Multiple COVID-19 Clusters on a University Campus - North Carolina, August 2020.

Preventing transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), in institutes of higher education presents a unique set of challenges because of the presence of congregate living settings and difficulty limiting socialization and group gatherings. Before August 2020, minimal data were available regarding COVID-19 outbreaks in these settings. On August 3, 2020, university A in North Carolina broadly opened campus for the first time since transitioning to primarily remote learning in March. Consistent with CDC guidance at that time (1,2), steps were taken to prevent the spread of SARS-CoV-2 on campus. During August 3-25, 670 laboratory-confirmed cases of COVID-19 were identified; 96% were among patients aged <22 years. Eighteen clusters of five or more epidemiologically linked cases within 14 days of one another were reported; 30% of cases were linked to a cluster. Student gatherings and congregate living settings, both on and off campus, likely contributed to the rapid spread of COVID-19 within the university community. On August 19, all university A classes transitioned to online, and additional mitigation efforts were implemented. At this point, 334 university A-associated COVID-19 cases had been reported to the local health department. The rapid increase in cases within 2 weeks of opening campus suggests that robust measures are needed to reduce transmission at institutes of higher education, including efforts to increase consistent use of masks, reduce the density of on-campus housing, increase testing for SARS-CoV-2, and discourage student gatherings.

Denosumab: Prevention and management of hypocalcemia, osteonecrosis of the jaw and atypical fractures.

Denosumab, a bone-modifying agent, reduces the risk of skeletal-related events in patients with bone metastases from solid tumors and is generally well tolerated. However, hypocalcemia, osteonecrosis of the jaw (ONJ) and atypical fracture are potential and important toxicities of denosumab therapy that require attention. In pivotal phase III trials in patients with bone metastases from solid tumors, the incidence of hypocalcemia was 9.6% in denosumab-treated patients, with most events being asymptomatic, grade 2 and resolving by week 4. Established hypocalcaemia requires additional short-term calcium and vitamin D supplementation and, if severe, administration of intravenous calcium. ONJ was reported in 1.8% of patients receiving denosumab over 3 years in these trials. Involvement of an experienced oro-maxillary surgeon is important if ONJ is suspected. Atypical fractures were rare in a large study of denosumab using the dose and scheduling approved for the treatment of osteoporosis. To prevent toxicities, patients should maintain calcium and vitamin D supplementation, good oral hygiene and regular dental reviews throughout treatment. This article presents case studies from our clinical practice and discusses the pathophysiology of these toxicities along with guidance on prevention, diagnosis and management.

Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small-cell lung cancer: an open-label phase II multicentre trial (COVeRT study).

Chemoradiotherapy regimens for stage III non-small-cell lung cancer (NSCLC) require ongoing evaluation. This South Australian multicentre prospective phase II study evaluated the safety, activity and outcomes of combination oral vinorelbine and cisplatin administered concurrently with radiotherapy for stage III NSCLC. Consecutive eligible patients received two cycles of oral vinorelbine 50 mg/m day 1 (D1), day 8 (D8) and intravenous cisplatin 50 mg/m D1 and D8 in a 21-day cycle. Chemotherapy was administered concurrently with radiotherapy at 60 Gy in 30 fractions, 2 Gy/fraction to the isocentre, all fields treated daily, 5 days a week over 6 weeks using 10 MV photons and three-dimensional conformal radiotherapy. The primary endpoint was to evaluate the progression-free survival (PFS). The secondary end points were safety, response rates and overall survival (OS). Forty-three eligible patients with stage III NSCLC - comprising 21 squamous cell carcinoma, 18 adenocarcinoma and four large cell carcinoma - were studied. Four patients did not complete the treatment. By intention-to-treat analysis, 25% showed a partial response and 65% had stable disease. None achieved a complete response. Of the 39 patients who completed protocol-specified treatment, 11 (28%) showed a partial response and 28 (72%) had stable disease. The median PFS was 25.2 months and the median OS was 48.3 months. Toxicities were manageable and generally mild, with the majority being either grade 1 (n=38) or grade 2 (n=21). Toxicities were mainly of oesophagitis, pneumonitis, fatigue, nausea and dysphagia. Two cycles of chemotherapy with oral vinorelbine and cisplatin administered concurrently with radical radiation had an acceptable toxicity profile and was active in inoperable stage III NSCLC. PFS and OS outcomes were encouraging. This regimen warrants further investigation.

Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced nonsquamous non-small-cell lung cancer.

PURPOSE: Linifanib, a potent, selective inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, has single-agent activity in non-small-cell lung cancer (NSCLC). We evaluated linifanib with carboplatin and paclitaxel as first-line therapy of advanced nonsquamous NSCLC. PATIENTS AND METHODS: Patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned to 3-week cycles of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) with daily placebo (arm A), linifanib 7.5 mg (arm B), or linifanib 12.5 mg (arm C). The primary end point was progression-free survival (PFS); secondary efficacy end points included overall survival (OS) and objective response rate. RESULTS: One hundred thirty-eight patients were randomly assigned (median age, 61 years; 57% men; 84% smokers). Median PFS times were 5.4 months (95% CI, 4.2 to 5.7 months) in arm A (n = 47), 8.3 months (95% CI, 4.2 to 10.8 months) in arm B (n = 44), and 7.3 months (95% CI, 4.6 to 10.8 months) in arm C (n = 47). Hazard ratios (HRs) for PFS were 0.51 for arm B versus A (P = .022) and 0.64 for arm C versus A (P = .118). Median OS times were 11.3, 11.4, and 13.0 months in arms A, B, and C, respectively. HRs for OS were 1.08 for arm B versus A (P = .779) and 0.88 for arm C versus A (P = .650). Both linifanib doses were associated with increased toxicity, including a higher incidence of adverse events known to be associated with VEGF/PDGF inhibition. Baseline plasma carcinoembryonic antigen/cytokeratin 19 fragments biomarker signature was associated with PFS improvement and a trend toward OS improvement with linifanib 12.5 mg. CONCLUSION: Addition of linifanib to chemotherapy significantly improved PFS (arm B), with a modest trend for survival benefit (arm C) and increased toxicity reflective of known VEGF/PDGF inhibitory effects.

A descriptive study of persistent oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer.

BACKGROUND: Prolonged neurotoxicity after systemic chemotherapy has the potential to impact on quality of life. We explored the frequency of persistent peripheral neuropathy in patients who received oxaliplatin for colorectal cancer at two local centres. PATIENTS AND METHODS: Questionnaires were sent to patients who completed treatment with oxaliplatin for colorectal cancer at least 20 months prior to entering the study. Neuropathy questions were adapted from the FACT/GOG-Ntx (V.4) questionnaire. RESULTS: Of the 56 eligible patients, 27 returned the questionnaire. Twenty-five patients (93 %) experienced neuropathic symptoms during their treatment; 11 had grade-2, and two had grade-3 symptoms. At the time of completing the questionnaire, 17 patients (63.0 %; 95%CI 43.9-79.4 %) were still symptomatic with 12 patients (44.4 %; 95%CI 26.8-63.3) having grade-2 or grade-3 symptoms and three patients (11.1 %; 95%CI 2.9-27.3) having grade-3 neuropathic symptoms. Participants who received more than 900 mg/m2 oxaliplatin had a significantly higher risk of persistent grade-2 or grade-3 neuropathy (p = 0.031, RR = 8.3 95%CI = 1.2-57.4). There was a trend toward increased risk of persistent neuropathy of any grade among participants with a history of regular alcohol use (p = 0.051; RR = 1.7 95%CI 1.0-2.8). CONCLUSION: Persistent oxaliplatin-induced neuropathy is not as uncommon as previously suggested, and the rate of grade-2 and grade-3 symptoms could be considerably higher than previous reports.

Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma.

PURPOSE: This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. PATIENTS AND METHODS: In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non-clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. RESULTS: Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. CONCLUSION: In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.

Small cell lung cancer: patterns of care and their influence on survival - 25 years experience of a single Australian oncology unit.

