Skeletal muscle adaptations in patients with lung cancer: Longitudinal observations from the whole body to cellular level.

BACKGROUND: Cancer and its treatment can adversely affect skeletal muscle, impacting physical function, treatment response and survival. No studies, however, have comprehensively characterized these muscle adaptations longitudinally in human patients at the cellular level. METHODS: We examined skeletal muscle size and function from the whole body to the sub-cellular level in 11 patients with non-small cell lung cancer (NSCLC; 6 male/5 female, mean age 58 ± 3 years) studied over a 2-month observation period starting during their first cycle of standard of care cancer treatment and in 11 age- and sex-matched healthy controls (HC) without a current or past history of cancer. Biopsies of the vastus lateralis were performed to assess muscle fibre size, contractility and mitochondrial content, along with assessments of physical function, whole muscle size and function, and circulating cytokines. RESULTS: Body weight, composition and thigh muscle area and density were unaltered over time in patients with NSCLC, while muscle density was lower in patients with NSCLC versus HC (P = 0.03). Skeletal muscle fibre size decreased by 18% over time in patients (all P = 0.02) and was lower than HC (P = 0.02). Mitochondrial fractional area and density did not change over time in patients, but fractional area was lower in patients with NSCLC compared with HC (subsarcolemmal, P = 0.04; intermyofibrillar, P = 0.03). Patients with NSCLC had higher plasma concentrations of IL-6 (HC 1.40 ± 0.50; NSCLC 4.71 ± 4.22; P < 0.01), GDF-15 (HC 569 ± 166; NSCLC 2071 ± 1168; P < 0.01) and IL-8/CXCL8 (HC 4.9 ± 1.8; NSCLC 10.1 ± 6.0; P = 0.02) compared with HC, but there were no changes in inflammatory markers in patients with NSCLC over time. No changes were observed in markers of satellite cell activation or DNA damage in patients and no group differences were noted with HC. Whole-muscle strength was preserved over time in patients with NSCLC coincident with improved single fibre contractility. CONCLUSIONS: This study is the first to comprehensively examine longitudinal alterations in skeletal muscle fibre size and function in patients with NSCLC and suggests that muscle fibre atrophy occurs during cancer treatment despite weight stability and no changes in conventional clinical measurements of whole body or thigh muscle size over this period.

Metastatic Malignant Paraganglioma Presenting as a Neck Mass Treated with Radiolabeled Somatostatin Analog.

Paragangliomas are rare neuroendocrine tumors that arise from chromaffin-containing tissue. Surgical resection and/or radiation are used for locoregional disease, and reduction of tumor burden with systemic therapy is reserved for metastatic disease. Iobenguane I-131, somatostatin analog (octreotide), and Sunitinib are noncytotoxic options for treatment, while cyclophosphamide, vincristine, and dacarbazine (CVD) and temozolomide are often used as initial chemotherapy options as studies have shown that they offer some tumor response. However, there are no randomized clinical trials demonstrating prolonged survival with the use of chemotherapeutics in metastatic cases. Investigation of alternative therapies that provide survival benefit is thus necessary. We present a case of a 69-year-old female with metastatic malignant paraganglioma presenting as a left parapharyngeal neck mass, which metastasized after surgery, requiring radiation therapy for bony metastasis who was treated with a radioisotope somatostatin analog for disease progression.

Effect of neuromuscular electrical stimulation on skeletal muscle size and function in patients with breast cancer receiving chemotherapy.

Exercise has numerous benefits for patients with cancer, but implementation is challenging because of practical and logistical hurdles. This study examined whether neuromuscular electrical stimulation (NMES) can serve as a surrogate for classic exercise by eliciting an exercise training response in skeletal muscle of women diagnosed with breast cancer undergoing chemotherapy. Patients (n = 22) with histologically confirmed stage I, II, or III breast cancer scheduled to receive neoadjuvant or adjuvant chemotherapy were randomized to 8 wk of bilateral neuromuscular electrical stimulation (NMES; 5 days/wk) to their quadriceps muscles or control. Biopsy of the vastus lateralis was performed at baseline and after 8 wk of intervention to assess muscle fiber size, contractility, and mitochondrial content. Seventeen patients (8 control/9 NMES) completed the trial and were included in analyses. NMES promoted muscle fiber hypertrophy (P < 0.001), particularly in fast-twitch, myosin heavy chain (MHC) IIA fibers (P < 0.05) and tended to induce fiber type shifts in MHC II fibers. The effects of NMES on single-muscle fiber contractility were modest, and it was unable to prevent declines in the function in MHC IIA fibers. NMES did not alter intermyofibrillar mitochondrial content/structure but was associated with reductions in subsarcolemmal mitochondria. Our results demonstrate that NMES induces muscle fiber hypertrophy and fiber type shifts in MHC II fibers but had minimal effects on fiber contractility and promoted reductions in subsarcolemmal mitochondria. Further studies are warranted to evaluate the utility of NMES as an exercise surrogate in cancer patients and other conditions.NEW & NOTEWORTHY This is the first study to evaluate whether neuromuscular electrical stimulation (NMES) can be used as an exercise surrogate to improve skeletal muscle fiber size or function in cancer patients receiving treatment. We show that NMES promoted muscle fiber hypertrophy and fiber type shifts but had minimal effects on single-fiber contractility and reduced subsarcolemmal mitochondria.

