Medical imaging and multimodal artificial intelligence models for streamlining and enhancing cancer care: opportunities and challenges.

INTRODUCTION: Artificial intelligence (AI) has the potential to transform oncologic care. There have been significant developments in AI applications in medical imaging and increasing interest in multimodal models. These are likely to enable improved oncologic care through more precise diagnosis, increasingly in a more personalized and less invasive manner. In this review, we provide an overview of the current state and challenges that clinicians, administrative personnel and policy makers need to be aware of and mitigate for the technology to reach its full potential. AREAS COVERED: The article provides a brief targeted overview of AI, a high-level review of the current state and future potential AI applications in diagnostic radiology and to a lesser extent digital pathology, focusing on oncologic applications. This is followed by a discussion of emerging approaches, including multimodal models. The article concludes with a discussion of technical, regulatory challenges and infrastructure needs for AI to realize its full potential. EXPERT OPINION: There is a large volume of promising research, and steadily increasing commercially available tools using AI. For the most advanced and promising precision diagnostic applications of AI to be used clinically, robust and comprehensive quality monitoring systems and informatics platforms will likely be required.

Osteoid Osteoma of the Coracoid Process Presenting as Adhesive Capsulitis in a 10-Year-Old Male: A Case Report.

A 10-year-old male presented with symptoms in his right shoulder indicative of adhesive capsulitis. Radiographic films did not demonstrate any osseous abnormalities. Magnetic resonance imaging demonstrated the presence of an eccentric lesion within the coracoid process consistent with an osteoid osteoma. Six months after surgical removal the patient is back to full activities. For the pediatric population, surgeons must always consider diagnoses that could alter a patient's growth or result in long-term disability. In particular, an atypical presentation of musculoskeletal disease in a pediatric patient presenting with a disease that typically is seen in the older population warrants further workup.

Does shoulder stability differ with or without subscapularis repair after primary reverse total shoulder arthroplasty? A systematic review.

The use of reverse total shoulder arthroplasty (RTSA) has expanded from its original indication as a rotator cuff arthropathy treatment to include a large variety of pathologies. A frequently reported complication with this surgery is postoperative shoulder instability with reported incidence varying widely from 2.3 to 38%. The etiology for this instability is broad and includes prosthesis design, mechanical impingement, surgical technique, and axillary/deltoid function. A PROSPERO-registered systematic review was performed utilizing PRISMA guidelines using Cochrane, PUBMED, Embase, and Eline. Of the 1442 studies initially identified, 7 studies met all inclusion criteria, all of which were level III or IV evidence. All 7 studies evaluated postoperative instability, but no study reported a statistically significant difference in instability rates between the groups. Dislocations occurred in 5 patients (5/679, 0.7%) with subscapularis repair and 8 patients (8/527, 1.5%) without repair. A nonsignificant difference in the risk of instability for surgeries with repair compared to surgeries without repair was found (overall risk difference: 0.01, random effects 95% confidence interval: -0.00 to 0.02, P = .11). This review suggests no difference in postoperative shoulder instability rates between patients that underwent primary RTSA with or without subsequent repair of the subscapularis tendon. Interestingly, one study comparing implants with a medialized or nonlateralized implant showed a significantly increased rate of dislocation with the medialized group compared to the lateralized group. When these groups were then stratified based on subscapularis repair status, there was no increased risk with a nonrepaired tendon. This study suggests that implant design may have more influence on the stability of RTSA than subscapularis status. However, overall, there does appear to be a trend suggesting improved postoperative clinical outcomes and active range of motion for patients with a subscapularis repair vs. without a repair. Further research is needed to better elucidate the ideal combination of surgical technique and implant design to minimize postoperative glenohumeral joint instability while optimizing postoperative clinical outcomes and range of motion after primary RTSA.

Radial Flow Perfusion Enables Real-Time Profiling of Cellular Metabolism at Low Oxygen Levels with Hyperpolarized 13C NMR Spectroscopy.

