Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial

Background

Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.

Objective

To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.

Design, setting, and participants

The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).

Intervention

Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.

Measurements

Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.

Results and limitations

In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.

Conclusions

Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.     

The effects of acute isovolemic hemodilution on oxygenation during one-lung ventilation

Data on the effects of isovolemic hemodilution (IH) on oxygenation during one-lung ventilation (OLV) are lacking. We studied 47 patients with hemoglobin >14 g/dL who were scheduled for lung surgery (17 with normal lung function [group NL], 17 with chronic obstructive pulmonary disease [COPD] [group COPD], and 13 with COPD as control for time/anesthesia effects [group CTRL]). Anesthesia was standardized. The tracheas were intubated with a double-lumen tube. Ventilatory settings and fraction of inspired oxygen remained constant. The study was performed with patients in the supine position before surgery. OLV was initiated for 15 min. Two-lung ventilation was reinstituted, and IH was performed (500 mL); an identical volume of hydroxyethyl starch was administered. Subsequently, OLV was again performed for 15 min. In group CTRL, the same sequences of OLV were performed without IH. At the end of each period of OLV, pulmonary mechanics and blood gases were recorded. Data were analyzed by analysis of variance (mean +/- sd). In group NL and group CTRL, the arterial oxygen partial pressure remained constant, whereas it decreased in group COPD from 119 +/- 21 mm Hg before IH to 86 +/- 16 mm Hg after IH (P <0.01). Mild IH impairs gas exchange during OLV in COPD patients, but not in patients with normal lung function.     

Histopathologic validation of the sentinel node concept in oral and oropharyngeal squamous cell carcinoma

BACKGROUND: In patients with head and neck squamous cell carcinoma (HNSCC), the presence of lymph node metastases is the most important prognosticator. Sentinel node (SN) biopsy has been shown to be an accurate staging technique for patients with breast cancer and melanoma and might also be suited for patients with HNSCC. This study was undertaken to determine whether the SN concept holds true for HNSCC and could be exploited for SN biopsy. METHODS: In 22 patients with T2 to T4 N0 oral or oropharyngeal squamous cell carcinoma (SCC) who were scheduled to undergo combined primary tumor excision and elective unilateral (n = 17) or bilateral (n = 5) neck dissection, SN identification was performed the day before surgery by use of lymphoscintigraphy after peritumoral injections of 99mTc-labeled colloidal albumin. After the neck dissection specimens were removed, all SNs, all other radioactive lymph nodes, and all nonradioactive lymph nodes were retrieved for histopathologic analysis, including serial sectioning at 250-microm intervals and immunohistochemical analysis (IHC). RESULTS: Overall, in 21 (78%) of 27 neck sides, an SN was identified by scintigraphy. Of the six neck sides in which SNs were not identified by scintigraphy, four were from three patients who underwent bilateral neck dissection. In another patient treated by bilateral neck dissection, the SN identified by scintigraphy could not be found in the specimen. In the remaining 20 neck dissection specimens, 23 SNs and 30 additional radioactive lymph nodes could be found. At histologic examination of the 20 neck specimens in which the SN was found, at least one SN was tumor positive in eight cases. In one neck specimen, a metastasis was detected in a nonradioactive lymph node, whereas the SN was tumor free, also at serial sectioning and IHC. In the remaining 11 neck sides in which the SN was tumor negative, none of the other radioactive (n = 13) and none of the nonradioactive (n = 279) lymph nodes contained tumor at histopathologic analysis, including serial sectioning and IHC. The sensitivity of the SN procedure for predicting lymph node metastases, therefore, was 89% (eight of nine neck specimens) when an SN was identified by scintigraphy and found in the specimen. The overall accuracy of the SN procedure for predicting the presence or absence of lymph node metastases in the neck was 95% (19 of 20 neck specimens). CONCLUSIONS: Our study seems to validate the SN hypothesis for oral and oropharyngeal cancer. The role of SN biopsy in the management of the N0 neck in such patients has yet to be established through prospective trials. SN identification (and thus biopsy) does not seem to be reliable in patients with tumors located in or close to the midline.     

