PIK3/Akt/mTOR pathway alterations in metastatic castration-sensitive prostate cancer.

BACKGROUND: Alterations in the PIK3/Akt/mTOR pathway are commonly seen in metastatic castration-sensitive prostate cancer (mCSPC), however their role in outcomes is unknown. We aim to evaluate the prognostic significance as well as the genetic landscape of PIK3/Akt/mTOR pathway alteration in mCSPC. METHODS: Fourhundred and seventy-two patients with mCSPC were included who underwent next generation sequencing. PIK3/Akt/mTor pathway alterations were defined as mutations in Akt1, mTOR, PIK3CA, PIK3CB, PIK3R1, PTEN, TSC1, and TSC2. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of castration resistant prostate cancer (tdCRPC), and overall survival (OS). Kaplan-Meier analysis was performed and Cox regression hazard ratios (HR) were calculated. RESULTS: One hundred and fifty-two (31.9%) patients harbored a PIK3/Akt/mTOR pathway alteration. Median rPFS and tdCRPC were 23.7 and 21.0 months in PIK3/Akt/mTOR altered compared to 32.8 (p = 0.08) and 32.1 months (p = 0.002) in wildtype tumors. On multivariable analysis PIK3/Akt/mTOR pathway alterations were associated with tdCRPC (HR 1.43, 95% CI, 1.05-1.94, p = 0.02), but not rPFS [Hazard ratio (HR) 1.20, 95% confidence interval (CI), 0.90-1.60, p = 0.21]. PIK3/Akt/mTOR pathway alterations were more likely to be associated with concurrent mutations in TP53 (40% vs. 28%, p = 0.01) and TMPRSS2-ERG (37% vs. 26%, p = 0.02) than tumors without PIK3/Akt/mTOR pathway alterations. Concurrent mutations were typically associated with shorter median times to rPFS and tdCRPC. DAVID analysis showed p53 signaling and angiogenesis pathways were enriched in PIK3/Akt/mTOR pathway altered tumors while beta-catenin binding and altered BRCA pathway were enriched in PIK3/Akt/mTOR pathway wildtype tumors. CONCLUSIONS: PIK3/Akt/mTOR pathway alterations were common in mCSPC and associated with poorer prognosis. The genetic landscape of PIK3/Akt/mTOR pathway altered tumors differed from wildtype tumors. Additional studies are needed to better understand and target the PIK3/Akt/mTOR pathway in mCSPC.

Metastasis-Directed Therapy for Oligometastatic Castration-Sensitive Prostate Cancer: An Alternative to ADT?

PURPOSE OF REVIEW: The standard treatment of patients with metastatic prostate cancer is systemic treatment with androgen-deprivation therapy (ADT). The spectrum-based model of metastatic disease includes the presence of an oligometastatic state, an intermediary between localized and widespread metastatic disease, in which radical local treatment might improve systemic control. Our purpose is to review the literature on metastasis-directed therapy in the treatment of oligometastatic prostate cancer. RECENT FINDINGS: Several prospective clinical trials have reported improvements in ADT-free survival and progression-free survival with metastasis-directed therapy of oligometastatic prostate cancer. Retrospective studies have found improvements in oncologic outcomes for patients with oligometastatic prostate cancer undergoing metastasis-directed therapy, and several recent prospective clinical trials have confirmed these results. Advancements in imaging as well as an understanding of the genomics of oligometastatic prostate cancer may allow for better patient selection for metastasis-directed therapy and the potential for cure in selected patients.

Morally injurious combat events as an indirect risk factor for postconcussive symptoms among veterans: The mediating role of posttraumatic stress.

