Implementing structured pathology reporting protocol for non-melanocytic skin cancers: practical considerations.

Non-melanocytic skin cancers (NMSCs) account for five times the incidence of all other cancers combined and cost US $6 billion annually. These are the most frequent specimens encountered in community pathology practice in many Western countries. Lack of standardised structured pathology reporting protocols (SPRPs) can result in omission of critical information or miscommunication leading to suboptimal patient management. The lack of standardised data has significant downstream public health implications, including insufficient data for reliable development of prognostic tools and health-economy planning. The Royal College of Pathologists of Australasia has developed an NMSC SPRP. A multidisciplinary expert committee including pathologists, surgeons, dermatologists, and radiation and medical oncologists from high volume cancer centres was convened. A systematic literature review was performed to identify evidence for including elements as mandatory standards or best practice guidelines. The SPRP and accompanying commentary of evidence, definitions and criteria was peer reviewed by external stakeholders. Finally, the protocol was revised following feedback and trialled in multiple centres prior to implementation. Some parameters utilised clinically for determining management and prognosis including tumour depth, lymphovascular invasion or distance to the margins lack high level evidence in NMSC. Dermatologists, surgeons, and radiation oncologists welcomed the SPRP. Pathologists indicated that the variety of NMSC specimens ranging from curettes to radical resections as well as significant differences in the biological behaviour of different tumours covered by the NMSC umbrella made use of a single protocol difficult. The feedback included that using a SPRP for low risk NMSC was neither clinically justified nor compensated adequately by the Australian Medicare Reimbursement Schedule. Following stakeholder feedback, the SPRP implementation was restricted to excision specimens of head and neck NMSC; and low-risk NMSC, such as superficial basal cell carcinoma, were excluded. Implementing NMSC SPRP fulfils an unmet clinical need. Unlike other cancers, NMSCs generate a range of specimen types and are reported in a wide range of pathology practices. Limiting use of SPRP to NMSC at higher risk of progression and providing formatted templates for easy incorporation into laboratory information systems were essential to successful deployment. In the future, further consideration should be given to implementing the SPRP to include all relevant specimens, including non-head and neck and low-risk NMSC specimens.

Treatment approaches and outcomes of a head and neck lymphedema service at an Australian comprehensive cancer center.

BACKGROUND: Patients treated for head and neck cancer are at high risk of developing head and neck lymphedema (HNL). We describe outcomes of HNL management at an Australian institution from 2018 to 2020. METHODS: Electronic records from Chris O'Brien Lifehouse were retrospectively reviewed from January 1, 2018 to December 31, 2020. Objective changes in HNL were assessed using The M. D. Anderson Cancer Center (MDACC) HNL rating scale and Assessment of Lymphedema of the Head and Neck (ALOHA). RESULTS: Among the 100 patients referred for management of HNL, surgery was the most frequent treatment modality (80%; 70% with neck dissection) and 69% underwent radiotherapy. Manual lymphatic drainage (MLD) was most often prescribed (96%), followed by self-MLD (93%). Small but significant improvements in ALOHA measurements were observed for 50 patients (50%). Only 5/29 (17%) patients had post-treatment improvements on the MDACC scale. CONCLUSIONS: Standardized, prospective measurement of treatment approaches and outcomes is needed to further evaluate the service.

Fascio-cutaneous and fascio-periosteal free flaps for treatment of intermediate stage osteoradionecrosis of the jaws.

OBJECTIVES: Osteoradionecrosis (ORN) of the jaw is a potentially devastating consequence of head and neck irradiation. Despite recent advances, there are patients who fail to respond to conventional therapies. Historically, free flaps were reserved for advanced cases requiring segmental resection and composite reconstruction, with early and intermediate disease treated more conservatively. We have adopted a more active surgical approach in selected intermediate cases. STUDY DESIGN: A retrospective review of patients with intermediate stage ORN who received debridement and either fascio-cutaneous or fascio-periosteal free flap reconstruction was performed. Demographic data, ORN severity, treatment, and outcomes are described. RESULTS: From 2019, 9 cases in 7 patients were identified. All cases were Notani grade II. There were 6 Epstein stage IIa and 3 Epstein stage IIIa. The mandible was the most common site (n = 8). Of the 7 patients, 2 had oropharyngeal primaries treated with chemoradiation, and 5 had oral cavity primaries treated with surgery and adjuvant radiation therapy. Three patients had prior hyperbaric oxygen therapy, and 2 had pentoxifylline/tocopherol therapy. After debridement, the radial forearm, ulnar artery perforator, and antero-lateral thigh fascio-cutaneous free flaps were each used in 1 case and the temporoparietal fascio-periosteal free flap was used in 6 cases. There was no recurrence or progression of ORN at the site of surgery, but 2 patients developed additional sites of ORN. CONCLUSIONS: For patients with unresponsive intermediate ORN, debridement and soft tissue free flap reconstruction is an alternative to ongoing conservative management or composite resection and reconstruction.

