Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.

Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma.

BACKGROUND: The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAFV600-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy. PATIENTS AND METHODS: Five hundred fourteen patients were randomized to atezolizumab (n = 256) or control (n = 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers. RESULTS: PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.52-1.02; P = 0.067] versus low TMB (<10 mutations/Mb; HR 0.92; 95% CI 0.65-1.30; P = 0.64) and similar between patients with strong IFN-γ (≥median; HR 0.76; 95% CI 0.54-1.06) versus weak IFN-γ (

Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease. Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial. We report long-term overall survival (OS) data after >5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy. PATIENTS AND METHODS: In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term OS was analyzed. RESULTS: In total, 88 patients were treated with avelumab. At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months). One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%). In patients with PD-L1+ versus PD-L1- tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25). CONCLUSION: Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.

Prognostic impact of baseline tumour immune infiltrate on disease-free survival in patients with completely resected, BRAFv600 mutation-positive melanoma receiving adjuvant vemurafenib.

BACKGROUND: We conducted a retrospective exploratory analysis to evaluate the effects of baseline tumour immune infiltrate on disease-free survival (DFS) outcomes in patients with fully resected stage IIC-IIIC melanoma receiving adjuvant vemurafenib monotherapy or placebo in the BRIM8 study. PATIENTS AND METHODS: BRIM8 was a phase III, international, double-blind, randomised, placebo-controlled study. Eligible patients with BRAFV600 mutation-positive, completely resected melanoma were randomly assigned to oral vemurafenib (960 mg twice daily) or matching placebo for 52 weeks. The primary end point was DFS. The association of CD8+ T-cell infiltration and programmed death ligand 1 (PD-L1) expression with DFS, as measured by immunohistochemistry, was explored retrospectively. RESULTS: Four hundred ninety-eight patients were randomly assigned to receive adjuvant vemurafenib (n = 250) or placebo (n = 248); tumour samples were available for biomarker analysis for approximately 60% of patients. In the pooled biomarker population, placebo-treated patients with <1% CD8+ T cells in the tumour centre had shorter median DFS than those with ≥1% CD8+ T cells (7.7 versus 47.8 months). DFS benefit from vemurafenib versus placebo was greater in patients with <1% CD8+ T cells [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.34-0.92) than in patients with ≥1% CD8+ T cells (HR 0.77; 95% CI 0.48-1.22). Likewise, median DFS was shorter among placebo-treated patients with <5% versus ≥5% PD-L1+ immune cells (IC) in the tumour (7.2 versus 47.8 months). A greater DFS benefit with vemurafenib versus placebo was observed in patients with <5% PD-L1+IC (HR 0.36; 95% CI 0.24-0.56) than in patients with ≥5% PD-L1+IC (HR 0.99; 95% CI 0.58-1.69). CONCLUSIONS: The presence of CD8+ T cells and PD-L1+IC are favourable prognostic factors for DFS. Treatment with adjuvant vemurafenib may overcome the poor DFS prognosis associated with low CD8+ T-cell count or PD-L1 expression. CLINICALTRIALS. GOV IDENTIFIER: NCT01667419.

Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study.

BACKGROUND: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. OBJECTIVES: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. METHODS: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. RESULTS: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. CONCLUSIONS: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC.

Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study.

BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. RESULTS: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). CONCLUSION: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

A phase I study of sorafenib and vorinostat in patients with advanced solid tumors with expanded cohorts in renal cell carcinoma and non-small cell lung cancer.

BACKGROUND: This phase I study evaluated the safety, tolerability and preliminary efficacy of sorafenib combined with vorinostat in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with sorafenib 400 mg po bid daily and vorinostat 200-400 mg po days 1-14 of a 21 day cycle to establish the recommended phase II dose (RP2D). The tolerability and efficacy of the RP2D was further tested in two cohorts of 6-12 patients each with advanced RCC and NSCLC. RESULTS: 17 patients were treated in the dose escalation phase that established the RP2D at sorafenib 400 mg po bid daily, vorinostat 300 mg po days 1-14. Dose limiting toxicities (DLT) included intolerable grade 2 hand-foot syndrome and multiple grade 1 toxicities causing dose interruption for more than 14 days. Despite good tolerance in the all-comers population, the RP2D was poorly tolerated in the RCC and NSCLC cohorts with the majority being unable to finish 2 full cycles of therapy. Although there were no confirmed responses, 1 patient each with NSCLC adenocarcinoma and renal sarcoma had unconfirmed partial responses and 5 of 8 patients with RCC having durable minor responses (11-26 %), including 2 who were on treatment for nearly a year. CONCLUSIONS: Although tolerable in other tumor types, sorafenib 400 mg po bid with vorinostat 300 mg po daily days 1-14 of a 21-day cycle is not tolerable without dose reductions/delays in RCC and NSCLC patients. These patients may require lower doses than the RP2D explored within this study. No confirmed responses were seen but minor responses particularly in RCC were observed.