OBJECTIVE: Psychosocial factors, including combat-related distress (e.g., posttraumatic stress disorder [PTSD]), contribute to postconcussive symptoms (PCS) among veterans with mild traumatic brain injury (mTBI). However, research on risk factors for PCS has focused solely on life-threatening combat experiences, neglecting the morally injurious dimension of combat-related trauma and associated implications for treatment. Morally injurious events (MIEs) are associated with PTSD symptoms among veterans, a robust risk factor of PCS. Nonetheless, the interplay between MIEs, PTSD symptoms, and PCS remains poorly understood. We sought to investigate MIEs as an indirect risk factor for PCS among Veterans with mTBI. METHOD: This cross-sectional study of 145 veterans with mTBI used path analysis to investigate whether PTSD symptoms mediated the relationship between MIEs (transgressions and betrayals) and PCS (mood-behavioral, vestibular-sensory, and cognitive domains) among 145 veterans with mTBI. We used the Moral Injury Event Scale, PTSD Checklist-Civilian Version, and Neurobehavioral Symptom Inventory to measure MIEs, PTSD, and PCS, respectively. RESULTS: Perceived transgressions were indirectly associated with mood-behavioral (ß = .21, p = .005), vestibular-sensory (ß = .17, p = .005), and cognitive PCS (ß = .20, p = .005), as mediated by PTSD. Greater transgressions were associated with more severe PTSD (ß = .27, p = .003), and greater PTSD was associated with more severe mood-behavioral (ß = .79, p < .001), vestibular-sensory (ß = .64, p < .001), and cognitive PCS (ß = .73, p < .001). Betrayals were not indirectly associated with PCS. CONCLUSIONS: Findings offer preliminary support for responses to MIEs being a modifiable risk factor for PCS among veterans. Interventions designed to foster veterans' recovery by targeting the unique emotions and beliefs associated with MIEs may be indicated. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Top Ten Tips Palliative Care Clinicians Should Know About Urological Care.

Patients receiving palliative care (PC) can present with or develop a host of urological needs or complications. These needs can include attention to sexual health, urinary incontinence, genitourinary bleeding, and urinary tract obstruction by benign, malignant, or urinary stone diseases. These varied conditions require that PC clinicians understand invasive and noninvasive medical, surgical, and radiation options for treatment. This article, written by a team of urologists, geriatricians, and PC specialists, offers information and guidance to PC teams in an accessible "Top Ten Tips" format to increase comfort with and skills around assessment, evaluation, and specialist referral for urological conditions common in the PC setting.

Use of immune checkpoint inhibitors in solid organ transplant recipients with advanced cutaneous malignancies.

Background: Immune checkpoint inhibitors (ICI) are standard of care therapy for patients with cutaneous malignancies, the most frequently diagnosed cancers in solid organ transplant (SOT) recipients. The activity and rate of allograft rejection in SOT recipients with advanced skin cancers treated with ICI is understudied. Methods: We conducted a retrospective analysis of SOT recipients with advanced melanoma, cutaneous squamous cell carcinoma (cSCC), and merkel cell carcinoma (MCC) who were treated with ICI. Unpublished cases from our institution and published cases from the literature were aggregated. Demographics, type of immunosuppressive therapy, type of ICI(s) administered, prior systemic therapies, tumor response to ICI, and evidence of organ rejection and/or failure were recorded. Objective response rates (ORR) and rates of graft rejection and failure are reported. Results: Ninety patients were identified; four patients from our institution and 86 unique patients from a literature review. ORR to first-line ICI for the entire cohort was 41.1% (37/90). ORR by tumor type was 31% (18/58), 64.3% (18/28), and 25.0% (1/4) for melanoma, cSCC, and MCC, respectively. The rate of graft rejection was 37.8% (34/90) with 61.8% (21/34) of these cases progressing to graft failure. Number of immunosuppressive agents (0, 1, 2, or 3) was inversely associated with rate of graft failure. Conclusions: In this retrospective analysis, ICIs demonstrate clinical activity in SOT recipients with cutaneous malignancies; however, the rate of graft rejection is high. Treatment plans should be individualized through thorough interdisciplinary discussion. Immunosuppressive modifications may be considered prior to starting treatment, but when feasible, enrollment on clinical trials is preferred.

HLA inherence as a potential parameter in checkpoint inhibitor-associated autoimmune adverse event assessment.