In this study, we describe new methods for studying cancer cell metabolism with hyperpolarized 13C magnetic resonance spectroscopy (HP 13C MRS) that will enable quantitative studies at low oxygen concentrations. Cultured hepatocellular carcinoma cells were grown on the surfaces of non-porous microcarriers inside an NMR spectrometer. They were perfused radially from a central distributer in a modified NMR tube (bioreactor). The oxygen level of the perfusate was continuously monitored and controlled externally. Hyperpolarized substrates were injected continuously into the perfusate stream with a newly designed system that prevented oxygen and temperature perturbations in the bioreactor. Computational and experimental results demonstrated that cell mass oxygen profiles with radial flow were much more uniform than with conventional axial flow. Further, the metabolism of HP [1-13C]pyruvate was markedly different between the two flow configurations, demonstrating the importance of avoiding large oxygen gradients in cell perfusion experiments.

Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy.

BACKGROUND AND AIMS: Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease-the principal causes of cancer mortality-have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE-induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. APPROACH AND RESULTS: In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histological viability. CONCLUSIONS: These studies provide a paradigm for imaging latent, treatment-refractory cancer cells, suggesting that DNP-MRSI provides a technology for this application.

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis.

The remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STSs) limits the clinical benefit of targeted therapies. Here, we show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of sarcoma subtypes, revealing an apparent common metabolic feature shared by diverse STSs. Enforced FBP2 expression inhibits sarcoma cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect," thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic-activity-independent manner by inhibiting the expression of nuclear respiratory factor and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and represses c-Myc-dependent TFAM expression. This unique dual function of FBP2 provides a rationale for its selective suppression in STSs, identifying a potential metabolic vulnerability of this malignancy and possible therapeutic target.

Misregulation of Drosophila Myc Disrupts Circadian Behavior and Metabolism.

Drosophila Myc (dMyc) is highly conserved and functions as a transcription factor similar to mammalian Myc. We previously found that oncogenic Myc disrupts the molecular clock in cancer cells. Here, we demonstrate that misregulation of dMyc expression affects Drosophila circadian behavior. dMyc overexpression results in a high percentage of arrhythmic flies, concomitant with increases in the expression of clock genes cyc, tim, cry, and cwo. Conversely, flies with hypomorphic mutations in dMyc exhibit considerable arrhythmia, which can be rescued by loss of dMnt, a suppressor of dMyc activity. Metabolic profiling of fly heads revealed that loss of dMyc and its overexpression alter steady-state metabolite levels and have opposing effects on histidine, the histamine precursor, which is rescued in dMyc mutants by ablation of dMnt and could contribute to effects of dMyc on locomotor behavior. Our results demonstrate a role of dMyc in modulating Drosophila circadian clock, behavior, and metabolism.

The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth.

Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis.

YAP1 enhances NF-κB-dependent and independent effects on clock-mediated unfolded protein responses and autophagy in sarcoma.