Vismodegib in basal cell carcinoma.

Vismodegib is a novel, small-molecule inhibitor of smoothened, a key component of the hedgehog signaling pathway. Increased hedgehog pathway signaling is critical in the development of hereditary and spontaneous basal cell carcinomas of the skin, and has been implicated in the development of a number of other tumors. In preclinical models, vismodegib demonstrated potent antitumor activity in hedgehog-dependent tumors, particularly basal cell carcinomas. Clinically, phase I and II studies showed dramatic anticancer activity in patients with advanced basal cell carcinomas. In January 2012, vismodegib was approved by the FDA for the treatment of unresectable or metastatic basal cell carcinomas of the skin.

Vemurafenib: the road to personalized medicine in melanoma.

Advanced melanoma has a poor prognosis due to its resistance to traditional chemotherapeutics, leading to the search for alternative treatment approaches. With the finding that approximately 50% of melanomas harbor an activating mutation in the serine/threonine-protein kinase B-raf gene (BRAF), inhibition of mutated B-raf represented an attractive and innovative focus for the development of novel targeted therapy potentially benefiting a large proportion of melanoma patients. Impressive response rates with an overall survival benefit in addition to minimal treatment-related toxicity in phase I-III clinical studies led to the FDA's approval of vemurafenib for patients with locally advanced/unresectable or metastatic BRAFV600E-mutated malignant melanoma in August 2011. While the majority of patients with BRAF-mutated disease show favorable treatment responses shortly after initiation of vemurafenib therapy, the median progression-free survival is 6 months, making the search for resistance mechanisms a high priority. While vemurafenib represents an excellent model for successful targeted anticancer therapy, long-term safety data are needed and rational combination with other agents will be critical to prevent or circumvent the development of resistance.

Report on a cryotherapy service for women with cervical intraepithelial neoplasia in a district hospital in western Kenya.

BACKGROUND: In low-resource settings, cryotherapy can be cost-effective, affordable, and a first-line treatment for cervical intraepithelial neplasia (CIN) of any grade. OBJECTIVES: To report the acceptability, safety and effectiveness of cryotherapy for women with cervical intraepithelial neoplasia (CIN) in Western Kenya. METHODS: Visual inspection with acetic acid (VIA)-positive women and those suspected of having cervical cancer based on an initial evaluation at a primary health facility were referred to the district hospital for colposcopy and additional evaluation using visual inspection with Lugol's iodine (VILI) and/or visual inspection with acetic acid and magnification (VIAM). Cryotherapy was offered immediately to women diagnosed with appropriate CIN lesions based on colposcopy or after waiting for a confirmatory cervical biopsy and a follow up visit occurred one year later. RESULTS: Ninety one 91 women 30 to 39 years of age had CIN appropriate for cryotherapy. Approximately 36% (24/67) were due for their 1 year follow up visit and 20 of 24 (83.3%) attended. Complete data were available for 18 of 20 (90%) and 13 (72.2%) had no sign of CIN. No serious adverse events were reported 1 to 3 months after cryotherapy. All respondents reported that the treatment experience was acceptable. CONCLUSIONS: Cryotherapy was acceptable, safe and effective.

Transesophageal echocardiography in the anesthetic management of total hip arthroplasty.

