Collection of Post-treatment PRO Data in Oncology Clinical Trials.

As patient-reported outcome (PRO) measures are being included more frequently in oncology clinical trials, regulatory and health technology assessment agencies have begun to request long-term, post-treatment PRO data to supplement traditional survival/progression endpoints. These data may be collected as part of cohort extension or registry studies to describe long-term outcomes of study participants after concluding their cancer treatment. While post-treatment PRO data may be expected to satisfy regulatory and payer expectations, significant practical barriers exist for the efficient incorporation of these data into oncology clinical trials, such as subject attrition, protocol deviations, and treatment crossover. The incorporation of post-treatment PRO assessments is a resource-intensive task requiring clear objectives for how the data will be analyzed and interpreted by both sponsors and regulators. Incorporating PRO data collection via electronic modalities (e.g., smartphone, web) may be a less expensive and more feasible option for incorporating long-term follow-up, reducing the frequency of manual study staff follow-up and expensive clinic visits. It is essential to include well-defined estimands for the statistical analysis, as well as to document limitations associated with the long-term follow-up data-collection approach. Analytical techniques will likely rely on descriptive and model-based statistics, and conclusions about treatment differences will likely be limited to preliminary findings of effectiveness (instead of efficacy). Finally, communications with health authorities and regulatory agencies regarding the LTFU study design and analysis should occur as early as possible to ensure that the PRO data to be collected offer an opportunity to properly evaluate the research question(s) of interest.

Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management.

OBJECTIVE: The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. METHODS: These recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care. Recommendations for Screening and Assessment: The task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation). Recommendations for Management: A comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

International Clinical Practice Guidelines for Sarcopenia (ICFSR): Screening, Diagnosis and Management.

OBJECTIVES: Sarcopenia, defined as an age-associated loss of skeletal muscle function and muscle mass, occurs in approximately 6 - 22 % of older adults. This paper presents evidence-based clinical practice guidelines for screening, diagnosis and management of sarcopenia from the task force of the International Conference on Sarcopenia and Frailty Research (ICSFR). METHODS: To develop the guidelines, we drew upon the best available evidence from two systematic reviews paired with consensus statements by international working groups on sarcopenia. Eight topics were selected for the recommendations: (i) defining sarcopenia; (ii) screening and diagnosis; (iii) physical activity prescription; (iv) protein supplementation; (v) vitamin D supplementation; (vi) anabolic hormone prescription; (vii) medications under development; and (viii) research. The ICSFR task force evaluated the evidence behind each topic including the quality of evidence, the benefit-harm balance of treatment, patient preferences/values, and cost-effectiveness. Recommendations were graded as either strong or conditional (weak) as per the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Consensus was achieved via one face-to-face workshop and a modified Delphi process. RECOMMENDATIONS: We make a conditional recommendation for the use of an internationally accepted measurement tool for the diagnosis of sarcopenia including the EWGSOP and FNIH definitions, and advocate for rapid screening using gait speed or the SARC-F. To treat sarcopenia, we strongly recommend the prescription of resistance-based physical activity, and conditionally recommend protein supplementation/a protein-rich diet. No recommendation is given for Vitamin D supplementation or for anabolic hormone prescription. There is a lack of robust evidence to assess the strength of other treatment options.

Management of complex abdominal wall defects associated with penetrating abdominal trauma.