Background: The success of immunotherapy has made it a lifesaving treatment, but not without side effects. Currently, the risk factors for developing immune-related adverse events (irAEs) in patients who receive immunotherapy are poorly understood, and there is no risk-stratifying mechanism for potentially fatal irAEs. It is postulated that oncology patients with preexisting autoimmune diseases are likely to have flares on immunotherapy. However, some patients develop de novo autoimmune conditions on immunotherapy without a prior history. Literature reports have postulated that human leukocyte antigen (HLA) inherence may play a role in irAEs. However, this potential remains underexplored. Methods: The oncology patients who developed autoimmune adverse events on immunotherapy for whom the continuation of treatment was prudent or lifesaving were selected. Of note, all nine patients received checkpoint inhibitors (CIs). Of the nine selected patients, only one had a prior history of an autoimmune condition. None of the nine selected patients had an active autoimmune condition at the time of CI initiation. Their HLA was typed, and the results were cross-referenced with the literature reports in PubMed and Google search with the corresponding autoimmune condition of each patient. Results: Herein, we report nine patients with irAEs for whom retrospective HLA typing revealed the inherence of multiple related HLA alleles that may correspond to the autoimmune condition that they had developed on immunotherapy. It is to be mentioned that the inherence of enriched disease-related HLA alleles was shared among patients with the same irAEs. These patients developed a range of irAEs including bullous pemphigoid, pemphigus foliaceus/vulgaris, thyroiditis, vitiligo, and hepatitis on immunotherapy. Although some combinations of disease-related HLA were well reported in otherwise idiopathic autoimmune diseases, a frequently repeated HLA allele combination in our patient population was found to be rarely seen in the general population. Conclusion: The authors suggest that an enriched inherence of disease-related HLA alleles may play a role in the genetic propensity for the development of irAEs in oncology patients, who receive immunotherapy, including CIs. Inherence of more than one or a cluster of particular autoimmune disease-related HLA alleles in patients who receive immunotherapy may unmask the corresponding autoimmune disease as the genotype inherence presents with the phenotype of the corresponding condition. It is suggested that enriched linked HLA genotypes, which are otherwise rare in the general population, may present as the corresponding phenotype of the autoimmune condition. Such clinical presentation, enhanced by immunotherapy, such as CIs, can play a role in risk stratifying patients for precision medicine and improve the outcome.

Virtual Tumor Board Increases Provider Attendance and Case Presentations.

PURPOSE: Many cancer centers engage in multidisciplinary tumor board meetings to determine the optimal approach to complex cancer care. With the onset of the COVID-19 pandemic, many institutions changed the format of these meetings from in-person to virtual. The aim of this study was to determine if the change to a virtual meeting format had an impact on attendance and cases presented. METHODS: Tumor board records were analyzed to obtain attendance and case presentation information at a National Cancer Institute-designated Comprehensive Cancer Center. Twelve-month in-person tumor board data were compared with 12-month virtual tumor board data to assess for difference in attendance and case presentation patterns. RESULTS: Seven separate weekly tumor board meetings at the beginning of the study (breast, GI, gynecology, liver, lung, melanoma, and urology) were expanded to nine meetings on the virtual platform (+endocrine and pancreas). Overall attendance increased by 46% on the virtual platform compared with in-person meetings (4,030 virtual attendances v 2,753 in-person, P < .001). Increased attendance was present across all specialties on the virtual platform. In addition, the number of patient cases discussed increased from 2,127 in in-person meeting to 2,656 on the virtual platform (a 20% increase, P < .001). CONCLUSION: A significant increase was observed in overall tumor board attendance and in case presentations per meeting, requiring the expansion of additional weekly meetings. Furthermore, in a major cancer center with multiple community affiliates, virtual tumor boards may encourage increased participation from remote sites with the benefit of obtaining expert specialist advice as compared with geographically challenging in-person meetings.

Participation Mediates the Relationship Between Postconcussive Symptoms and Suicidal Ideation Among Veterans.