Total hip arthroplasty is a common procedure in the elderly and thromboembolism continues to be a cause of mortality and morbidity associated with this procedure. When properly diagnosed and treated the mortality rate from pulmonary embolism can be reduced significantly. Transesophageal echocardiograpic (TEE) detection of central pulmonary artery thromboemboli in patients with severe pulmonary embolism has been reported to have a sensitivity of 96.7% and a specificity of 88%. However TEE is not universally available due to its cost and expertise that is required. Taking into consideration its cost/effectiveness we suggest that in patients undergoing the cement type of total hip arthroplasty who are cardiopulmonary compromised, debilitated or elderly the use of TEE is indicated.

Early intervention and school nursing practice.

The most vital and critical period for early intervention is in the first 3 years of life. The school nurse working in an early childhood program plays a pivotal role in assessing and meeting the health and developmental needs of very young children and their families. This article discusses early intervention, as defined by federal law, as an age-related service delivered within a family-focused, multidisciplinary, interagency, and collaborative model. An assessment framework for school nurses working with this population is described, which includes physical, social, and emotional domains. Identifying children early and then providing needed interventions and services will assist at-risk children in realizing their developmental potential.

Mental health in schools: expanded opportunities for school nurses.

Emerging trends are reshaping the work of school nurses and other school service personnel. With respect to direct service and consultation, school nurses increasingly are called upon to deal with psychosocial and mental health problems. Beyond that, school nurses must continue to actuate their roles as advocates, catalysts, brokers, and facilitators of the type of reforms that can effectively address barriers to student learning and promote healthy development. Continuing education is seen as key to enabling school nurses to build capacity for such roles and functions. The newly formed Center for Mental Health in Schools at the University of California, Los Angeles (UCLA) hopes to be of assistance in this respect. This presentation highlights the Center's orientation to mental health in schools and offers a draft outline for related continuing education.

Rat hepatoma L35 cells, a liver-differentiated cell line, display resistance to bile acid repression of cholesterol 7 alpha-hydroxylase.

A stable hepatoma cell line (L35 cells) showing an activation of the cholesterol 7 alpha-hydroxylase gene (CYP7) that had been silent in the parental hepatoma cell line (H35 cells) was used to examine the influence of bile acids on its gene expression and activity. L35 cells were found to concentrate taurocholate from the culture medium, without any significant effect on the expression of 7 alpha-hydroxylase. At physiologic levels (up to 100 microM), CYP7 mRNA expression was not repressed by any bile acid. At supra-physiologic levels (1 mM), the more hydrophobic dihydroxy bile acids, taurodeoxycholate and taurochenodeoxycholate, decreased CYP7 mRNA without decreasing the relative abundance of beta-actin mRNA. Similar results were obtained by culturing cells with sodium dodecylsulfate (50 microM). The medium of L35 cells treated with either taurochenodeoxycholate (1 mM), taurodeoxycholate (1 mM), or sodium dodecylsulfate (50 microM) contained significantly greater activities of two cytosolic enzymes, lactate dehydrogenase and phosphoglucose isomerase, indicating a cytotoxic response. Activation of protein kinase C by phorbol esters decreased the expression of 7 alpha-hydroxylase mRNA without evidence of cytotoxicity; therefore, the inability of L35 cells to show bile acid repression cannot be ascribed to a lack of an effect by this secondary messenger system. In addition, insulin decreased and dexamethasone increased 7 alpha-hydroxylase mRNA without increasing the release of the cytoplasmic enzyme markers. The combined data suggest that L35 cells are resistant to repression of CYP7 gene expression by bile acids, but display physiologic expression to hormones and protein kinase C activation.

An empirical classification of drinking patterns among alcoholics: binge, episodic, sporadic, and steady.

Steady (daily, continuous) versus nonsteady (binge, episodic, bout, intermittent) drinking pattern have been influential Jellinek's (1960) formulation of delta and gamma drinkers, and are used as variables in various typological systems and drinker profiles. However, definitions of drinking patterns vary widely across studies, and most studies rely on one self-report item to establish a subject's pattern. To systematize and empirically test drinking-pattern schemas, we developed detailed definitions of binge, episodic, sporadic, and steady drinking patterns. A computer algorithm was written in SAS to classify 94 male alcoholics participating in outpatient conjoint therapy, using 6-month pretreatment drinking data from the Timeline Followback Interview. The final classification was: 3 (3%) binge, 33 (35%) episodic, 12 (13%) sporadic, and 40 (43%) steady drinkers. Six (6%) were unclassifiable (due to too few drinking days or too many interruptions to the pattern) by the computer. Episodic, sporadic, and steady drinkers did not differ in demographics, alcohol-related consequences, global psychological distress, or marital satisfaction. Steady drinking was associated with later onset of drinking problems (> 25), while episodic and sporadic drinking were associated with earlier onset. These results are contrary to current use of "binge drinking" as a variable associated with Type 1 alcoholism. Predictive validity analyses indicated that steady drinkers continued to drink more frequently than episodic and sporadic drinkers during treatment and 6 months posttreatment. Also, preliminary data indicate that pretreatment drinking pattern may be predictive of similar within-treatment urge-to-drink patterns. Implications for research and treatment are discussed.