Peritraumatic distress across the lifespan: Clinical implications of age differences during the COVID-19 pandemic

The Peritraumatic Distress Inventory (PDI) is a well-known self-report questionnaire indexing the distress experienced during and shortly after a most stressful or traumatic event. Although sociodemographic factors contributing to peritraumatic distress have been previously investigated, no research has examined the nature and severity of peritraumatic distress reactions in a non-clinical, community sample as a function of age. An international sample of 5621 adult participants were grouped according the World Health Organization's age stratification protocol. Mean scores and item endorsement on the PDI were compared across groups with respect to their worst experience of the COVID-19 pandemic. A significant between-group difference was found, F(55,615) = 30.74, p < 0.001, n² = 0.027 whereby participants aged 18–39 years old reported the highest levels of peritraumatic distress. This group also endorsed a higher proportion of items on the PDI's two main factors (emotional distress and physical reactions), and were more likely to endorse feelings of helplessness, than older participants. It appears that severity of peritraumatic distress during the pandemic has affected younger people the most. Results are discussed in light of clinical implications.     

Total hip prosthesis CT with single-energy projection-based metallic artifact reduction: impact on the visualization of specific periprosthetic soft tissue structures

Objectives

To compare the image quality of CT with iterative reconstruction alone and in association with projection-based single-energy metal artifact reduction (SEMAR) for the visualization of specific periarticular soft tissue structures in patients with hip prostheses.

Methods

CT studies from 48 consecutive patients with a hip prosthesis (24 unilateral and 24 bilateral) were retrospectively reconstructed using two different methods: iterative reconstruction (IR) alone and IR associated with SEMAR. The influence of metallic artifacts on the identification of various periarticular structures was evaluated subjectively by two readers. The image quality was compared in patients with unilateral and bilateral prostheses.

Results

Visualization of periprosthetic soft tissue was significantly improved by the SEMAR algorithm (p?<?0.0001). When SEMAR was associated with IR, the gluteus minimus and medius tendons, obturator internus muscle, prostate/uterus and bladder could be seen with medium or high confidence. There were no significant differences in image quality between patients with unilateral or bilateral prosthesis when SEMAR was used (p?>?0.2). This algorithm increased the detection of periarticular masses by 30 %.

Conclusion

SEMAR significantly improves the image quality of periarticular soft-tissue structures in patients with hip prostheses.     

Influence of Calcium on Choline Measurements by 1H MR Spectroscopy of Thigh Muscles

Objective

To study the effects of calcium on the choline peak measurements with 1H MR spectroscopy.

Material and methods

The thigh muscles of two cadaveric specimens were prospectively evaluated on a 3 T MR unit before and after the injection of calcium carbonate (up to 0.4322 g). The choline peaks of 147 spectra from 10 different anatomic locations were quantitatively evaluated. The influence of the calcium concentration and its disposition with respect to the main magnetic field were considered. B₀ phase maps were used to evaluate field inhomogeneities.

Results

The presence of calcium led to a 43 % underestimation of the choline peak and the choline concentration (p?=?0.0002 and 0.0036). The mean choline concentrations before and after CaCO3 injection were 3.53?±?1.72 mmol/l and 1.58?±?0.63 mmol/l. The influence of calcium carbonate on the choline peak estimations was proportional to the calcium concentration. There was a significant position-dependent difference in the estimation of the choline peak amplitude (p?<?0.0154). Calcium injection led to a measurable increase in field inhomogeneities.

Conclusion

There was a significant underestimation of the choline peak amplitude and concentration in the presence of calcium, which might cause misinterpretations of MR spectra.

Key Points

? The presence of calcium led to significant underestimation of choline measurements. ? The influence of calcium is dependent on its concentration and distribution. ? Quantitative MR spectroscopy of calcified tumours should be interpreted with caution.     

