Evaluation of an enhanced pathological examination protocol for sentinel lymph nodes from patients with breast carcinoma

Clinical trials have shown that many patients with breast cancer with limited sentinel lymph node (SLN) metastatic disease can safely avoid axillary lymph node dissection. Ultra-staging of initially negative SLNs may not confer additional clinical benefit. Despite this, protocols of ‘enhanced pathological examination’ (EPE) are still widely used. We evaluated the impact of our EPE protocol. If initial SLN H&Es are negative, we cut three additional H&E levels at 500 µm intervals with two spare sections at each level, to allow for immunohistochemistry if necessary. Occult micrometastases or isolated tumour cells were identified, using this protocol, in 3.4%, resulting in change of N stage in 3%. 1% of patients had further axillary surgery based on these findings. Our SLN-EPE protocol provided additional information in a small number of cases and changed axillary management in a minority. It represented a significant workload for scientists and pathologists, and had time and cost implications. We concluded that emphasising careful gross examination along with judicious use of additional levels and immunohistochemistry may be more beneficial than our current protocol.

Long-term survival from pembrolizumab (pembro) completion and pembro retreatment: Phase III KEYNOTE-006 in advanced melanoma.

10013 Background: 5-year follow-up of the phase 3 KEYNOTE-006 study (NCT01866319) showed pembro improved OS vs ipilimumab (ipi) in patients (pts) with advanced melanoma. 3-y OS rate from pembro completion for pts who completed 2 y of pembro was 93.8%. Results with 8 mo of additional follow-up are presented to inform clinical care. Methods: Eligible pts with ipi-naive advanced melanoma, ≤1 prior therapy for BRAF-mutant disease, and ECOG PS 0 or 1 were randomized to pembro 10 mg/kg Q2W or Q3W for ≤2 y or ipi 3 mg/kg Q3W for 4 doses. Pts discontinuing pembro with CR, PR, or SD after ≥94 weeks were considered pts with 2-y pembro. Pts who stopped pembro with SD, PR or CR could receive ≤12 mo of additional pembro (2nd course) upon disease progression if still eligible. ORR was assessed per immune-related response criteria by investigator review. OS was estimated using the Kaplan-Meier method. Pembro arm data were pooled. Post hoc ITT efficacy analyses are shown. Results: Median follow-up from randomization to data cutoff (Jul 31, 2019) was 66.7 mo in the pembro and 66.9 mo in the ipi arms. OS outcomes are shown in Table. For the 103 pts with 2-y pembro (30 CR, 63 PR, 10 SD), median follow-up from completion was 42.9 mo (95% CI, 39.9-46.3).Median DOR was not reached. 36-mo OS from pembro completion was 100% (95% CI, 100.0-100.0) for pts with CR, 94.8% (95% CI, 84.7-98.3) for pts with PR, and 66.7% (95% CI, 28.2-87.8) for pts with SD. 15 pts received 2nd-course pembro; BOR in 1st course was 6 CR, 6 PR, and 3 SD. Median time from end of 1st course to start of 2ndcourse was 24.5 mo (range, 4.9-41.4). Median follow-up in pts who received 2nd-course pembro was 25.3 mo (range, 3.5-39.4). Median duration of 2nd-course pembro was 8.3 mo (range, 1.4-12.6). BOR on 2ndcourse was 3 CR, 5 PR (ongoing responses, 7 pts), 3 SD (ongoing, 2 pts), and 2 PD (1 death); 2 pts pending. Conclusions: Pembro improves the long-term survival vs ipi in pts with advanced melanoma, with all pts who completed therapy in CR still alive at 5 years. Retreatment with pembro at progression in pts who stopped at SD or better can provide additional clinical benefit in a majority of pts. Clinical trial information: NCT01866319. [Table: see text]

Results of a phase II study evaluating trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC).