INTRODUCTION: The paradigm of Damage Control Surgery (DCS) has radically improved the management of abdominal trauma, but less well described are the options for managing the abdominal wall itself in an austere environment. This article describes a series of patients with complex abdominal wall problems managed at the UK-led Role 3 Medical Treatment Facility (MTF) in Camp Bastion, Afghanistan. METHOD: Contemporaneous review of a series of patients with complex abdominal wall injuries who presented to the Role 3 MTF between July and November 2012. RESULTS: Five patients with penetrating abdominal trauma associated with significant damage to the abdominal wall were included. All patients were managed using DCS principles, leaving the abdominal wall open at the end of the first procedure. Subsequent management of the abdominal wall was determined by a multidisciplinary team of general and plastic surgeons, intensivists and specialist nurses. The principles of management identified included minimising tissue loss on initial laparotomy by joining adjacent wounds and marginal debridement of dead tissue; contraction of the abdominal wall was minimised by using topical negative pressure dressing and dermal-holding sutures. Definitive closure was timed to allow oedema to settle and sepsis to be controlled. Closure techniques include delayed primary closure with traction sutures, components separation, and mesh closure with skin grafting. DISCUSSION: A daily multidisciplinary team discussion was invaluable for optimal decision making regarding the most appropriate means of abdominal closure. Dermal-holding sutures were particularly useful in preventing myostatic contraction of the abdominal wall. A simple flow chart was developed to aid decision making in these patients. This flow chart may prove especially useful in a resource-limited environment in which returning months or years later for closure of a large ventral hernia may not be possible.

Test-Retest Reliability of an Interactive Voice Response (IVR) Version of the EORTC QLQ-C30.

OBJECTIVE: The objective of this study was to assess the test-retest reliability of an interactive voice response (IVR) version of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. METHODS: A convenience sample of outpatient cancer clinic patients (n = 127) was asked to complete the IVR version of the QLQ-C30 twice, 2 days apart. The QLQ-C30 is a 30-item, cancer-specific questionnaire composed of single-item and multi-item scales. The instrument has five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea/vomiting), and a global quality-of-life scale. The remaining single items assess dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial problems. The analyses focused on intraclass correlation coefficients (ICCs), comparing the ICC 95 % lower confidence interval (CI) value with a critical value of 0.70. RESULTS: The ICCs for the nine multi-item scales were all above 0.69, ranging from 0.698 to 0.926 (ICC 95 % lower CI value range 0.588-0.895). All of the scales were significantly different from our threshold reliability of 0.70, with the exception of the cognitive functioning scale. The ICCs for the six single items ranged from 0.741 to 0.883 (ICC 95 % lower CI value range 0.646-0.835), and three of the six were statistically different from 0.70. The evidence supports the stability of 11 of the 15 scores obtained on the IVR version of the QLQ-C30 upon repeated measurement. CONCLUSION: The measurement equivalence of the IVR and paper versions of the QLQ-C30 has been reported elsewhere. This analysis provides evidence demonstrating adequate test-retest reliability of the IVR version for 11 of the QLQ-C30's 15 scores.

Testing the measurement equivalence of paper and interactive voice response system versions of the EORTC QLQ-C30.

PURPOSE: The objective of this study was to evaluate the measurement equivalence of an interactive voice response system (IVRS) version and the original paper-based version of the EORTC QLQ-C30. METHODS: The QLQ-C30 is a cancer-specific, health-related quality of life questionnaire consisting of nine multi-item scales (physical, role, emotional, cognitive and social functioning, fatigue, nausea/vomiting, pain, and quality of life) and six single item measures (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial problems). This study utilized a crossover design with subjects randomly assigned to one of two assessment orders: (1) paper then IVRS or (2) IVRS then paper. Equivalence between the two administration modes was established by comparing the 95% lower confidence interval (CI) of the intraclass correlation coefficients (ICCs) for each scale, with a critical value of 0.70. RESULTS: The ICCs for the nine multi-item scales were all above 0.79, ranging from 0.791 to 0.899 (ICC 95% lower CI range 0.726-0.865) and significantly different from our threshold reliability of 0.70. The ICCs for the six single items ranged from 0.689 to 0.896 (ICC 95% lower CI range 0.611-0.888). Two of the items, insomnia and appetite loss, were not statistically different from 0.70. When considered together, the per-protocol analysis results support the equivalence of the paper and IVRS versions of the QLQ-C30 for 13 of the 15 scores. CONCLUSION: This analysis provides evidence that the scores obtained from the IVRS version of the QLQ-C30 are equivalent to those obtained with the original paper version except for the insomnia and appetite loss items.