Importance of family history and indications for genetic testing.

Family history is an important cancer risk assessment tool, and it is easy to use. The family history is integral in identifying an individual's risk for primary cancer and assists in the assessment of risk for a second primary cancer. For oncology providers, the critical family history is defined as including first- and second-degree family history, maternal and paternal history, type of primary cancer, and age at diagnosis and ethnicity. Family history should be taken at diagnosis and updated periodically. Despite the importance of family history to patient care, there are significant barriers to taking a family history. We review the impact of collecting complete family history data with respect to calculation of cancer risk, recommendations for screening, and prevention strategies and referral for genetic testing.

Multidisciplinary Tumor Boards in Dermatologic Surgery.

BACKGROUND: Recent advances in diagnostic and therapeutic modalities have made oncologic care ever more challenging, and multidisciplinary tumor boards (MTBs) are increasingly being used as a forum to discuss and coordinate care for complex oncology patients. Literature on the use of MTBs specific to cutaneous oncology and dermatologic surgery remains limited. OBJECTIVE: To share our experiences with cutaneous oncology MTBs at the University of Vermont Medical Center (UVMMC). METHODS: We describe the formation, timing, participation, clinical discussion, case follow-up, and coordination of care of our MTBs. RESULTS: A log of all cases discussed at cutaneous oncology MTBs from August 2018 to August 2019 is presented as an example. Five specific cases are described in further detail to demonstrate critical components of multidisciplinary care. CONCLUSION: The MTBs at UVMMC has created a collaborative environment for providers in multiple specialties to jointly formulate and coordinate optimal treatment plans for difficult cases, particularly when treatment guidelines do not exist or are insufficient. Furthermore, MTBs can serve as an educational forum for all participants.

Inhibition of the chimeric DnaJ-PKAc enzyme by endogenous inhibitor proteins.

The chimeric DnaJ-PKAc enzymeresulting from an approximately 400-kb deletion of chromosome 19 is a primary contributor to the oncogenic transformation that occurs in fibrolamellar hepatocellular carcinoma, also called fibrolamellar carcinoma (FLC). This oncogenic deletion juxtaposes exon 1 of the DNAJB1 heat shock protein gene with exon 2 of the PRKACA gene encoding the protein kinase A catalytic subunit, resulting in DnaJ-PKAc fusion under the transcriptional control of the DNAJB1 promoter. The expression of DnaJ-PKAc is approximately 10 times that of wild-type (wt) PKAc catalytic subunits, causing elevated and dysregulated kinase activity that contributes to oncogenic transformation. In normal cells, PKAc activity is regulated by a group of endogenous proteins, termed protein kinase inhibitors (PKI) that competitively inhibit PKAc and assist with the nuclear export of the enzyme. Currently, it is scarcely known whether interactions with PKI are perturbed in DnaJ-PKAc. In this report, we survey existing data sets to assess the expression levels of the various PKI isoforms that exist in humans to identify those that are candidates to encounter DnaJ-PKAc in both normal liver and FLC tumors. We then compare inhibition profiles of wtPKAc and DnaJ-PKAc against PKI and demonstrate that extensive structural homology in the active site clefts of the two enzymes confers similar kinase activities and inhibition by full-length PKI and PKI-derived peptides.

When Clinical Trial Participation Is Not an Option in the Era of Personalized Medicine: The Case of Two Patients.

The combination of personalized therapy with immunotherapy might lead to rapid complete remission in patients who are too sick to be eligible for clinical trials. We report 2 such extraordinary responders. A discussion on the use and purpose of clinical trials in this new era of very active anticancer drug discovery concludes that a paradigm shift is urgently needed.