The dynamics of integration and integrated care: An exploratory study of physician organizations.

BACKGROUND: Substantial variation exists in how well health care is integrated, even across similarly structured organizations, yet research about what physician organizations (POs) do that enables or inhibits integrated care is limited. PURPOSE: The aim of this study was to explore the dynamics that enable POs to integrate care. METHODOLOGY/APPROACH: We ranked a stratified sample of POs according to patient perceptions of integrated care, as measured in a survey. We interviewed professionals, patients, and family members in 10 higher and 3 lower ranked POs about the process of caring for patients with complex conditions. We derived integration-related themes from the interview data and quantified their prevalence. Using a quasi-statistical approach, we explored relationships among themes and their associations with patient perceptions of integrated care. RESULTS: From 6,104 coded references, we derived a set of themes representing integration perspectives, integration engagement mechanisms, and integration failures. POs experienced frequent integration failures. Higher ranked POs experienced these failures less often because of a combination of functional, interpersonal, and stakeholder engagement mechanisms, which appear to complement one another. Integration perspectives, including both people-oriented and systems-oriented mindsets, appear to play a role in generating these integration dynamics. CONCLUSION: Delivering integrated care depends on a PO's ability to limit integration failures, keeping provider attention focused on patients. Building on the attention-based view, we present a framework suggesting that this ability is a function of both integration perspectives and integration engagement mechanisms. PRACTICE IMPLICATIONS: POs interested in delivering more integrated care should employ a variety of complementary integration engagement mechanisms and facilitate these efforts by nurturing both people-oriented and system-oriented mindsets among PO decision-makers.

Medical Group Structural Integration May Not Ensure That Care Is Integrated, From The Patient's Perspective.

Structural integration is increasing among medical groups, but whether these changes yield care that is more integrated remains unclear. We explored the relationships between structural integration characteristics of 144 medical groups and perceptions of integrated care among their patients. Patients' perceptions were measured by a validated national survey of 3,067 Medicare beneficiaries with multiple chronic conditions across six domains that reflect knowledge and support of, and communication with, the patient. Medical groups' structural characteristics were taken from the National Study of Physician Organizations and included practice size, specialty mix, technological capabilities, and care management processes. Patients' survey responses were most favorable for the domain of test result communication and least favorable for the domain of provider support for medication and home health management. Medical groups' characteristics were not consistently associated with patients' perceptions of integrated care. However, compared to patients of primary care groups, patients of multispecialty groups had strong favorable perceptions of medical group staff knowledge of patients' medical histories. Opportunities exist to improve patient care, but structural integration of medical groups might not be sufficient for delivering care that patients perceive as integrated.

The Inositol-3-Phosphate Synthase Biosynthetic Enzyme Has Distinct Catalytic and Metabolic Roles.

Inositol levels, maintained by the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), are altered in a range of disorders, including bipolar disorder and Alzheimer's disease. To date, most inositol studies have focused on the molecular and cellular effects of inositol depletion without considering Ino1 levels. Here we employ a simple eukaryote, Dictyostelium discoideum, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in an inositol auxotrophy that can be rescued only partially by exogenous inositol. Removal of inositol supplementation from the ino1(-) mutant resulted in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis, and substrate adhesion. Inositol depletion also caused a dramatic generalized decrease in phosphoinositide levels that was rescued by inositol supplementation. However, loss of Ino1 triggered broad metabolic changes consistent with the induction of a catabolic state that was not rescued by inositol supplementation. These data suggest a metabolic role for Ino1 that is independent of inositol biosynthesis. To characterize this role, an Ino1 binding partner containing SEL1L1 domains (Q54IX5) and having homology to mammalian macromolecular complex adaptor proteins was identified. Our findings therefore identify a new role for Ino1, independent of inositol biosynthesis, with broad effects on cell metabolism.

Investigating the effect of arachidonate supplementation on the phosphoinositide content of MCF10a breast epithelial cells.

