primary care clinician. Data analysis was performed from March 2022 to February 2023. Exposure: Laboratory-confirmed SARS-CoV-2 infection. Main Outcomes and Measures: Patients responded to surveys that included questions about perceived cognitive deficits modified from the Perceived Deficits Questionnaire, Fifth Edition, (ie, trouble being organized, trouble concentrating, and forgetfulness) and symptoms of PCC at 30, 60, and 90 days after hospital discharge or initial laboratory-confirmed infection of SARS-CoV-2. Perceived cognitive deficits were scored on a scale from 0 to 4. Development of PCC was determined by patient self-report of persistent symptoms 60 or 90 days after initial SARS-CoV-2 infection or hospital discharge. Results: Of 1296 patients enrolled in the program, 766 (59.1%) (mean [SD] age, 60.0 [16.7] years; 399 men [52.1%]; 317 Hispanic/Latinx patients [41.4%]) completed the perceived cognitive deficit items at 30 days after hospital discharge or outpatient diagnosis. Of the 766 patients, 276 (36.1%) perceived a cognitive deficit, with 164 (21.4%) having a mean score of greater than 0 to 1.5 and 112 patients (14.6 %) having a mean score greater than 1.5. Prior cognitive difficulties (odds ratio [OR], 1.46; 95% CI, 1.16-1.83) and diagnosis of depressive disorder (OR, 1.51; 95% CI, 1.23-1.86) were associated with report of a perceived cognitive deficit. Patients reporting perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection were more likely to report symptoms of PCC than those without perceived cognitive deficits (118 of 276 patients [42.8%] vs 105 of 490 patients [21.4%]; χ21, 38.9; P < .001). Adjusting for demographic and clinical factors, perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 were associated with PCC symptoms (patients with a cognitive deficit score of >0 to 1.5: OR, 2.42; 95% CI, 1.62-3.60; patients with cognitive deficit score >1.5: OR, 2.97; 95% CI, 1.86-4.75) compared to patients who reported no perceived cognitive deficits. Conclusions and Relevance: These findings suggest that patient-reported perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection are associated with PCC symptoms and that there may be an affective component to PCC in some patients. The underlying reasons for PCC merit additional exploration.

Long-term quality of life after treatment in sinonasal malignancy: A prospective, multicenter study.

BACKGROUND: Quality of life (QOL) for individuals with sinonasal malignancy (SNM) is significantly under-studied, yet it is critical for counseling and may impact treatment. In this study we evaluated how patient, treatment, and disease factors impact sinonasal-specific and generalized QOL using validated metrics in a large cohort over a 5-year posttreatment time frame. METHODS: Patients with SNM who underwent definitive treatment with curative intent were enrolled in a prospective, multisite, longitudinal observational study. QOL was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22) and University of Washington Quality of Life Questionnaire (UWQOL) instruments at pretreatment baseline and multiple follow-ups through 5 years posttreatment. Multivariable modeling was used to determine demographic, disease, and treatment factors associated with disease-specific and generalized physical and social/emotional function QOL. RESULTS: One hundred ninety-four patients with SNM were analyzed. All QOL indices were impaired at pretreatment baseline and improved after treatment. SNOT-22 scores improved 3 months and UWQOL scores improved 6 to 9 months posttreatment. Patients who underwent open compared with endoscopic tumor resection had worse generalized QOL (p < 0.001), adjusted for factors including T stage. Pterygopalatine fossa (PPF) involvement was associated with worse QOL (SNOT-22, p < 0.001; UWQOL Physical dimension, p = 0.02). Adjuvant radiation was associated with worse disease-specific QOL (p = 0.03). Neck dissection was associated with worse generalized physical function QOL (p = 0.01). Positive margins were associated with worse generalized social/emotional function QOL (p = 0.01). CONCLUSION: Disease-specific and generalized QOL is impaired at baseline in patients with SNM and improves after treatment. Endoscopic resection is associated with better QOL. PPF involvement, adjuvant radiation, neck dissection, and positive margins were associated with worse QOL posttreatment.

Neonatal Mycoplasma and Ureaplasma Infections.