Test-retest reliability of an interactive voice response version of the EQ-5D in a sample of cancer survivors.

BACKGROUND: Electronic data capture technologies, such as interactive voice response (IVR) systems, are emerging as important alternatives for collecting patient-reported outcome data. OBJECTIVE: The objective of this study was to assess the test-retest reliability of an IVR version of the EQ-5D. METHODS: Outpatient cancer clinic patients (n = 127) were asked to complete the IVR-based EQ-5D twice, 2 days apart. The analyses tested for mean differences (paired t-test) and test-retest reliability (intraclass correlation coefficient [ICC]) to assess measurement stability over time. Equivalence of the means was established if the 95% confidence interval (CI) was within the minimally important difference (MID) interval; namely -0.035 to 0.035 for the EQ-5D index and -3.0 to 3.0 for the visual analog scale (i.e. EQ VAS). Adequacy of the ICC was established by testing whether it differed from a value of 0.70. RESULTS: Both administrations were completed per protocol by 114 subjects (EQ-5D index) and 110 subjects (EQ VAS). For the EQ-5D index, the means (SD) of the first and second administrations were 0.871 (0.14) and 0.871 (0.15), respectively. The 95% CI of the mean difference was -0.013, 0.013, within the equivalence interval. The ICC was 0.876 (95% lower bound of 0.826) and was significantly different from 0.70. The EQ VAS means (SD) were 81.3 (17.5) and 80.8 (17.5), respectively. The 95% CI of the mean difference was -0.598, 1.617, within the equivalence interval. The EQ VAS ICC was 0.944 (95% lower bound of 0.919) and was significantly greater than 0.70. CONCLUSION: This analysis provides substantial evidence that the scores obtained from the IVR version of the EQ-5D are reliable upon repeated administrations.

Measurement equivalence of interactive voice response and paper versions of the EQ-5D in a cancer patient sample.

OBJECTIVE: To assess the measurement equivalence of an interactive voice response (IVR) version of the EQ-5D with the original paper version. METHODS: Subjects were randomly assigned to: 1) paper then IVR, or 2) IVR then paper and asked to complete the questionnaire two days apart. The analyses tested mean differences (repeated measures analysis of variance) and reliability (intraclass correlation coefficient [ICC]). Equivalence of the means was established if the 95% confidence interval (CI) of the mean difference was within the minimally important difference interval: -0.035 to 0.035 for the EQ-5D index and -3 to 3 for the visual analog scale (EQ VAS). ICC adequacy was tested by comparing the ICC 95% lower CI with a critical value of 0.70. RESULTS: The analyses included 113 subjects for the index and 109 subjects for the EQ VAS. For the index, the adjusted means of the paper and IVR versions were 0.789 ± 0.016 and 0.798 ± 0. 017, respectively. The 95% CI of the mean difference was -0.024 to 0.006, within the equivalence interval. The ICC was 0.894 (95% lower CI 0.857), significantly greater than 0.70. For the EQ VAS, the adjusted means were 71.94 ± 1.87 for paper and 74.63 ± 1.79 for IVR. The 95% CI of the mean difference was -4.347 to -1.049, partially within the equivalence interval. The ICC was 0.887 (95% lower CI 0.840), significantly greater than 0.70. CONCLUSIONS: The results provide evidence that the EQ-5D scores on the IVR version were sufficiently equivalent to those obtained on the paper version.

Exploring household income as a predictor of psychological well-being among long-term colorectal cancer survivors.