Phosphoinositides in primary mammalian tissue are highly enriched in a stearoyl/arachidonyl (C38:4) diacylgycerol backbone. However, mammalian cells grown in culture typically contain more diverse molecular species of phosphoinositides, characterised by a reduction in arachidonyl content in the sn-2 position. We have analysed the phosphoinositide species in MCF10a cells grown in culture by mass spectrometry. Under either serum or serum starved conditions the most abundant species of PI, PIP, PIP2 and PIP3 had masses which corresponded to C36:2, C38:4, C38:3, C38:2 and C36:1 diacylglycerol backbones and the relative proportions of each molecular species were broadly similar between each phosphoinositide class (approx. 50%, 25%, 10%, 10% and 10% respectively, for the species listed above). Supplementing the culture medium with BSA-loaded arachidonic acid promoted a rapid increase in the proportion of the C38:4 species in all phosphoinositide classes (from approx. 25%-60% of total species within 24 h), but the total amount of all combined species for each class remained remarkably constant. Stimulation of cells, cultured in either normal or arachidonate-enriched conditions, with 2 ng/ml EGF for 90 s caused substantial activation of Class I PI3K and accumulation of PIP3. Despite the increased proportion of C38:4 PIP3 under the arachidonate-supplemented conditions, the total amount of all combined PIP3 species accumulating in response to EGF was the same, with or without arachidonate supplementation; there were however small but significant preferences for the conversion of some PIP2 species to PIP3, with the polyunsaturated C38:4 and C38:3 species being more favoured over other species. These results suggest the enzymes which interconvert phosphoinositides are able to act on several different molecular species and homoeostatic mechanisms are in place to deliver similar phosphoinositide pool sizes under quite different conditions of arachidonate availability. They also suggest enzymes regulating PIP3 levels downstream of growth factor stimulation (i.e. PI3Ks and PIP3-phosphatases) show some acyl selectivity and further work should be directed at assessing whether different acyl species of PIP3 exhibit differing signalling potential.

Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: an international multicenter retrospective study.

IMPORTANCE: The current American Joint Committee on Cancer (AJCC) staging system for oral cancer demonstrates wide prognostic variability within each primary tumor stage and provides suboptimal staging and prognostic information for some patients. OBJECTIVE: To determine if a modified staging system for oral cancer that integrates depth of invasion (DOI) into the T categories improves prognostic performance compared with the current AJCC T staging. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 3149 patients with oral squamous cell carcinoma treated with curative intent at 11 comprehensive cancer centers worldwide between 1990 and 2011 with surgery ± adjuvant therapy, with a median follow-up of 40 months. MAIN OUTCOMES AND MEASURES: We assessed the impact of DOI on disease-specific and overall survival in multivariable Cox proportional hazard models and investigated for institutional heterogeneity using 2-stage random effects meta-analyses. Candidate staging systems were developed after identification of optimal DOI cutpoints within each AJCC T category using the Akaike information criterion (AIC) and likelihood ratio tests. Staging systems were evaluated using the Harrel concordance index (C-index), AIC, and visual inspection for stratification into distinct prognostic categories, with internal validation using bootstrapping techniques. RESULTS: The mean and median DOI were 12.9 mm and 10.0 mm, respectively. On multivariable analysis, DOI was a significantly associated with disease-specific survival (P < .001), demonstrated no institutional prognostic heterogeneity (I² = 6.3%; P = .38), and resulted in improved model fit compared with T category alone (lower AIC, P < .001). Optimal cutpoints of 5 mm in T1 and 10 mm in T2-4 category disease were used to develop a modified T staging system that was preferred to the AJCC system on the basis of lower AIC, visual inspection of Kaplan-Meier curves, and significant improvement in bootstrapped C-index. CONCLUSIONS AND RELEVANCE: We propose an improved oral cancer T staging system based on incorporation of DOI that should be considered in future versions of the AJCC staging system after external validation.

Minimum nodal yield in oral squamous cell carcinoma: defining the standard of care in a multicenter international pooled validation study.

PURPOSE: There is evidence to suggest that a nodal yield <18 is an independent prognostic factor in patients with clinically node negative (cN0) oral squamous cell carcinoma (SCC) treated with elective neck dissection (END). We sought to evaluate this hypothesis with external validation and to investigate for heterogeneity between institutions. PATIENTS AND METHODS: We analyzed pooled individual data from 1,567 patients treated at nine comprehensive cancer centers worldwide between 1970 and 2011. Nodal yield was assessed with Cox proportional hazard models, stratified by study center, and adjusted for age, sex, pathological T and N stage, margin status, extracapsular nodal spread, time period of primary treatment, and adjuvant therapy. Two-stage random-effects meta-analyses were used to investigate for heterogeneity between institutions. RESULTS: In multivariable analyses of patients undergoing selective neck dissection, nodal yield <18 was associated with reduced overall survival [hazard ratio (HR) 1.69; 95 % confidence interval (CI) 1.22-2.34; p = 0.002] and disease-specific survival (HR 1.88; 95 % CI 1.21-2.91; p = 0.005), and increased risk of locoregional recurrence (HR 1.53; 95 % CI 1.04-2.26; p = 0.032). Despite significant differences between institutions in terms of patient clinicopathological factors, nodal yield, and outcomes, random-effects meta-analysis demonstrated no evidence of heterogeneity between centers in regards to the impact of nodal yield on disease-specific survival (p = 0.663; I (2) statistic = 0). CONCLUSION: Our data confirm that nodal yield is a robust independent prognostic factor in patients undergoing END for cN0 oral SCC, and may be applied irrespective of the underlying patient population and treating institution. A minimum adequate lymphadenectomy in this setting should include at least 18 nodes.