48 Background: Patients (pts) with colorectal cancer (CRC) with microsatellite instability (MSI) have recently been shown to respond to anti–programmed death (PD)-1 drugs. Preclinical data suggest that trifluridine/tipiracil (FTD/TPI) treatment converts MSS CRC cells to MSI, sensitizing them to the activity of anti–PD-1 drugs. The aim of this phase 2 study was to evaluate this hypothesis. Methods: This was a multicenter, single-arm, safety lead-in, phase 2 study that used Simon’s 2-stage design to evaluate the safety and efficacy of FTD/TPI (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks) in pts with heavily pretreated MSS mCRC. Pts had histologically proven metastatic or locally advanced colorectal adenocarcinoma that was MSS (assessed by a local laboratory based on either previous or fresh biopsy), ≥1 measurable lesion for RECIST and immune-related response criteria (irRC) assessment, and failure of ≥2 previous lines of chemotherapy. Six pts were to be enrolled in the safety lead-in, and in order to proceed to Simon’s stage 2, ≥2 of the first 15 pts had to demonstrate a partial or complete response within 6 months based on irRC assessment. Results: The first 6 dose-limiting toxicity (DLT)-evaluable pts enrolled tolerated dosing with no DLTs. A total of 18 pretreated pts enrolled in the first stage (50% males; median age 56.5 yr), among whom 72% had colon cancer and 100% had MSS disease, 56% with RAS mutations. Pts received a median of 2.5 cycles of study therapy (range 1-8). The most common grade 3/4 adverse events (AEs) were neutropenia (28%); diarrhea (17%); and nausea, abdominal pain, fatigue, and anemia (11% each). No pts discontinued treatment due to AEs. No pts achieved a tumor response (either per RECIST or irRC), and the study did not progress to the second stage. Median (6-month) progression-free survival was 2.8 months (21%) per RECIST and 2.2 months (30%) per irRC. Conclusions: The combination of FTD/TPI and nivolumab was feasible and tolerated at the full dose of both compounds. Adding nivolumab to FTD/TPI did not provide additional clinical benefit in pts with previously treated MSS mCRC. Clinical trial information: NCT02860546.

Evaluation of the Repeatability and Accuracy of the Wideband Real-Ear-to-Coupler Difference

The real-ear-to-coupler difference (RECD) is an ANSI standardized method for estimating ear canal sound pressure level (SPL) thresholds and assisting in the prediction of real-ear aided responses. It measures the difference in dB between the SPL produced in the ear canal and the SPL produced in an HA-1 2-cc coupler by the same sound source. Recent evidence demonstrates that extended high-frequency bandwidth, beyond the hearing aid bandwidth typically measured, is capable of providing additional clinical benefit. The industry has, in turn, moved toward developing hearing aids and verification equipment capable of producing and measuring extended high-frequency audible output. As a result, a revised RECD procedure conducted using a smaller, 0.4-cc coupler, known as the wideband-RECD (wRECD), has been introduced to facilitate extended high-frequency coupler-based measurements up to 12.5 kHz.This study aimed to (1) compare test–retest repeatability between the RECD and wRECD and (2) measure absolute agreement between the RECD and wRECD when both are referenced to a common coupler.RECDs and wRECDs were measured bilaterally in adult ears by calculating the dB difference in SPL between the ear canal and coupler responses. Real-ear probe microphone measures were completed twice per ear per participant for both foam-tip and customized earmold couplings using the Audioscan Verifit 1 and Verifit 2 fitting systems, followed by measurements in the respective couplers.Twenty-one adults (mean age = 67 yr, range = 19–78) with typical aural anatomy (as determined by measures of impedance and otoscopy) participated in this study, leading to a sample size of 42 ears.Repeatability within RECD and wRECD was assessed for each coupling configuration using a repeated-measures analysis of variance (ANOVA) with test–retest and frequency as within-participants factors. Repeatability between the RECD and wRECD was assessed within each configuration using a repeated-measures ANOVA with test–retest, frequency, and coupler type as within-participants factors. Agreement between the RECD and wRECD was assessed for each coupling configuration using a repeated-measures ANOVA with RECD value, coupler type, and frequency as within-participants factors. Post hoc comparisons with Bonferroni corrections were used when appropriate to locate the frequencies at which differences occurred. A 3-dB criterion was defined to locate differences of clinical significance.Average absolute test–retest differences were within ±3 dB within each coupler and coupling configuration, and between the RECD and wRECD. The RECD and wRECD were in absolute agreement following HA-1-referenced transforms, with most frequencies agreeing within ±1 dB, except at 0.2 kHz for the earmold, and 0.2–0.25 kHz for the foam tip, where the average RECD exceeded the average wRECD by slightly >3 dB.Test–retest repeatability of the RECD (up to 8 kHz) and wRECD (up to 12.5 kHz) is acceptable and similar to previously reported data. The RECD and wRECD are referenced to different couplers, but can be rendered comparable with a simple transform, producing values that are in accordance with the ANSI S3.46-2013 standard.

Optimising the use of cetuximab in the continuum of care for patients with metastatic colorectal cancer

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment ofRASwild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on later-line cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring ofRASstatus may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintainedRASwt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion ofRAS-mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose thatRASstatus determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment benefit can be extended, adding to established continuum-of-care strategies in patients with mCRC.

Comparing physician and nurse ECOG performance status ratings as predictors of clinical outcomes in cancer patients.