IMPORTANCE: Veterans with mild traumatic brain injury (mTBI) and associated symptoms are at risk for suicide. Postconcussive symptoms (PCS) may heighten risk for suicidal thoughts by limiting veterans' participation. OBJECTIVE: To investigate whether participation mediates the relationship between PCS and suicidal ideation. DESIGN: Cross-sectional, exploratory design. Structural equation models were used to investigate whether participation mediated the relationship between PCS and suicidal ideation. SETTING: Community. PARTICIPANTS: Veterans with mTBI (N = 145). OUTCOMES AND MEASURES: The Ohio State University TBI Identification Method was used to establish mTBI diagnosis. We identified latent variables for PCS and participation using the Neurobehavioral Symptom Inventory and select domains of the Medical Outcomes Study Short Form-36, respectively. We used the Beck Scale for Suicide Ideation to measure the presence of suicidal ideation. RESULTS: Participation mediated the relationship between PCS and the presence of suicidal ideation (odds ratio [OR] = 1.09, p = .011). More severe PCS were associated with lesser participation (ß = -.86, p < .001); greater participation was associated with lower odds of suicidal ideation (OR = 0.92, p = .007). CONCLUSIONS AND RELEVANCE: PCS may heighten risk for suicidal thoughts among veterans by limiting successful participation, a primary target of occupational therapy intervention. Thus, the results suggest that occupational therapy practitioners can play a substantial role in suicide prevention services for veterans with mTBI. Preventive services could mitigate suicide risk among veterans with mTBI by enabling sustained engagement in meaningful and health-promoting activity (e.g., reasons for living) and targeting PCS. What This Article Adds: Researchers have proposed that occupational therapy practitioners can help prevent veteran suicide by supporting their engagement in meaningful, health-promoting activity and by targeting suicide risk factors within their scope of practice. To the best of our knowledge, this is the first study to offer empirical support for such proposed suicide prevention efforts. Although additional research is needed, these results are promising and highlight a distinct role for occupational therapy in suicide prevention.

Immunohistochemical location of Na+, K+-ATPase α1 subunit in the human inner ear.

Na+, K+-ATPase (Na,K-ATPase) is an ubiquitous enzyme in the inner ear and a key factor in the maintenance of the osmotic gradient of the endolymph. This study uses Na,K-ATPase α1 subunit immunoreactivity (IR) to identify cellular structures in the normal and disease human cochlea. Formalin-fixed celloidin-embedded (FFCE) human temporal bone sections were immunoreacted with mouse monoclonal antibodies against Na,K-ATPase α1 subunit. Na,K-ATPase α1 IR was examined in the cochlea of 30 patients: four with normal hearing, 5 with Meniere's disease, and 21 with other inner ear diseases: 11 male, 19 female; ages 42 to 96 years-old (yo), average age of 77 yo. Na,K-ATPase α1 IR area was quantified using the ImageJ software program. Na,K-ATPase α1 IR was located in the stria vascularis, and in type I, II and IV fibrocytes of the spiral ligament in the cochlea from patients with normal hearing. Na,K-ATPase α1 IR was seen in Deiters's cells and inner phalangeal cells of the organ of Corti. Na,K-ATPase α1 IR was present in satellite cells that surround the neurons of the spiral ganglia. In the inner ear of pathological specimens, Na,K-ATPase IR area was decreased (compared to the normal) in the stria vascularis, supporting cells in the organ of Corti and satellite cells of the spiral ganglia. These results show that Na,K-ATPase α1 IR is a good marker to identify cellular structures of the human inner ear and may be used to study cellular changes in the cochlea associated with aging and disease. The ubiquitous localization of Na,K-ATPase α1 in the human cochlea is consistent with the Na,K-ATPase role in ionic homeostasis and osmolarity, similar to that seen in animal models.

Introduction to Clerkship: Bridging the Gap Between Preclinical and Clinical Medical Education.

BACKGROUND: Despite a diverse range of curricular advancements to address the difficult transition from classroom learning to clinical training during medical education, hurdles persist. A 4-week course was designed at the Philadelphia College of Osteopathic Medicine (PCOM) to make this transition easier. OBJECTIVES: To determine whether PCOM students' comfort and preparedness increased after taking a 4-week clinical transition course before third-year clinical clerkships, and to determine whether faculty perceptions of student preparedness and comfort were improved after participation in the course compared with previous third-year students. METHODS: Second-year osteopathic medical students at PCOM participated in a 4-week course, Introduction to Clinical Clerkship (I2C). The course included 16 small-group exercises, which all took place before students began their third-year clerkship rotations. The exercises in the course extended beyond the skills learned during their classroom years. Students were given a pre- and postcourse survey to evaluate their comfort level with 58 different aspects of clinical practice. Participating faculty were surveyed to evaluate their perception of student preparedness and comfort compared with previous third-year students who had not undergone the exercise. RESULTS: After completing the I2C course, third-year osteopathic medical students (n=232) reported increased comfort with 57 of the 58 learning objectives and each of the 5 coded clinical competency areas (patient assessment, effective communication, hospital logistics, procedural skills, and core knowledge) (P<.01). Preceptors reported that students who completed the I2C course were more prepared (54.5%) and more comfortable (63.4%) with clinical duties, as compared with their recollections of previous third-year osteopathic medical students. CONCLUSION: Within the 5 competencies, students on average felt more comfortable and were perceived by faculty as better prepared than previous students who had not taken the I2C course. The establishment of a preclinical transition exercise appears to help bridge the gap between the preclinical and clinical years. This learning model allows medical students to feel both more comfortable and better prepared throughout the transition from classroom learning to clinical rotations.