Terminal differentiation opposes proliferation in the vast majority of tissue types. As a result, loss of lineage differentiation is a hallmark of aggressive cancers, including soft tissue sarcomas (STS). Consistent with these observations, undifferentiated pleomorphic sarcoma (UPS), an STS subtype devoid of lineage markers, is among the most lethal sarcomas in adults. Though tissue-specific features are lost in these mesenchymal tumors they are most commonly diagnosed in skeletal muscle, and are thought to develop from transformed muscle progenitor cells. We have found that a combination of HDAC (Vorinostat) and BET bromodomain (JQ1) inhibition partially restores differentiation to skeletal muscle UPS cells and tissues, enforcing a myoblast-like identity. Importantly, differentiation is partially contingent upon downregulation of the Hippo pathway transcriptional effector Yes-associated protein 1 (YAP1) and nuclear factor (NF)-κB. Previously, we observed that Vorinostat/JQ1 inactivates YAP1 and restores oscillation of NF-κB in differentiating myoblasts. These effects correlate with reduced tumorigenesis, and enhanced differentiation. However, the mechanisms by which the Hippo/NF-κB axis impact differentiation remained unknown. Here, we report that YAP1 and NF-κB activity suppress circadian clock function, inhibiting differentiation and promoting proliferation. In most tissues, clock activation is antagonized by the unfolded protein response (UPR). However, skeletal muscle differentiation requires both Clock and UPR activity, suggesting the molecular link between them is unique in muscle. In skeletal muscle-derived UPS, we observed that YAP1 suppresses PERK and ATF6-mediated UPR target expression as well as clock genes. These pathways govern metabolic processes, including autophagy, and their disruption shifts metabolism toward cancer cell-associated glycolysis and hyper-proliferation. Treatment with Vorinostat/JQ1 inhibited glycolysis/MTOR signaling, activated the clock, and upregulated the UPR and autophagy via inhibition of YAP1/NF-κB. These findings support the use of epigenetic modulators to treat human UPS. In addition, we identify specific autophagy, UPR, and muscle differentiation-associated genes as potential biomarkers of treatment efficacy and differentiation.

IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers.

Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here, we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway through multiple molecular mechanisms in a variety of c-Myc- and N-Myc-dependent cancers. In particular, Myc-overexpressing cells require IRE1α/XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity. Pharmacological and genetic XBP1 inhibition induces Myc-dependent apoptosis, which is alleviated by exogenous unsaturated fatty acids. Of note, SCD1 inhibition phenocopies IRE1α RNase activity suppression in vivo. Furthermore, IRE1α inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1α/XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.

Definitive Radiotherapy for Squamous Cell Carcinoma of the Glottic Larynx.

BACKGROUND: Depending on the extent of disease, squamous cell carcinoma (SCC) of the glottis is managed with surgery, radiotherapy (RT), or a combination of these modalities. Patients with advanced disease may receive concomitant chemotherapy in conjunction with definitive or postoperative RT. METHODS: The treatment policies of the University of Florida and patient outcomes are reviewed. RESULTS: The likelihood of cure after RT for carcinoma in situ (Tis) to T2 glottic SCC varies from 70% to 94% depending on tumor stage. Consideration should be given to adding weekly cisplatin for patients with T2b SCC because of the high local recurrence rate after RT alone. The probability of cure is about 65% to 80% for select low-volume (≤ 3.5 cc) T3 to T4 glottic SCC after RT. These patients should be considered for concomitant weekly cisplatin. Higher-volume tumors, particularly those with airway compromise, should be treated with laryngectomy and postoperative RT. CONCLUSION: Definitive RT is an excellent treatment for select patients with laryngeal cancer.

Targeting ACLY sensitizes castration-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism.

The androgen receptor (AR) plays a central role in prostate tumor growth. Inappropriate reactivation of the AR after androgen deprivation therapy promotes development of incurable castration-resistant prostate cancer (CRPC). In this study, we provide evidence that metabolic features of prostate cancer cells can be exploited to sensitize CRPC cells to AR antagonism. We identify a feedback loop between ATP-citrate lyase (ACLY)-dependent fatty acid synthesis, AMPK, and the AR in prostate cancer cells that could contribute to therapeutic resistance by maintaining AR levels. When combined with an AR antagonist, ACLY inhibition in CRPC cells promotes energetic stress and AMPK activation, resulting in further suppression of AR levels and target gene expression, inhibition of proliferation, and apoptosis. Supplying exogenous fatty acids can restore energetic homeostasis; however, this rescue does not occur through increased ß-oxidation to support mitochondrial ATP production. Instead, concurrent inhibition of ACLY and AR may drive excess ATP consumption as cells attempt to cope with endoplasmic reticulum (ER) stress, which is prevented by fatty acid supplementation. Thus, fatty acid metabolism plays a key role in coordinating ER and energetic homeostasis in CRPC cells, thereby sustaining AR action and promoting proliferation. Consistent with a role for fatty acid metabolism in sustaining AR levels in prostate cancer in vivo, AR mRNA levels in human prostate tumors correlate positively with expression of ACLY and other fatty acid synthesis genes. The ACLY-AMPK-AR network can be exploited to sensitize CRPC cells to AR antagonism, suggesting novel therapeutic opportunities for prostate cancer.