The immediate effect of soleus trigger point pressure release on restricted ankle joint dorsiflexion: A pilot randomised controlled trial.

OBJECTIVES: The primary aim of this study was to investigate the immediate effect on restricted active ankle joint dorsiflexion range of motion (ROM), after a single intervention of trigger point (TrP) pressure release on latent soleus myofascial trigger points (MTrPs). The secondary aim was to assess aspects of the methodological design quality, identify limitations and propose areas for improvement in future research. DESIGN: A pilot randomised control trial. PARTICIPANTS: Twenty healthy volunteers (5 men and 15 women; mean age 21.7±2.1 years) with a restricted active ankle joint dorsiflexion. INTERVENTION: Participants underwent a screening process to establish both a restriction in active ankle dorsiflexion and the presence of active and latent MTrPs in the soleus muscle. Participants were then randomly allocated to an intervention group (TrP pressure release) or control group (no therapy). RESULTS: The results showed a statistically significant (p=0.03) increase of ankle ROM in the intervention compared to the control group. CONCLUSION: This study identified an immediate significant improvement in ankle ROM after a single intervention of TrP pressure release on latent soleus MTrPS. These findings are clinically relevant, although the treatment effect on ankle ROM is smaller than a clinical significant ROM (5°). Suggestions for methodological improvements may inform future MTrP research and ultimately benefit clinical practice in this under investigated area.

Integration of prospective quality of life and nutritional assessment as routine components of multidisciplinary care of patients with head and neck cancer.

BACKGROUND: Quality of life (QOL) and nutritional assessment of patients with head and neck cancer can provide additional information about the effects of treatment beyond the standard measures of disease control and survival. Integrating a prospective evaluation program into a multidisciplinary service may ensure that a more holistic model of care is developed. METHODS: Prospective evaluation of QOL and nutrition before and after treatment for head and neck cancer was implemented in 2001. All patients enrolled in the program were treated with curative intent. Patients completed the European Organisation for Research and Treatment of Cancer Core QOL Questionnaire and Head and Neck Specific Module before treatment and at 3, 6 and 12 months after completion of therapy. In conjunction, patients underwent nutritional assessment by body mass index, biochemical parameters and the patient-generated subjective global assessment tool. RESULTS: Among 288 patients who consented to participate in this study, 134 patients completed the QOL assessment criteria and were eligible for evaluation. Examples of QOL and nutritional data for patients with cancers of the oral cavity, oropharynx, nasopharynx, larynx, hypopharynx, parotid gland and paranasal sinus, and also unknown primary cancers are given. Implementation of this prospective assessment program required appropriate resources and was hampered by time constraints, logistics with blood tests and patient compliance. CONCLUSIONS: Despite difficulties with implementation, the information concerning QOL and nutritional status obtained in this study provided an appreciation of the long-term functional effects of treatment for head and neck cancer. Prospective QOL assessment and nutritional evaluation should become integral components of the care of patients with cancers of the head and neck.

Prospective evaluation of quality of life and nutrition before and after treatment for nasopharyngeal carcinoma.

OBJECTIVE: To prospectively assess quality of life in patients undergoing chemoradiation therapy for nasopharyngeal cancer. Concurrent chemoradiotherapy is standard for advanced nasopharyngeal cancer; however, the toxic effects of this treatment are substantial. DESIGN: Prospective evaluation of quality of life and nutritional status before and after treatment for nasopharyngeal carcinoma. PATIENTS AND INTERVENTION: A cohort of 14 patients, treated with concurrent chemoradiotherapy for 7 weeks, completed the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire and Head and Neck Module before and 3, 6, 12, and 24 months after treatment. Changes in score were analyzed and correlated with the toxic effect grade. RESULTS: Quality of life issues during the 24 months of follow-up included poorer global health (P = .01), fatigue (P = .01), appetite loss (P<.001), swallowing difficulties (P = .002), sense problems (P = .03), difficulty with social eating (P = .005), dental problems (P = .045), trismus (P = .001), xerostomia (P<.001), sticky saliva (P = .001), cough (P = .02), and feeling ill (P = .03). Pain (P = .004) and emotional functioning (P<.001) significantly improved from the pretreatment rating. The median weight loss was 7 kg, with most weight loss occurring during treatment, despite nutritional support with gastrostomy feeding tubes. One patient still required percutaneous endoscopic gastrostomy feeding at 2 years after treatment. Physician-scored toxic effects correlated poorly with quality-of-life scores. CONCLUSIONS: Quality of life and functional assessment should be important end points in the follow-up of patients with nasopharyngeal cancer who receive chemoradiotherapy. This study supports the need for ongoing support and rehabilitation in a multidisciplinary setting.