Towards an Explainable AI Platform to Study Interruptions in Cancer Radiation Therapy.

Radiation therapy interruptions drive cancer treatment failures; they represent an untapped opportunity for improving outcomes and narrowing treatment disparities. This research reports on the early development of the X-CART platform, which uses explainable AI to model cancer treatment outcome metrics based on high-dimensional associations with our local social determinants of health dataset to identify and explain causal pathways linking social disadvantage with increased radiation therapy interruptions.

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer.

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.

The anatomy of COVID-19 comorbidity networks among hospitalized Korean patients.

OBJECTIVES: We aimed to examine how comorbidities were associated with outcomes (illness severity or death) among hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: Data were provided by the National Medical Center of the Korea Disease Control and Prevention Agency. These data included the clinical and epidemiological information of all patients hospitalized with COVID-19 who were discharged on or before April 30, 2020 in Korea. We conducted comorbidity network and multinomial logistic regression analyses to identify risk factors associated with COVID-19 disease severity and mortality. The outcome variable was the clinical severity score (CSS), categorized as mild (oxygen treatment not needed), severe (oxygen treatment needed), or death. RESULTS: In total, 5,771 patients were included. In the fully adjusted model, chronic kidney disease (CKD) (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.19 to 5.61) and chronic obstructive pulmonary disease (COPD) (OR, 3.19; 95% CI, 1.35 to 7.52) were significantly associated with disease severity. CKD (OR, 5.35; 95% CI, 2.00 to 14.31), heart failure (HF) (OR, 3.15; 95% CI, 1.22 to 8.15), malignancy (OR, 3.38; 95% CI, 1.59 to 7.17), dementia (OR, 2.62; 95% CI, 1.45 to 4.72), and diabetes mellitus (OR, 2.26; 95% CI, 1.46 to 3.49) were associated with an increased risk of death. Asthma and hypertension showed statistically insignificant associations with an increased risk of death. CONCLUSIONS: Underlying diseases contribute differently to the severity of COVID-19. To efficiently allocate limited medical resources, underlying comorbidities should be closely monitored, particularly CKD, COPD, and HF.

Genomic profiling of endometrial cancer and relationship with volume of endometrial cancer disease spread.

OBJECTIVES: Lymph node (LN) metastasis and genomic profiles are important prognostic factors in endometrial cancer (EMCA). However, the prognostic significance of low volume metastasis found in sentinel lymph nodes (SLN) is unknown. We sought to determine if genomic mutations were associated with metastatic volume. METHODS: Surgically staged women with EC who were enrolled in both a SLN clinical trial and tumor sequencing protocol were eligible. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Three specific gene mutations were evaluated, TP53, PTEN and PIK3CA in the primary tumor of patients with LN negative, LN positive and ITC disease. RESULTS: 42 patients were eligible; of these, 7 (16.7%) had ITC only and 7 (16.7%) had micrometastatic or macrometastatic (LN positive) disease. No differences were seen in TP53, PIK3CA or PTEN between groups. All ITC patients with TP53 mutations were of non-endometrioid histology (2/7). Deeper myometrial invasion and lymph vascular space invasion were more likely to occur in the LN positive group (p < 0.01 for both). No patients with ITC had a recurrence in a median 67.7 months of follow-up since surgery. CONCLUSIONS: This pilot investigation did not identify differences between frequency of PIK3CA, PTEN or TP53 mutations in tumors and volume of LN metastasis. Low number of ITC limited the ability to detect genomic differences, however mutations appeared to align with expected histology. More work is needed to define the relationship between genomic mutations, histology, ITC, and prognosis.

Novel Use of Biphasic Cuirass Ventilation During Definitive Radiation Therapy: A Technical Report.

The use of biphasic cuirass ventilator supported radiation therapy has never been documented. We present the first technical report here. A 57-year-old man with obstructive sleep apnea presented with a T0N1M0 right sided, human papillomavirus related head and neck cancer diagnosed on excisional lymph node biopsy. On further workup, the cancer was found to have originated in the right tonsil and was staged as T1N1. The patient started definitive treatment with concurrent chemo-radiation therapy, but after 5 treatments was no longer able to lay in a supine position for treatment. Diagnostic imaging workup eventually revealed an idiopathic right sided hemi-diaphragm eventration. After consultation with cardiology, pulmonology, and head and neck surgery, recommendation was made for tracheostomy to tolerate supine radiotherapy position, but the patient refused. Instead, computed tomography simulation for radiotherapy replanning was performed using a combination of biphasic cuirass ventilation, home continuous positive airway pressure and oxygen. The patient then tolerated definitive treatment to a dose of 69.96 Gray in 33 fractions with concurrent chemotherapy and experienced no unexpected side effects. Although complex, daily treatment setup was consistent. Daily onboard imaging was precise and accurate. The patient continues to follow up with radiation oncology, medical oncology, and pulmonology. This is the first use of biphasic cuirass ventilator supported radiotherapy reported in the scientific literature. Although daily treatment setup is complex, its use could be considered in patients unable to tolerate radiation therapy treatment positioning as an alternative to tracheostomy.

Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma.

Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.

Phase II Trial of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: To report the results of a phase II clinical trial of de-intensified chemoradiotherapy for patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma. MATERIALS AND METHODS: Major inclusion criteria were (1) having American Joint Committee on Cancer (AJCC) 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) being p16 positive, and (3) reporting minimal or remote smoking history. Treatment was limited to 60 Gy intensity-modulated radiotherapy with concurrent intravenous cisplatin 30 mg/m2 once per week. Patients with T0-T2 N0-1 (AJCC 7th edition) did not receive chemotherapy. All patients had a 10- to 12-week post-treatment positron emission tomography/computed tomography to assess for neck dissection. The primary end point was 2-year progression-free survival. Secondary end points included 2-year local-regional control, distant metastasis-free survival and overall survival, and patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events). RESULTS: One hundred fourteen patients were enrolled (median follow-up of 31.8 months), with 81% having a minimum follow-up of 2 years. Eighty percent of patients had 10 or fewer tobacco pack-years. Two-year local-regional control, distant metastasis-free survival, progression-free survival, and overall survival were as follows: 95%, 91%, 86%, and 95%, respectively. Mean pre- and 2-year post-treatment European Organisation for Research and Treatment of Cancer quality of life scores were as follows: global, 79/84 (lower worse); swallowing, 8/9 (higher worse); and dry mouth, 14/45 (higher worse). Mean pre- and 2-year post-treatment patient-reported outcomes version of the Common Terminology Criteria for Adverse Events scores (0 to 4 scale, higher worse) were as follows: swallowing, 0.5/0.7, and dry mouth, 0.4/1.3. Thirty-four percent of patients required a feeding tube (median, 10.5 weeks; none permanent). There were no grade 3 or higher late adverse events. CONCLUSION: Clinical outcomes with a de-intensified chemoradiotherapy regimen of 60 Gy intensity-modulated radiotherapy with concurrent low-dose cisplatin are favorable in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma. Neither neoadjuvant chemotherapy nor routine surgery is needed to obtain favorable results with de-escalation.

Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: To perform a prospective, multi-institutional, phase 2 study of a substantial decrease in concurrent chemoradiation therapy (CRT) intensity as primary treatment for favorable-risk, human papillomavirus-associated oropharyngeal squamous cell carcinoma. METHODS AND MATERIALS: The major inclusion criteria were: (1) T0 to T3, N0 to N2c, M0; (2) human papillomavirus or p16 positive; and (3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatinum (30 mg/m(2)). The primary study endpoint was pathologic complete response (pCR) rate based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Power computations were performed for the null hypothesis that the pCR rate is 87% and n=40, resulting in a type 1 error of 14.2%. Secondary endpoint measures included physician-reported toxicity (Common Toxicity Terminology for Adverse Events, CTCAE), patient-reported symptoms (PRO-CTCAE), and modified barium swallow studies. RESULTS: The study population was 43 patients. The pCR rate was 86% (37 of 43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very severe symptoms was as follows: mucositis 34%/45%, general pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55%, and xerostomia 2%/75%. Grade 3/4 hematologic toxicities were 11%. Thirty-nine percent of patients required a feeding tube for a median of 15 weeks (range, 5-22 weeks). There were no significant differences in modified barium swallow studies before and after CRT. CONCLUSIONS: The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatinum is very high in favorable-risk oropharyngeal squamous cell carcinoma, with evidence of decreased toxicity compared with standard therapies. ClinicalTrials.gov ID: NCT01530997.

Comprehensive genomic profiles of small cell lung cancer.

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

Processed pseudogenes acquired somatically during cancer development.

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.

Prognostic significance of bone invasion for oral cavity squamous cell carcinoma considered T1/T2 by American joint committee on cancer size criteria.

BACKGROUND: It is unclear whether bone invasion in small oral cavity squamous cell carcinomas (OCSCC) results in worse prognosis. METHODS: Two hundred fifty-four patients with OCSCC were identified and divided into 3 cohorts: (1) ≤4 cm with no bone invasion; (2) ≤4 cm with bone invasion; and (3) ≥4 cm or other factors (eg, skin invasion, deep muscle invasion) that would qualify for American Joint Committee on Cancer (AJCC) T4 classification aside from bone invasion. Depth of bone invasion (none, cortical, or medullary) was also recorded. RESULTS: Cohorts 1 and 2 had similar outcomes. Cohort 3 had lower rates of regional control (p = .04), disease-specific survival (DSS; p < .01), and overall survival (OS; p < .01). On multivariate analysis, margin status and medullary bone invasion were associated with worse outcomes. CONCLUSION: Bone invasion does not seem to significantly influence outcomes in patients with small primary tumors treated with surgery/radiation. Medullary bone invasion seems to result in reduced rates of control and survival.