In vivo dimeric association of class I MHC heavy chains. Possible relationship to class I MHC heavy chain-beta 2-microglobulin dissociation.

Class I MHC molecules have been thought to occur in vivo both as class I MHC heavy chain-beta 2-m heterodimers, which are or are not associated with antigenic peptide, and as free class I MHC heavy chains. Class I MHC molecules are now found also to occur in another type of structure: a heavy chain-heavy chain dimer. Biochemical studies show that heavy chain dimers are disulfide-linked via a conserved cytoplasmic domain cysteine. H-2Ld, H-2Db, and H-2Dd class I dimers fail to react with certain alpha 1 and alpha 2 domain-specific antibodies. Furthermore, although beta 2-m-specific antibodies coprecipitate class I MHC heavy chains, they do not coprecipitate class I MHC heavy chain dimers. Pulse-chase studies show that heavy chain dimer formation occurs at different points in the biosynthesis of class I MHC molecules in beta 2-m+ and beta 2-m- cells: in beta 2-m+ cells, heavy chain dimers form after the class I molecules have traversed the medial Golgi cisternae, whereas in beta 2-m- cells they form immediately. Culturing of beta 2-m+ cells with exogenous beta 2-m prevents the formation of H-2Ld/Db heavy chain dimers. We conclude that dimer formation occurs as a consequence of loss or unavailability of beta 2-m. Class I MHC heavy chain dimerization may provide a mechanism for removal of immunologically dysfunctional molecules.

Pathophysiology of prenatal drug-exposure: in utero, in the newborn, in childhood, and in agencies.

Medical communities are documenting an increase in the numbers of infants being born with prenatal drug exposure. Medical, educational, and social agencies are serving large numbers of these infants, toddlers, and their families. These infants and toddlers constitute a population whose short-term and long-term needs have not been adequately identified or addressed in the health, social, emotional, or developmental domains. This article discusses the pathophysiology in prenatal drug exposure and the role of the nurse when providing services to these infants, toddlers, and their families.

Activated T cells transcribe an alternatively spliced mRNA encoding a soluble form of Qa-2 antigen.

Among the best characterized non-classical mouse major histocompatibility antigens are the Qa-2 molecules. These proteins can serve as targets for allogenic cytotoxic T cells and as signal transducing molecules. They are structurally similar to H-2 transplantation antigens in their N-terminal and beta 2-microglobulin binding domains but differ at their C-termini. While the H-2 antigens span the cell membrane, the Qa-2 molecules are attached to the cell surface via phospholipid anchors. The genetic information encoding this attachment is contained in exon 5. In concanavalin A activated splenocytes the expression of membrane bound Qa-2 antigens declines and, simultaneously, soluble forms of Qa-2 molecules are secreted. We demonstrate here that the soluble Qa-2 polypeptides are translated from alternatively spliced mRNAs lacking exon 5, while the membrane forms are encoded by the full-size transcripts. In cultured cells the alternative splicing of the Qa-2 message is induced by T-cell activation splicing of the Qa-2 message is induced by T-cell activation with concanavalin A. The canonical mRNA encoding the membrane form of Qa-2 predominates in unstimulated mouse tissues but the cultured cell lines, like activated T cells, express enhanced levels of the truncated mRNA. In some cell lines almost all Qa-2 transcripts lack exon 5. For example, in L cells, mRNAs encoding soluble Qa-2 molecules are at least 10 times more abundant than Qa-2 transcripts encoding phospholipid anchored antigens. These findings are discussed in terms of potential functions of membrane bound and secreted Qa-2 molecules.