248 Background: The Eastern Cooperative Oncology Group Performance Status (ECOG) scale is commonly used in the clinical and research setting, and has been shown to correlate with cancer morbidity, mortality, and tolerance to chemotherapy. ECOG is frequently rated by physicians (MDs) and nurses (RNs), and MD-RN ECOG score agreement varies widely in the literature. It remains unclear whether MD and RN ECOG scores differ in their ability to predict clinical outcomes. Methods: As part of a quality initiative at Cedars-Sinai Cancer Center, oncologists and chemotherapy RNs independently scored ECOGs for a random sample of 309 patients with various solid malignancies, on one or more visits, for a total of 506 pairs of ECOG scores. MD/RN interrater agreement was evaluated using the Cohen's kappa coefficient. Logistic regression models were fit to evaluate the ability of RN and MD ECOG scores, as well as the RN-MD score difference, to predict the occurrence of chemotoxicity (CTCAE v4, grade≳3) and hospitalizations within 1 month from ECOG ratings as well as 6-month mortality/hospice referrals. Results: The agreement among 506 ECOG MD/RN pairs was 71% (Kappa = 0.485, p < 0.0001). RN ECOGs had a stronger odds ratio (OR) for 6-month mortality/hospice (OR = 3.55, CI 2.2-5.7) compared to MD ECOGs (OR = 2.99, CI 1.67-5.3). RN ECOG scores also significantly correlated with one-month chemotoxicity (OR = 1.39, CI 1.02-1.90), but MD ECOGs did not. Both MD and RN ECOG scores did not significantly correlate with 1-month hospitalizations. The magnitude of RN to MD ECOG score difference was also positively associated with 6-month mortality/hospice (OR = 3.42, CI 1.87-6.3), but not with 1-month hospitalization or chemotoxicity. Conclusions: Our findings suggest that RN-rated ECOGs may be stronger predictors of chemotoxicity and 6-month mortality/hospice compared to MD ECOGs. Furthermore, the magnitude of difference between ECOG MD and RN ratings was associated with increased mortality/hospice rates, specifically when the MD rating was “healthier” than that of the RN. As ECOG scores are frequently used for prognostication and to inform treatment decisions, ECOG scoring by RNs may result in additional clinical benefit.

Clozapine augmented with risperidone in treatment-resistant schizophrenia

IntroductionThe evolution of various pharmacological therapies for schizophrenia has given rise to several pharmacological models for the neuroreceptor targets of antipsychotics and the influence of various neuroreceptors on specific symptoms and side effects.ObjectivesExperience in clinical practice affirms clozapine's position as the treatment of choice for patients with treatment-refractory schizophrenia. Unlike clozapine, risperidone has a more targeted profile of neurotransmitter binding, with particular predilection for dopamine and serotonin receptors. Risperidone is, to date, the most extensively documented clozapine augmentation agent.AimThe aim was to evaluate clinical efficacy, safety and tolerability of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia.MethodsIn a randomized, double-blind, placebo-controlled 8-week trial, 10 patients unresponsive or partially responsive to 300 mg/day of clozapine monotherapy (n = 5) received a steady dose of 450 mg/day clozapine combined with or up to 4 mg/day of risperidone (n = 5). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS) and Clinical Global Impression (CGI) improvement scale.ResultsFrom baseline to week 4 and week 8, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine monotherapy group. Clozapine/risperidone treatment did not induce additional weight gain or agranulocytosis compared with clozapine monotherapy treatment.ConclusionsClozapine augmentation with risperidone appears to be well tolerated, safe and may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Recombinant Human Insulin in Global Diabetes Management – Focus on Clinical Efficacy

Biosynthetic human insulin and insulin analogues are the mainstay of insulin therapy for both type 1 and type 2 diabetes although access to human insulin at affordable prices remains a global issue. The world is experiencing an exponential rise in the prevalence of diabetes presenting an urgent need to establish effective diabetes therapy in countries burdened by inadequate health care budgets, malnutrition and infectious diseases. Recombinant human insulin has replaced animal insulins and animal-based semisynthetic human insulin thereby available in sufficient quantities and at affordable prices able to provide global access to insulin therapy. In many patients, analog insulins can offer additional clinical benefit, although at a considerably higher price thus severely restricting availability in low income countries. The approval process for recombinant human insulins (i.e. biosimilars) and analogue insulins is highly variable in the developing countries in contrast to Europe and in North America, where it is well established within a strict regulatory framework. This review aims to discuss the future access to human insulin therapy in a global context with an ever increasing burden of diabetes and significant economic implications.