Behavior-Change Intervention Targeting Physical Function, Walking, and Disability After Dysvascular Amputation: A Randomized Controlled Pilot Trial.

OBJECTIVE: To determine preliminary efficacy of a home-based behavior-change intervention designed to promote exercise, walking activity, and disease self-management. DESIGN: A single-blind, randomized controlled pilot trial. SETTING: One Veterans Administration and 2 regional medical centers. PARTICIPANTS: A total of 38 participants randomized to behavior-change intervention (n=19) or attention control (CTL; n=19) group. INTERVENTIONS: Weekly 30-minute telephone sessions for 12 weeks with intervention group sessions focused on health behavior change and CTL group sessions focused on health status monitoring. MAIN OUTCOME MEASURES: Physical function, walking activity (steps/d averaged over 10d), and disability were measured at baseline, 12 weeks (intervention end), and 24 weeks after baseline with the Timed Up and Go (TUG) test as the primary outcome measure. RESULTS: The TUG test was not changed from baseline in either group and was not different between groups after 12 or 24 weeks. Several exploratory outcomes were assessed, including daily step count, which increased 1135 steps per day in the intervention group compared to 144 steps per day in the CTL group after 12 weeks (P=.03). Only the intervention group had within-group increase in steps per day from baseline to 12 (P<.001) and 24 (P=.03) weeks and spent significantly less time in sedentary activity (4.8% decrease) than the CTL group (0.2% decrease) at 24 weeks (P=.04). There were no other between-group differences in physical function or disability change over time. CONCLUSION: The behavior-change intervention demonstrates promise for increasing walking activity for people with dysvascular transtibial amputation (TTA). The efficacy of implementing such intervention in the scope of conventional TTA rehabilitation should be further studied.

Explaining modified 2-min walk test outcomes in male Veterans with traumatic or nontraumatic lower-limb amputation.

Little evidence exists to support the presence of differences in spatiotemporal gait parameters and ambulation ability between those individuals with traumatic and nontraumatic lower-limb amputation (LLA). We conducted an exploratory study of 81 male Veterans with unilateral amputation to quantify differences in spatiotemporal gait parameters and ambulatory mobility between Veterans with traumatic and nontraumatic LLA. Furthermore, we identified variables that significantly contributed to the explanation of variability in modified 2-min walk test distance. All participants completed the modified 2-min walk test and a spatiotemporal gait analysis using an instrumented walkway during a routine physical therapy visit. Veterans with nontraumatic LLA walked significantly shorter mean distances during a modified 2-min walk test than Veterans with traumatic LLA. Variables identified as significant contributors to modified 2-min walk test variability were amputated limb stance time, amputated limb step length, and percentage of the gait cycle spent in double support. These findings demonstrate that differences in spatiotemporal gait parameters and ambulatory mobility exist between Veterans with traumatic and nontraumatic LLA and identify important spatiotemporal parameters of gait contributing to this decline. These parameters should be considered as targets for intervention and future investigation.

Functional Outcomes After the Prosthetic Training Phase of Rehabilitation After Dysvascular Lower Extremity Amputation.