PURPOSE: The purpose of this analysis was to determine the unique contribution of household income to the variance explained in psychological well-being (PWB) among a sample of colorectal cancer (CRC) survivors. METHODS: This study is a secondary analysis of data collected as part of the Health-Related Quality of Life in Long-Term Colorectal Cancer Survivors Study, which included CRC survivors with (cases) and without (controls) ostomies. The dataset included socio-demographic, health status, and health-related quality of life (HRQOL) information. HRQOL was assessed with the modified City of Hope Quality of Life (mCOH-QOL)-Ostomy questionnaire and SF-36v2. To assess the relationship between income and PWB, a hierarchical linear regression model was constructed combining data from both cases and controls. RESULTS: After accounting for the proportion of variance in PWB explained by the other independent variables in the model, the additional variance explained by income was significant (R (2) increased from 0.228 to 0.250; P = 0.006). CONCLUSIONS: Although the study design does not allow causal inference, these results demonstrate a significant relationship between income and PWB in CRC survivors. The findings suggest that for non-randomized group comparisons of HRQOL, income should, at the very least, be included as a control variable in the analysis.

The bispecific antibody 500A2 x 96.5 targets T-lymphocytes activated in vivo with staphylococcal enterotoxin B (SEB) against CL62 melanoma cells in vitro.

Bispecific antibodies (BAb) direct T-lymphocytes to lyse selected tumour targets, both in vitro and in vivo. Significant tumour cell lysis with BAb requires pre-expansion of T-lymphocytes, which may be achieved in vitro by the addition of anti-CD3 monoclonal antibody plus interleukin-2 (IL-2), but anti-CD3 may cause immunosuppression. We investigated an alternative agent for in vivo immunostimulation, staphyloccal enterotoxin B (SEB), which selectively activates certain T-cell subsets and may result in less immunosuppression than with anti-CD3. We activated T-lymphocytes in vivo with SEB, expanded them in vitro with IL-2, and directed them against a tumour target with the BAb 500A2 x 96.5, specific for the murine CD3 antigen and the melanoma p97 antigen expressed by the CL62 tumour. C3H mice received SEB 50 micrograms intraperitoneally (i.p.). After 18 h mice were sacrificed and splenocytes extracted and either passed over a nylon wool column to isolate T-lymphocytes, or cultured in vitro for 3 to 7 days with 100 U ml-1 of IL-2. A 4-h chromium-release assay was used to assess the ability of T-lymphocytes to lyse the tumour target CL 62 in the presence or absence of the bispecific antibody 500A2 x 96.5. The addition of BAb significantly enhanced tumour lysis by SEB activated cells after a period of in vitro culture with IL-2. In vivo SEB results in the activation of T-lymphocytes which may be directed by bispecific antibodies to increase the lysis of selected tumour targets in vitro.

Heteroconjugated antibodies enhance lymphocyte-mediated tumour cell lysis in vitro and in vivo.

Covalent linkage of an antitumour antibody specific for a tumour cell surface antigen to an antilymphocyte antibody specific for the T lymphocyte receptor complex produces a heteroconjugated antibody that can activate and redirect cytotoxic T lymphocytes to lyse tumour cells. The ability of an antilymphocyte-antitumour heteroconjugate (500A2 x 96.5) to direct the lysis of murine melanoma cells by cultured murine lymphocytes was tested in vitro using a 4-h chromium release assay and in vivo with a tumour neutralization assay. In vitro, the addition of heteroconjugated antibody significantly increased tumour lysis by murine C3H/HeN lymphocytes (median specific lysis 82.7 per cent with lymphocytes plus heteroconjugate versus 9.5 per cent for lymphocytes alone, P less than 0.001). In vivo, treatment with heteroconjugated antibody plus lymphocytes significantly reduced the development of pulmonary metastases after intravenous tumour administration (median number of pulmonary metastases 28.5 for combined treatment versus 250 for heteroconjugate or lymphocytes alone, P less than 0.001).

Enhancement of in vitro tumor-infiltrating lymphocyte cytotoxicity by heteroconjugated antibodies.