Critical influence of natural regulatory CD25+ T cells on the fate of allografts in the absence of immunosuppression

BACKGROUND: Allografts are occasionally accepted in the absence of immunosuppression. Because naturally occurring CD4(+)CD25(+) regulatory T cells (natural CD25(+) Treg cells) have been shown to inhibit allograft rejection, we investigated their influence on the outcome of allografts in nonimmunosuppressed mouse recipients. METHODS: We compared survival times of male CBA/Ca skin grafts in female CBA/Ca recipients expressing a transgenic anti-HY T-cell receptor on a RAG-1(+/+) (A1[M]RAG+) or a RAG-1(-/-) (A1[M]RAG-) background. Depletion of natural CD25(+) Treg cells in A1[M]RAG+ mice was achieved by in vivo administration of the PC61 monoclonal antibody. The influence of natural CD25(+) Treg cells on the fate of major histocompatibility complex class II-mismatched (C57BL/6X bm12)F1 skin or bm12 heart transplants in C57BL/6 recipients was also assessed. Finally, we investigated the impact of natural CD25(+) Treg cells on the production of T-helper (Th)1 and Th2 cytokines in mixed lymphocyte cultures between C57BL/6 CD4(+) CD25(-) T cells as responders and bm12 or (C57BL/6X bm12)F1 antigen-presenting cells as stimulators. RESULTS: Male allografts were spontaneously accepted by female A1(M)RAG+ mice but readily rejected by female A1(M)RAG+ mice depleted of natural CD25(+) Treg cells by pretreatment with the PC61 monoclonal antibody. Depletion of CD25(+) Treg cells also enhanced eosinophil-determined rejection of (C57BL/6X bm12)F1 skin grafts or bm12 cardiac grafts in C57BL/6 recipients. Finally, natural CD25(+) Treg cells inhibited the production of interleukin (IL)-2, interferon-gamma, IL-5, and IL-13 in mixed lymphocyte culture in a dose-dependent manner. CONCLUSION: Natural CD25(+) Treg cells control Th1- and Th2-type allohelper T-cell responses and thereby influence the fate of allografts in nonimmunosuppressed recipients.     

Surgical treatment of solitary adrenal metastasis from non-small cell lung cancer

BACKGROUND: Management of solitary adrenal metastasis from non-small cell lung cancer is still debated. Although classically considered incurable, various reports with small numbers of patients have shown that surgical treatment might improve long-term survival. The aim of this study was to review our experience and to identify factors that could affect survival. METHODS: From January 1989 through April 2003, 23 patients underwent complete resection of an isolated adrenal metastasis after surgical treatment of non-small cell lung cancer. There were 19 men and 4 women, with a mean age of 54 +/- 10 years. The diagnosis of adrenal metastasis was synchronous with the diagnosis of non-small cell lung cancer in 6 patients and metachronous in 17 patients. The median disease-free interval for patients with metachronous metastasis was 12.5 months (range, 4.5-60.1 months). RESULTS: The overall 5-year survival was 23.3%. Univariate and multivariate analysis demonstrated that a disease-free interval of greater than 6 months was an independent and significant predictor of increased survival in patients after adrenalectomy. All patients with a disease-free interval of less than 6 months died within 2 years of the operation. The 5-year survival was 38% after resection of an isolated adrenal metastasis that occurred more than 6 months after lung resection. Adjuvant therapy and pathologic staging of non-small cell lung cancer did not affect survival. CONCLUSIONS: Surgical resection of metachronous isolated adrenal metastasis with a disease-free interval of greater than 6 months can provide long-term survival in patients previously undergoing complete resection of the primary non-small cell lung cancer.     

Total posterior condylar separation in a juvenile knee: open fixation through a posterior arthrotomy

The authors report a case of separation involving the posterior aspect of the lateral femoral condyle in a 13-year-old boy. The patient presented with a 2-year history of vague knee discomfort and recurrent knee effusions in the absence of a single acute traumatic event. A large mobile osteochondral fragment involving most of the posterior aspect of the lateral condyle was refixed surgically with two screws via a posterolateral arthrotomy. The knee has recovered full function and the lesion is radiologically stable.