OBJECTIVE: To describe physical function outcomes and modes of physical therapy intervention for a cohort of patients with dysvascular lower extremity amputation (LEA) during the prosthetic training phase of rehabilitation. DESIGN: A retrospective cohort study. SETTING: Physical rehabilitation clinics at a Veterans Affairs medical center and a university hospital. PATIENTS: Forty-two patients (38 men, 4 women, age 60.2 ± 8.4 years) who completed outpatient physical therapy rehabilitation with prosthetic training after dysvascular LEA. METHODS: All patients underwent a prosthetic training phase of rehabilitation, with standardized outcome measures performed at initiation and discharge. MAIN OUTCOME MEASURES: Performance-based physical function measures included Two-Minute Walk (2 MW), Timed-Up and Go (TUG), and 5-meter gait speed. Self-report physical function measures included the Prosthesis Evaluation Questionnaire-Mobility Section (PEQ-MS) and the Patient-Specific Functional Scale. Rehabilitation dose was tracked as total number of clinic visits, rehabilitation duration, and specific intervention modes. RESULTS: There were significant improvements between initial and discharge values (mean ± SD) for the Two-Minute Walk (67.5 ± 29.9 m and 103.3 ± 45.8 m, respectively, P < .001), gait speed (0.58 ± 0.27 m/s and 0.88 ± 0.39 m/s, respectively, P < .001), TUG (34.8 ± 21.3 seconds and 18.6 ± 13.9 seconds, respectively, P < .001), PEQ-MS (2.2 ± 0.9 and 2.8 ± 0.8, respectively, P < .001), and Patient-Specific Functional Scale (3.2 ± 2.0 and 5.9 ± 2.3, respectively, P < .001). Performance-based (TUG) and self-report (PEQ-MS) changes in functional mobility from initial exam to discharge had low or no correlations with rehabilitation dose measures. The number of clinic visits was 12.7 ± 13.1 and rehabilitation duration was 13.7 ± 16.8 weeks. CONCLUSIONS: Significant improvements in performance-based and self-report measures of physical function occurred during the prosthetic training phase of physical rehabilitation after dysvascular major LEA. Despite improvements in function, gait speed, and TUG outcomes remained below clinically important thresholds, indicating patients were limited in community ambulation and at risk for falls. Lack of moderate or greater correlation between rehabilitation dose and outcome measures may indicate the need for more specific rehabilitation dose measures.

TLR3 agonists improve the immunostimulatory potential of cetuximab against EGFR+ head and neck cancer cells.

Toll-like receptor 3 (TLR3) agonists have been extensively used as adjuvants for anticancer vaccines. However, their immunostimulatory effects and precise mechanisms of action in the presence of antineoplastic monoclonal antibodies (mAbs) have not yet been evaluated. We investigated the effect of TLR3 agonists on cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) against head and neck cancer (HNC) cells, as well as on dendritic cell (DC) maturation and cross-priming of epidermal growth factor receptor (EGFR)-specific CD8+ T cells. The cytotoxic activity of peripheral blood mononuclear cells (PBMCs) or isolated natural killer (NK) cells expressing polymorphic variants (at codon 158) of the Fcγ receptor IIIa (FcγIIIa) was determined in 51Cr release assays upon incubation with the TLR3 agonist poly-ICLC. NK cell stimulation was measured based on activation and degranulation markers, while DC maturation in the presence of poly-ICLC was assessed using flow cytometry. The DC-mediated cross priming of EGFR-specific CD8+ T cells was monitored upon in vitro stimulation with tetramer-based flow cytometry. TLR3-stimulated, unfractionated PBMCs from HNC patients mediated robust cetuximab-dependent ADCC, which was abrogated by NK-cell depletion. The cytolytic activity of TLR3-stimulated NK cells differed among cells expressing different polymorphic variants of FcγRIIIa, and NK cells exposed to both poly-ICLC and cetuximab expressed higher levels of CD107a and granzyme B than their counterparts exposed to either stimulus alone. Poly-ICLC plus cetuximab also induced a robust upregulation of CD80, CD83 and CD86 on the surface of DCs, a process that was partially NK-cell dependent. Furthermore, DCs matured in these conditions exhibited improved cross-priming abilities, resulting in higher numbers of EGFR-specific CD8+ T cells. These findings suggest that TLR3 agonists may provide a convenient means to improve the efficacy of mAb-based anticancer regimens.

Repetitively dosed docetaxel and ¹5³samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer.