Tumor-infiltrating lymphocytes (TIL) were obtained from a mouse melanoma cell line (CL 62) transfected with the gene for the human melanoma Ag p97. TIL were cultured with anti-CD3 antibody and IL-2 for up to 38 days. Flow cytometry identified these TIL as Thy-1.2 + ve/CD4-ve/CD8 + ve cells. A heteroconjugated antibody 500A2 x 96.5, specific for both the CD3 Ag on TIL and the p97 Ag on CL 62 melanoma cells, was prepared using N-succinimidyl-3-(2-pyridyldithio)-propionate as a linking agent. TIL alone demonstrated low levels of cytotoxicity against autologous CL 62 tumor and also against the parental K1735 tumor and an allogeneic murine melanoma (B16). The addition of 500A2 x 96.5 heteroconjugated antibody enhanced TIL-mediated lysis of CL 62 tumor, but not of the K1735 or B16 tumors. This enhanced cytotoxicity was elicited at E:T ratios as low as 0.4:1, and in TIL cultured for 7 to 38 days. These results suggest that hetero-conjugated antibody may enhance the anti-tumor effect of TIL in vivo.

Expression of neu protein, epidermal growth factor receptor, and transforming growth factor alpha in breast cancer. Correlation with clinicopathologic parameters.

The major objectives of this study were twofold: to determine 1) if growth factors or growth factor receptors were expressed similarly or differently in a clinically well-characterized group of breast cancer patients and 2) if these phenotypic characteristics were associated with any of the commonly used prognostic parameters. Formalin-fixed paraffin-embedded tumor tissue from 51 node-positive breast cancer patients were analyzed for the expression of neu, epidermal growth factor-receptor (EGF-R), and transforming growth factor alpha (TGF alpha) using immunoperoxidase staining. Positive membranous staining for neu was observed in 15 (29%) tumors. Over-expression of neu was observed in high-grade, estrogen-receptor-negative tumors (P less than 0.05). Epidermal growth factor receptor was expressed in 22 (43%) of the tumors analyzed and found to a greater degree in estrogen-receptor-negative and high-grade tumors (P less than 0.025). A significant correlation between neu and EGF-R expression was also noted. Tumors expressing membranous staining of neu had a greater than 70% chance of expressing EGF-R (P less than 0.01). Expression of TGF alpha was found in 68% of tumors and TGF alpha was detected in grade 1 and 2 tumor to a greater degree than EGF-R. The authors conclude that assaying tumors for these antigens may give additional phenotypic characteristics that can give further insight into the biology of breast cancer.

The use of fine-needle aspirates of breast cancers to evaluate hormone-receptor status.

The objective of this study was to determine the reliability of immunocytochemical assays of hormone receptors using specimens obtained by fine-needle aspiration of breast cancers. A peroxidase-antiperoxidase immunocytochemical assay was used on 96 aspirates from 47 patients to determine estrogen and progesterone receptor status. Of 27 estrogen receptor-positive cases by steroid-binding analysis, 25 were positive by immunocytochemical assay. Of 21 estrogen receptor-negative cases, 17 were negative by immunocytochemical assay. Of 21 progesterone receptor-positive cases 19 were positive by immunocytochemical assay. Of 27 progesterone receptor-negative cases 25 were negative by immunocytochemical assay. An additional 11 small tumors were evaluated by immunocytochemical assay alone and results were interpretable based on our prior data. With the caveat that a cellular aspirate is obtained, immunocytochemical assay can distinguish hormone receptor-negative and hormone receptor-positive tumors and can be used to assay tumors too small for standard steroid-binding analysis.

The use of fine needle aspirates in the evaluation of progesterone receptor content in breast cancer.