Mycoplasma species (spp.) can be commensals or opportunistic pathogens of the urogenital tract, and they can be commonly isolated from amniotic fluid, placenta, and fetal/neonatal tissue or blood in mothers delivering prematurely or their preterm infants. Although the presence of Mycoplasma spp. has been associated with adverse maternal-fetal outcomes such as preterm birth and maternal chorioamnionitis, it is less clear whether vertical transmission to the neonate results in colonization or active infection/inflammation. Moreover, the presence of Mycoplasma spp. in neonatal blood, cerebrospinal fluid, or tissue has been variably associated with increased risk of neonatal comorbidities, especially bronchopulmonary dysplasia (BPD). Although the treatment of the mother or neonate with antibiotics is effective in eradicating ureaplasma, it is not clear that the treatment is effective in reducing the incidence of major morbidities of the preterm neonate (eg, BPD). In this article, we review the animal and clinical data for ureaplasma-related complications and treatment strategies. [Pediatr Ann. 2020;49(7):e305-e312.].

Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response.

Most demographic studies are now associating current smoking status with increased risk of severe COVID-19 and mortality from the disease but there remain many questions about how direct cigarette smoke exposure affects SARS-CoV-2 airway cell infection. We directly exposed mucociliary air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term cigarette smoke and infected them with live SARS-CoV-2. We found an increase in the number of infected airway cells after cigarette smoke exposure as well as an increased number of apoptotic cells. Cigarette smoke exposure alone caused airway injury that resulted in an increased number of ABSCs, which proliferate to repair the airway. But we found that acute SARS-CoV-2 infection or the combination of exposure to cigarette smoke and SARS-CoV-2 did not induce ABSC proliferation. We set out to examine the underlying mechanism governing the increased susceptibility of cigarette smoke exposed ALI to SARS-CoV-2 infection. Single cell profiling of the cultures showed that infected airway cells displayed a global reduction in gene expression across all airway cell types. Interestingly, interferon response genes were induced in SARS-CoV-2 infected airway epithelial cells in the ALI cultures but smoking exposure together with SARS-CoV-2 infection reduced the interferon response. Treatment of cigarette smoke-exposed ALI cultures with Interferon ß-1 abrogated the viral infection, suggesting that the lack of interferon response in the cigarette smoke-exposed ALI cultures allows for more severe viral infection and cell death. In summary, our data show that acute smoke exposure allows for more severe proximal airway epithelial disease from SARS-CoV-2 by reducing the mucosal innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to cigarette smoke.

Direct Exposure to SARS-CoV-2 and Cigarette Smoke Increases Infection Severity and Alters the Stem Cell-Derived Airway Repair Response.

Current smoking is associated with increased risk of severe COVID-19, but it is not clear how cigarette smoke (CS) exposure affects SARS-CoV-2 airway cell infection. We directly exposed air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term CS and then infected them with SARS-CoV-2. We found an increase in the number of infected airway cells after CS exposure with a lack of ABSC proliferation. Single-cell profiling of the cultures showed that the normal interferon response was reduced after CS exposure with infection. Treatment of CS-exposed ALI cultures with interferon ß-1 abrogated the viral infection, suggesting one potential mechanism for more severe viral infection. Our data show that acute CS exposure allows for more severe airway epithelial disease from SARS-CoV-2 by reducing the innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to CS.

Both the intratumoral immune and microbial microenvironment are linked to recurrence in human colon cancer: results from a prospective, multicenter nodal ultrastaging trial.