Bonded Cumomer Analysis of Human Melanoma Metabolism Monitored by 13C NMR Spectroscopy of Perfused Tumor Cells.

A network model for the determination of tumor metabolic fluxes from (13)C NMR kinetic isotopomer data has been developed and validated with perfused human DB-1 melanoma cells carrying the BRAF V600E mutation, which promotes oxidative metabolism. The model generated in the bonded cumomer formalism describes key pathways of tumor intermediary metabolism and yields dynamic curves for positional isotopic enrichment and spin-spin multiplets. Cells attached to microcarrier beads were perfused with 26 mm [1,6-(13)C2]glucose under normoxic conditions at 37 °C and monitored by (13)C NMR spectroscopy. Excellent agreement between model-predicted and experimentally measured values of the rates of oxygen and glucose consumption, lactate production, and glutamate pool size validated the model. ATP production by glycolytic and oxidative metabolism were compared under hyperglycemic normoxic conditions; 51% of the energy came from oxidative phosphorylation and 49% came from glycolysis. Even though the rate of glutamine uptake was ∼ 50% of the tricarboxylic acid cycle flux, the rate of ATP production from glutamine was essentially zero (no glutaminolysis). De novo fatty acid production was ∼ 6% of the tricarboxylic acid cycle flux. The oxidative pentose phosphate pathway flux was 3.6% of glycolysis, and three non-oxidative pentose phosphate pathway exchange fluxes were calculated. Mass spectrometry was then used to compare fluxes through various pathways under hyperglycemic (26 mm) and euglycemic (5 mm) conditions. Under euglycemic conditions glutamine uptake doubled, but ATP production from glutamine did not significantly change. A new parameter measuring the Warburg effect (the ratio of lactate production flux to pyruvate influx through the mitochondrial pyruvate carrier) was calculated to be 21, close to upper limit of oxidative metabolism.

Lessons from a standardized program using PET-CT to avoid neck dissection after primary radiotherapy for N2 squamous cell carcinoma of the oropharynx.

OBJECTIVES: To report the results of a standardized program using positron emission tomography (PET)-computed tomography (CT) approximately 12 weeks after primary radiotherapy to determine the need for a planned neck dissection in patients with radiographic N2 squamous cell carcinoma (SCC) of the oropharynx. METHODS: Fifty consecutive patients with T1-4 and hemineck radiographic stage N2A-B SCC of the oropharynx for whom the only indication for planned neck dissection was a positive PET-CT performed ∼12 weeks after completing primary treatment with radiotherapy. RESULTS: Results of PET-CT to identify residual neck disease were as follows: sensitivity and positive predictive value, 0%; specificity, 89%; negative predictive value, 91%; potential neck recurrence from using this 12-week PET-CT program, 2%. The time between negative PET-CT and detection of neck recurrence was 0.5, 0.6, 1.2, and 2.0 years. The rate of successful (>1 year) salvage of neck recurrence was 25% (1/4). CONCLUSIONS: PET-CT approximately 12 weeks after radiotherapy for oropharyngeal cancer is an excellent way to identify patients who do not need neck dissection. Approximately half of neck recurrences present over 1 year after negative PET-CT and the chance of successful salvage is low.

Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis.

Glutaminase (GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, and proliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affect cancer cell-autonomous growth or the host microenvironment or have off-target effects is unknown. Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competent MYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animals with MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without any apparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line (P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493 tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing a BPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment. Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493 xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed at mouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell-autonomous dependence on GLS for cancer therapy.