BACKGROUND: ß-emitting bone-seeking radiopharmaceuticals have historically been administered for pain palliation whereas docetaxel prolongs life in patients with metastatic castration-resistant prostate cancer (mCRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize antitumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established. METHODS: Patients with progressive mCRPC and ≥ 3 bone lesions received (153) Sm-EDTMP (samarium-153 ethylene diamine tetramethylene phosphonate) at a dose of 1.0 mCi/kg every 9 weeks and docetaxel at a dose of 75 mg/m(2) every 3 weeks. In the absence of unacceptable toxicity, patients were allowed to continue additional cycles, defined by 9 weeks of treatment, until intolerance or biochemical/radiographic disease progression. RESULTS: Of the 30 patients treated, approximately 50% were considered to be taxane-naive, 36.7% were taxane-refractory, and 13.3% had previously been exposed to taxanes but were not considered refractory. Patients received on average 2.5 cycles of treatment (6.5 doses of docetaxel and 2.5 doses of (153) Sm-EDTMP). Twelve patients (40%) demonstrated a decline in their prostate-specific antigen level of ≥ 50%. The median progression-free survival (biochemical or radiographic) was 7.0 months and the overall survival was 14.3 months. Nine patients (30%) did not recover platelet counts >100 K/mm(3) after a median of 3 cycles to allow for additional treatment, with 4 patients experiencing prolonged thrombocytopenia. The most common reasons for trial discontinuation were progressive disease and hematologic toxicity. CONCLUSIONS: The results of the current study indicate that (153) Sm-EDTMP can be safely combined with docetaxel at full doses on an ongoing basis in patients with mCRPC. Although thrombocytopenia limited therapy for some patients, preliminary efficacy supports the strategy of combining a radiopharmaceutical with chemotherapy, which is an appealing strategy given the anticipated availability of α emitters that can prolong survival.

TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells.

BACKGROUND: Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that prolongs survival in the treatment for head and neck cancer (HNC), but only in 10-20 % of patients. An immunological mechanism of action such as natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells. OBJECTIVE: To determine the capability of TLR8-stimulation to enhance the activation and function of NK cells and dendritic cells (DC) in the presence of cetuximab-coated HNC cells. METHODS: Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8(+) T cells were isolated and analyzed using (51)Cr release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR853-861 tetramer staining. RESULTS: TLR8 stimulation of unfractionated PBMC led to enhanced cetuximab-mediated ADCC in healthy donors (p < 0.01) and HNC patients (p < 0.001), which was dependent on NK cells. Secretion of Th1 cytokines TNFα (p < 0.0001), IFNγ (p < 0.0001), and IL-12p40 (p < 0.005) was increased. TLR8 stimulation of PBMC augmented cetuximab-enhanced NK cell degranulation (p < 0.001). TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in co-culture with cetuximab-treated HNC cells. TLR8 stimulation of NK-DC co-cultures significantly increased DC priming of EGFR-specific CD8(+) T cells in the presence of cetuximab. DISCUSSION: VTX-2337 and cetuximab combination therapy can activate innate and adaptive anti-cancer immune responses. Further investigation in human trials will be important for determining the clinical benefit of this combination and for determining biomarkers of response.

Bone scan index: a quantitative treatment response biomarker for castration-resistant metastatic prostate cancer.

PURPOSE: There is currently no imaging biomarker for metastatic prostate cancer. The bone scan index (BSI) is a promising candidate, being a reproducible, quantitative expression of tumor burden seen on bone scintigraphy. Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure. PATIENTS AND METHODS: We retrospectively examined serial bone scans from patients with castration-resistant metastatic prostate cancer (CRMPC) enrolled in four clinical trials. We calculated BSI at baseline and at 3 and 6 months on treatment and performed univariate and bivariate analyses of PSA, BSI, and survival. RESULTS: Eighty-eight patients were scanned, 81 of whom have died. In the univariate analysis, the log percent change in BSI from baseline to 3 and 6 months on treatment prognosticated for survival (hazard ratio [HR], 2.44; P = .0089 and HR, 2.54; P < .001, respectively). A doubling in BSI resulted in a 1.9-fold increase in risk of death. Log percent change in PSA at 6 months on treatment was also associated with survival (HR, 1.298; P = .013). In the bivariate analysis, change in BSI while adjusting for PSA was prognostic at 3 and 6 months on treatment (HR, 2.368; P = .012 and HR, 2.226; P = .002, respectively), but while adjusting for BSI, PSA was not prognostic. CONCLUSION: These data furnish early evidence that on-treatment changes in BSI are a response indicator and support further exploration of bone scintigraphy as an imaging biomarker in CRMPC.