AIM: Evidence supporting improved outcomes for small cell lung cancer (SCLC) in recent decades is limited. This study aimed to identify patterns of care and survival over two time periods; 1 January 1987 to 31 December 1996 (cohort A) and 1 January 1997 to 31 December 2006 9 (cohort B). METHODS: Patients' characteristics, management and outcome data were extracted from the Hospital Cancer Registry and clinical records. Survival analysis was determined using the Kaplan-Meier method and the log-rank test. Factors influencing survival outcome were assessed using Cox proportional hazards regression. RESULTS: The total number of patients was 392 (224 in cohort A, 168 in cohort B). Overall 38% patients in cohort A and 24% in cohort B had limited stage (LS) disease at diagnosis. Combined chemoradiotherapy for LS increased from 5% in cohort A to 65% in cohort B. Overall 19% of patients in cohort A and 24% in cohort B received symptomatic treatment alone (STA). Median survival for LS in cohort B was significantly higher (19.5 months), than in cohort A (11.8 months) (P = 0.03). In extensive stage (ES) disease, median survival was 6.2 months in cohort A and 4.3 months in cohort B (P = 0.7). Variables for poorer outcome were STA, male gender, poor performance status, ES and whether the diagnosis was made in the earlier time period in cohort A. CONCLUSION: Outcomes for LS SCLC have improved with combined chemoradiotherapy, in keeping with worldwide data. The trends may also reflect recent improvements in staging and standardization of treatment. The outcome for ES-SCLC remains poor.

Reversing Hyperammonemia in Neuroendocrine Tumors.

Ammonia is a neurotoxin that is normally cleared by the intact liver and if not, hyperammonemia results in hepatic encephalopathy. Hyperammonemia may be owing to primary or secondary causes. Early diagnosis is important to prevent permanent brain damage. Advanced malignancy involving the liver is associated with hyperammonemia as a result of abnormality of the portal venous system or massive hepatic tumor burdon. Neuroendocrine tumors are an example of a malignant process that frequently involves the liver but despite this, may still have a relatively good prognosis, and are often characterized by chronic manageable symptoms and slow progression. Hyperammonemia in neuroendocrine tumor would represent a potentially reversible but ongoing process associated with an indolent malignancy. We present 2 cases that are examples of this diagnosis and discuss the diagnostic and management issues that may arise.

Identification of circulating tumour cells in early stage breast cancer patients using multi marker immunobead RT-PCR.

INTRODUCTION: The ability to screen blood of early stage operable breast cancer patients for circulating tumour cells is of potential importance for identifying patients at risk of developing distant relapse. We present the results of a study of the efficacy of the immunobead RT-PCR method in identifying patients with circulating tumour cells. RESULTS: Immunomagnetic enrichment of circulating tumour cells followed by RT-PCR (immunobead RT-PCR) with a panel of five epithelial specific markers (ELF3, EPHB4, EGFR, MGB1 and TACSTD1) was used to screen for circulating tumour cells in the peripheral blood of 56 breast cancer patients. Twenty patients were positive for two or more RT-PCR markers, including seven patients who were node negative by conventional techniques. Significant increases in the frequency of marker positivity was seen in lymph node positive patients, in patients with high grade tumours and in patients with lymphovascular invasion. A strong trend towards improved disease free survival was seen for marker negative patients although it did not reach significance (p = 0.08). CONCLUSION: Multi-marker immunobead RT-PCR analysis of peripheral blood is a robust assay that is capable of detecting circulating tumour cells in early stage breast cancer patients.

Optimisation of the RT-PCR detection of immunomagnetically enriched carcinoma cells.

BACKGROUND: Immunomagnetic enrichment followed by RT-PCR (immunobead RT-PCR) is an efficient methodology to identify disseminated carcinoma cells in the blood and bone marrow. The RT-PCR assays must be both specific for the tumor cells and sufficiently sensitive to enable detection of single tumor cells. We have developed a method to test RT-PCR assays for any cancer. This has been investigated using a panel of RT-PCR markers suitable for the detection of breast cancer cells. METHODS: In the assay, a single cell line-derived tumor cell is added to 100 peripheral blood mononuclear cells (PBMNCs) after which mRNA is isolated and reverse transcribed for RT-PCR analysis. PBMNCs without added tumor cells are used as specificity controls. The previously studied markers epidermal growth factor receptor (EGFR), mammaglobin 1 (MGB1), epithelial cell adhesion molecule (EpCAM/TACSTD1), mucin 1 (MUC1), carcinoembryonic antigen (CEA) were tested. Two new epithelial-specific markers ELF3 and EphB4 were also tested. RESULTS: MUC1 was unsuitable as strong amplification was detected in 100 cell PBMNC controls. Expression of ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 was found to be both specific for the tumor cell, as demonstrated by the absence of a signal in most 100 cell PBMNC controls, and sensitive enough to detect a single tumor cell in 100 PBMNCs using a single round of RT-PCR. CONCLUSIONS: ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 are appropriate RT-PCR markers for use in a marker panel to detect disseminated breast cancer cells after immunomagnetic enrichment.