Impact of radiographic findings on for prognosis skin cancer with perineural invasion.

OBJECTIVES: Update our experience using radiotherapy (RT) for head-and-neck squamous or basal cell carcinoma with clinical perineural invasion (PNI) and correlate radiographic findings with outcomes. MATERIALS AND METHODS: We treated 65 patients with cT4N0 head-and-neck skin cancers with clinical PNI from 1965 to 2009 (N0 disease, 59; N1 disease, 6). Treatment included RT alone (N=18), RT with concurrent chemotherapy (N=14), surgery and postoperative RT (N=26), or postoperative RT with concurrent chemotherapy (N=5), and preoperative RT and surgery (N=2). Patients were stratified by imaging-negative disease (N=11), minimal or moderate peripheral disease (N=18), and macroscopic and/or central disease (N=36). Median RT dose was 72.6 Gy (50.4 to 79.2 Gy). Median follow-up overall and for living patients was 5.4 and 11.6 years, respectively. RESULTS: Five-year outcomes for imaging-negative disease versus minimal/moderate peripheral disease versus macroscopic/central disease were: local control, 81% versus 60% versus 47% (P=0.23); local-regional control, 80% versus 54% versus 47% (P=0.22); neck control, 100% versus 89% versus 93% (P=0.45); and distant metastasis-free survival, 89% versus 100% versus 93% (P=0.57), respectively. Five-year survival rates for imaging-negative disease versus minimal/moderate peripheral disease versus macroscopic/central disease were: overall survival, 82% versus 50% versus 52% (P=0.26), and cause-specific survival, 100% versus 58% versus 65% (P=0.08). Twenty-two (34%) patients had 1 or more severe (grade ≥3) late complications. CONCLUSIONS: There is a nonsignificant trend towards improved local control for imaging-negative patients and patients with minimal/moderate peripheral disease compared with macroscopic/central disease. Although survival appears better for imaging-negative patients, extent of imaging-positive PNI did not impact overall or cause-specific survival.

Advances in diagnostic modalities to detect occult lymph node metastases in head and neck squamous cell carcinoma.

Regional metastasis is a prominent feature of head and neck squamous cell carcinoma (HNSCC) and is an important prognostic factor. The currently available imaging techniques for assessment of the neck have limitations in accuracy; thus, elective neck dissection has remained the usual choice of management of the clinically N0 neck (cN0) for tumors with significant (≥20%) incidence of occult regional metastasis. As a consequence, the majority of patients without regional metastasis will undergo unnecessary treatment. The purpose of this review was to discuss new developments in techniques that potentially improve the accuracy of the assessment of the neck in patients with HNSCC. Although imaging has improved in the last decades, a limitation common to all imaging techniques is a lack of sensitivity for small tumor deposits. Therefore, complementary to improvements in imaging techniques, developments in more invasive diagnostic procedures, such as sentinel node biopsy (SNB) will add to the accuracy of diagnostic algorithms for the staging of the neck.

Fructose-1,6-bisphosphatase opposes renal carcinoma progression.

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.

Impact of primary tumor volume on local control after definitive radiotherapy for head and neck cancer.

BACKGROUND: The impact of primary tumor volume (pTV) on local control after definitive radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) is unclear. METHODS: Pertinent literature was reviewed to address the impact of pTV on local control after definitive RT for HNSCC. RESULTS: Reproducibility of pTV calculations is probably influenced by interobserver variability and may be reduced by relying on experienced observers. The impact of pTV on local control after definitive RT is probably influenced by primary site. A relatively limited impact of pTV on local control after RT for oropharyngeal squamous cell carcinomas (SCCs) might be attributable to human papillomavirus (HPV) positivity. CONCLUSION: pTV may be a useful parameter to select patients for treatment with definitive RT, particularly for those with laryngeal SCCs. Patients with high-volume primary cancers, in which the probability of local control with a functional larynx is low, are likely better treated with surgery.