Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

Capsule endoscopy for small‐intestinal disorders: Current status

Small‐bowel capsule endoscopy (SBCE) is used widely because of its non‐invasive and patient‐friendly nature. SBCE can visualize entire small‐intestinal mucosa and facilitate detection of small‐intestinal abnormalities. In this review article, we focus on the current status of SBCE. Several platforms for SBCE are available worldwide. Third‐generation SBCE (PillCam^® SB3) has a high‐resolution camera equipped with an adaptive frame rate system. Several software modes have been developed to reduce the reading time for capsule endoscopy and to minimize the possibility of missing lesions. The main complication of SBCE is capsule retention. Thus, the main contraindication for SBCE is known or suspected gastrointestinal obstruction unless intestinal patency is proven. Possible indications for SBCE are obscure gastrointestinal bleeding, Crohn's disease, small‐intestinal polyps and tumors, and celiac disease. Colon capsule endoscopy (CCE) can observe inflamed colonic mucosa non‐invasively, and allows for the continuous and non‐invasive observation of the entire intestinal tract (pan‐endoscopy). Recently, application of CCE as pan‐enteric endoscopy for inflammatory bowel diseases (including Crohn's disease) has been reported. In the near future, reading for CE will be assisted by artificial intelligence, and reading CE videos for long periods will not be required.     

YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

Molecular‐targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan‐HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2‐positive breast cancer. However, acquired resistance of various cancers to molecular‐targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib‐resistant cell lines from HER2‐amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1‐amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.     

Outcomes After Aortic Valve Replacement for Asymptomatic Severe Aortic Regurgitation and Normal Ejection Fraction

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The Impact of Comprehensive Care for Joint Replacement Bundled Payment Program on Care Delivery

Background

Comprehensive Care for Joint Replacement (CJR) is a Medicare initiative to test the impact of holding a hospital accountable for services provided during an episode of care for a lower extremity joint arthroplasty on costs and quality. This study examines whether hospital participation in CJR is associated with having programs focused on improving posthospitalization care or reducing costs using a survey of orthopedic surgeons.

Diffuse Astrocytoma Initially Presenting as a Massive Intracerebral Hemorrhage: Case Report

We report the case of a 58-year-old woman with low-grade astrocytoma, who developed massive intracranial hemorrhage as the first presentation of this disease, and become comatose and subsequently underwent an emergency craniotomy. A small amount of tumor-like tissue was observed on the wall of the hematoma cavity. Histological analysis of the resected specimen indicated diffuse astrocytoma [World Health Organization (WHO) grade II]. The patient was discharged without neurological deficits 2 weeks after the operation. A non-enhanced tumor-like nodule was observed on magnetic resonance imaging 3 months after the operation, which was monitored carefully but was not treated by adjuvant therapy. The tumor grew gradually, and a second operation was performed 3 years after the first, in which the tumor was completely resected. Histological analysis of the resected specimen again indicated diffuse astrocytoma (WHO grade II). Although rare, brain tumors, including low-grade astrocytoma, should be considered a possible cause of subcortical hemorrhage in patients without risk factors for intracranial hemorrhage.