Material obtained by fine needle aspiration (FNA) from 30 surgically removed breast carcinomas was tested for the immunocytochemical localization of progesterone receptor (PR) using a monoclonal antibody (MAb) developed against human breast cancer PR. When compared to values obtained by conventional biochemical analysis of cytosol protein in the same tissue, a semiquantitative relationship suggested that a high intensity (3+) stain in cases in which more than 30% of the cells were positive was compatible with a PR concentration of greater than 200 fmol/mg. An absence of nuclear stain was indicative of a PR concentration of less than 10 fmol/mg, while a stain of an intermediate intensity (2+) or a stain of high intensity (3+) in less than 30% of the cells correlated with a PR level of 51-200 fmol/mg. Only one case in this group showed weak staining with a PR concentration of 85.5 fmol/mg. Cases containing a low concentration of PR (less than 50 fmol/mg) demonstrated a weak nuclear stain (1+) in less than 10% of the cells. Localization of nuclear PR by MAb staining of FNA cytologic specimens affords a relatively simple, inexpensive method of obtaining potentially significant information regarding tumor response to hormonal therapy and the recurrence potential of a tumor in patients with primary breast cancer; at the same time, this technique obviates several important disadvantages of conventional biochemical analysis.

Culture of human neoplastic gastrointestinal smooth muscle cells.

Due to limited growth potential of primary cultures and the absence of continuous lines of healthy enteric smooth muscle, we have studied the culture behavior of neoplastic gastrointestinal smooth muscle cells. Forty-six human enteric smooth muscle neoplasms (leiomyomas and leiomyosarcomas) were studied while fresh and/or after culture in vitro and growth in vivo in athymic nude mice, with assessments made of morphology, growth characteristics, and biochemical markers of differentiation. The state of differentiation of the tumors varied, with well-differentiated tumors tending to express binding sites for the gastrointestinal hormone cholecystokinin, whereas less well-differentiated tumors did not. Poorly differentiated tumors were the easiest to establish in culture in vitro and to grow in vivo in nude mice. When the cells placed directly into culture proliferated to confluent density, they underwent morphologic differentiation from a spread, fibroblastlike shape to a slender spindle morphology, with these cells possessing fewer biosynthetic organelles and arranging themselves in characteristic "hill and valley" arrays. However, the highly differentiated characteristics of expression of desmin or cholecystokinin-binding sites were not observed in cultured cells. In contrast, cells that had been passaged in nude mice before culture displayed a proliferative phenotype and failed to undergo morphologic differentiation on reaching confluent density. Four human enteric smooth muscle cell lines (documented by chromosomal analysis) originating in stomach, jejunum, ileum, and rectum were established using this strategy.

Monoclonal antibody B72.3. An adjunct for evaluation of suspicious aspiration biopsy cytology from the breast.

Monoclonal antibody B72.3 (MoAb B72.3) is a potentially valuable diagnostic adjunct when applied to aspiration biopsy cytology (ABC). In this prospective study, its reactivity was tested on the ABC from 25 breast lesions interpreted as suspicious. The stain was applied directly to the Papanicolaou-stained specimen by the avidin-biotin peroxidase methodology at a concentration of 40 micrograms/ml. In 11 aspirates from invasive carcinomas, the reactivity to MoAb B72.3 was strongly positive in nine cases and weakly positive in two. Ten of these tumors were homogeneous or heterogeneous infiltrating lobular neoplasms, tumors causing special diagnostic pitfalls by ABC. The cells from seven of the nine benign lesions were nonreactive, and in two cases from fibrocystic change, weakly reactive. The ABC from five patients with noninvasive carcinomas or atypical lobular hyperplasia showed a variety of responses. The findings indicate that in select circumstances, MoAb B72.3 used in conjunction with clinical and cytologic findings may be a useful diagnostic adjunct.

Carcinoid tumor metastatic to breast diagnosed by fine needle aspiration. Case report and literature review.

Fine needle aspiration (FNA) biopsy was used to study a mass in the left breast in a patient with a previous history of an ileal carcinoid tumor and later lymph node metastases who presented with bilateral palpable breast masses. The FNA specimens showed the lesion to be a carcinoid tumor. The metastatic nature of the lesion was proven by positive restaining of FNA smears by both the Sevier-Munger technique (demonstrating abundant argyrophilic cytoplasmic granules) and the Fontana-Masson method (showing argentaffin cytoplasmic granules). The distinction between primary and metastatic carcinoid tumors of the breast is discussed, as is their origin and their differentiation from other malignancies of the breast.