Peripheral vascular disease severity impacts health outcomes and health-related quality of life in maintenance hemodialysis patients in the HEMO Study.

BACKGROUND: In patients with end-stage renal disease, peripheral vascular disease (PVD) is prevalent. We assessed the extent to which severity of PVD predicts mortality, hospitalizations and health-related quality of life (HRQOL) in hemodialysis (HD) patients enrolled in the Hemodialysis (HEMO) Study. METHODS: We performed a subanalysis of the HEMO Study, a randomized controlled trial. Adjusted predictors of PVD were analyzed through a multivariable stepwise ordinal logistic model. Relationships between PVD severity and mortality and hospitalizations were determined with Cox proportional hazards models. Relationships between PVD severity and HRQOL were modeled via linear regression and generalized estimating equations. RESULTS: Older age, diabetes, non-African-American race, ischemic heart disease, cerebrovascular disease and longer transplant wait time were associated with more severe PVD. Patients with severe PVD were more likely to suffer from all-cause mortality [hazard ratio (HR) 1.77, 95% confidence interval 1.30-2.40, P<0.001], cardiac death [HR 1.89 (95% confidence interval 1.15-3.11), P=0.001] and infectious death [HR 1.75 (95% confidence interval 1.30-2.34), P<0.001]. Increasing PVD severity was also associated with first cardiac hospitalization or all-cause mortality (P=0.05) and first cardiac hospitalization or cardiac death (P=0.03). HRQOL scores were lower for patients with increasingly severe PVD. CONCLUSIONS: These findings underscore the burden of clinically symptomatic PVD in HD patients and its impact on morbidity and mortality. Whether early detection of PVD and prompt initiation of therapy to prevent its progression in the HD population would improve HRQOL and survival outcomes remain to be proven.

Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer.

BACKGROUND: Growth of selected castration-resistant prostate cancer (CRPC) cell lines and animal models can be repressed by reexposure to androgens. Low doses of androgens, however, can stimulate tumor growth. OBJECTIVE: We performed a phase 1 clinical trial to determine the safety of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer (CRMPC). DESIGN, SETTING, AND PARTICIPANTS: Patients with progressive CRMPC who had been castrate for at least 1 yr received three times the standard replacement dose of transdermal testosterone. INTERVENTION: Cohorts of 3-6 patients received testosterone for 1 wk, 1 mo, or until disease progression. MEASUREMENTS: Toxicities, androgen levels, prostate-specific antigen (PSA) assays, computed tomography (CT) scans, bone scintigraphy, positron emission tomography (PET) scans, and metastatic tumor biopsy androgen receptor levels were assessed. RESULTS AND LIMITATIONS: Twelve patients were treated-three in cohorts 1 and 2 and six in cohort 3. No pain flares were noted. One patient came off study because of epidural disease, which was treated with radiation. Average testosterone levels were within normal limits, although dihydrotestosterone (DHT) levels on average were supraphysiologic in cohort 3. One patient achieved a PSA decline of >50% from baseline. No objective responses were seen. For cohort 3, median time on treatment was 84 d (range: 23-247 d). CONCLUSIONS: We have demonstrated that patients with CRMPC can be safely treated in clinical trials using high-dose exogenous testosterone. Patients did not, on average, achieve sustained supraphysiologic serum testosterone levels. Future studies should employ strategies to maximize testosterone serum levels, use contemporary methods of identifying patients with androgen receptor overexpression, and utilize PSA Working Group II Consensus Criteria clinical trial end points. TRIAL REGISTRATION: ClinicalTrials.gov; NCT00006044.

Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer.

PURPOSE: Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam. PATIENTS AND METHODS: Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. RESULTS: Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. CONCLUSION: Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.