Colon cancer (CC) is the third most common cancer diagnosed in the United States and the incidence has been rising among young adults. We and others have shown a relationship between the immune infiltrate and prognosis, with improved disease-free survival (DFS) being associated with a higher expression of CD8+ T cells. We hypothesized that a microbial signature might be associated with intratumoral immune cells as well as DFS. We found that the relative abundance of one Operational Taxonomic Unit (OTU), OTU_104, was significantly associated with recurrence even after applying false discovery correction (HR 1.21, CI 1.08 to 1.36). The final multivariable model showed that DFS was influenced by three parameters: N-stage, CD8+ labeling, as well as this OTU_104 belonging to the order Clostridiales. Not only were CD8+ labeling and OTU_104 significant contributors in the final DFS model, but they were also inversely correlated to each other (p=0.022). Interestingly, CD8+ was also significantly associated with the microbiota composition in the tumor: CD8+ T cells was inversely correlated with alpha diversity (p=0.027) and significantly associated with the beta diversity. This study is the first to demonstrate an association among the intratumoral microbiome, CD8+ T cells, and recurrence in CC. An increased relative abundance of a specific OTU_104 was inversely associated with CD8+ T cells and directly associated with CC recurrence. The link between this microbe, CD8+ T cells, and DFS has not been previously shown.

Prognostic Utility of Immunoprofiling in Colon Cancer: Results from a Prospective, Multicenter Nodal Ultrastaging Trial.

BACKGROUND: Retrospective data indicate that immunoprofiling of T cell markers can be prognostic in colon cancer. Prospective T cell immunoprofiling of colon cancer has not been well defined for patients whose lymph nodes are ultrastaged. STUDY DESIGN: A prospective cohort was selected from patients enrolled in an ongoing phase II multicenter trial of nodal ultrastaging for colon cancer. Primary tumor specimens from 89 patients were analyzed by immunohistochemistry for the T cells CD3(+), CD4(+), CD8(+), and FOXP3(+). Lymphocyte populations were quantified with digital image analysis. Results were examined for their association with 5-year disease-free survival along with TNM stage and clinicopathologic variables. RESULTS: Longer disease-free survival was associated with higher CD3(+) counts at the invasive margin (IM) (p = 0.005), higher CD8(+) counts at the tumor center (TC) and IM (p = 0.002), a lower CD4(+)/CD8(+) ratio at the TC+IM (p = 0.027), and a higher CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.020). After multivariable analysis, CD8(+) at the TC+IM (p = 0.002), the CD8(+)/FOXP3(+) ratio at the TC+IM (p = 0.004), and the number of tumor-positive lymph nodes (p = 0.003) remained significant. CONCLUSIONS: This is the first prospective demonstration of the prognostic utility of immunoprofiling in colon cancer after nodal ultrastaging. Staging based on tumor immunoprofile can augment TNM staging and provide targets for specific immunotherapies.

Correlation of immune activation during late pregnancy and early postpartum with increases in plasma HIV RNA, CD4/CD8 T cells, and serum activation markers.

A previously observed rise in the plasma viral load postpartum in both treated and untreated HIV-positive women remains unexplained. Virological and immunological markers were evaluated in HIV-negative controls and HIV-positive pregnant women with and without antiretroviral treatment. Plasma HIV RNA, CD4/CD8 T cells, and serum activation markers were sequentially measured during the third trimester, at delivery, and 2 to 8 weeks postpartum in a cohort of HIV-positive pregnant women (n = 96) enrolled in a maternal-fetal HIV transmission study and a control group of HIV-negative pregnant women (n = 28). Mean plasma HIV RNA (P = 0.003) increased from delivery to postpartum, and mean CD4 T cells (P = 0.002) and serum ß2-microglobulin (P < 0.0001) increased from the third trimester through postpartum among the HIV-positive women. Mean CD8 T cells increased from the third trimester through postpartum in women receiving zidovudine (ZDV) and in those not treated (P < 0.05) but remained stable in those on highly active antiretroviral therapy (HAART) and the HIV-negative controls. Increases in serum ß2-microglobulin were correlated with increases in HIV RNA (P = 0.01). HIV-positive pregnant women showed postpartum increases in plasma HIV RNA, CD4 T cells, and serum ß2-microglobulin regardless of the treatment regimen. The rise in CD4 T cells and ß2-microglobulin was also observed in HIV-negative pregnant women, suggesting hormonal changes and/or labor-induced cytokines may contribute to immune activation. Immune activation correlated with increased plasma HIV RNA in postpartum women despite treatment, although HAART appeared to blunt the effect. The observed rise in plasma HIV RNA postpartum, which correlated with markers of immune activation, may have implications for enhanced transmission to infants through early breast-feeding and to sexual partners.