Clinical significance of indeterminate pulmonary nodules in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this study was to determine whether indeterminate pulmonary nodules (IPNs) at staging are predictive of lung metastasis, primary lung carcinoma, or survival in patients with advanced head and neck squamous cell carcinoma (HNSCC). METHODS: One hundred ten patients with IPN at staging who had follow-up imaging and 100 patients without IPN were identified from an HNSCC database. The primary endpoints were lung progression-free survival (PFS) and overall survival (OS). RESULTS: Two-year lung PFS for the IPN and No-IPN cohorts were 66% versus 61% (p = .92) and the OS for these cohorts were 71% versus 68% (p = .77). Within the IPN cohort, level IV/V lymph node involvement (odds ratio = 4.34; p = .03), hypopharynx primary (odds ratio = 21.5; p = .005), and race (odds ratio = 9.29; p = .001) were independent predictors of developing lung malignancy. CONCLUSION: IPNs at staging in patients with HNSCC do not affect prognosis and should neither influence initial treatment planning nor the frequency of posttreatment surveillance.

Patterns of local failure for sinonasal malignancies.

PURPOSE: To identify the patterns of local failure for sinonasal malignancies treated with radiation therapy (RT). METHODS AND MATERIALS: We retrospectively identified 79 patients with sinonasal malignancies treated between 2000 and 2011. The median follow-up was 34 months (7-137). Fifty patients (63%) had surgery and RT with or without chemotherapy, and 29 (37%) received definitive chemoradiation therapy. Twenty-six of 79 patients (33%) failed locally; 11 had persistent disease and 15 had local recurrence (LR). The patients with LR had at least a 3-month disease-free interval posttreatment. Imaging of the 15 LR was registered to the treatment planning computed tomography. Failures were categorized as in-field, marginal, or out-of-field if >95%, 20%-95%, or <20% of the LR was within the 95% prescription isodose line, respectively. RESULTS: Of the 15 patients with LR, 7 were in-field, 2 were marginal, and 6 were out-of-field. For 3 patients, treatment plans were not retrievable; however, it was apparent from clinical records that 2 had in-field LR and 1 had an out-of-field LR (untreated contralateral maxillary sinus). No patient with a marginal or out-of-field recurrence had more than 39% of their recurrent tumor volume within 95% of the prescribed dose. Coverage of the LR by 54 Gy and 45 Gy was suboptimal in 7/7 and 5/7 patients with LR, respectively. Marginal and out-of-field LR were predominantly above the pretreatment tumor location and at the level of or superior to the eyes. CONCLUSIONS: Sinonasal malignancies failed marginally or out-of-field in 53% (8/15) of LR and 31% (8/26) of all local failures. The anatomic location of these marginal and out-of field LR are predominately at, or superior to, the level of the eyes. This pattern of failure may be directly related to efforts to minimize RT to the optic structures and the degree of difficulty of skull base operations.

Incidence of nodal disease after nonsurgical therapy in head and neck squamous cell carcinoma patients with bilateral neck disease: can a bilateral neck dissection be avoided?

BACKGROUND: We evaluated whether classifying 1 side of a patients' neck as "high risk" would help in deciding the extent of neck dissection in patients with bilateral nodal disease. METHODS: We conducted a retrospective review of 44 patients (88 heminecks) with head and neck squamous cell carcinoma who had bilateral nodal disease and received definitive chemoradiotherapy (CRT). For lateralized lesions (70%), the ipsilateral neck was designated as the "high-risk" neck. For midline lesions, pre-CRT and post-CRT computed tomography scans were used to stage each side of the neck (hemineck); the higher staged hemineck was designated as the "high-risk" neck. RESULTS: Twenty-seven patients had died at the time of analysis. Patients had a median follow-up of 27.8 months (range, 6 to 150 mo). Two-year neck control and overall survival were 83% and 56%, respectively. Sixty-two heminecks (71%) were dissected. A total of 6/22 (27%) "low-risk" necks were positive after CRT if the "high-risk" neck was positive versus 0/22 if the "high-risk" neck was negative (P=0.02). CONCLUSIONS: Identifying the more "high-risk" neck may be useful when deciding the extent of neck dissection after CRT. For patients with bilateral nodal disease treated with CRT, dissection of the "low-risk" hemineck may be omitted if the "high-risk" neck is pathologically negative.

Management of nonesthesioneuroblastoma sinonasal malignancies with neuroendocrine differentiation.

OBJECTIVES/HYPOTHESIS: Report the outcomes of patients with nonesthesioneuroblastoma (non-ENB) sinonasal malignancies with neuroendocrine differentiation. STUDY DESIGN: Single Institution Retrospective Case Series. METHODS: We conducted a retrospective chart review of 19 biopsy-proven non-ENB sinonasal neuroendocrine carcinomas diagnosed between 1997 and 2010 and treated with multimodality therapy. Kaplan-Meier estimates of local-regional control (LRC), distant metastases-free survival (DMFS), and overall survival (OS) were calculated. RESULTS: The 3-year LRC, FFDM, and OS rates were 63%, 50%, and 64%, respectively. All nine patients receiving neoadjuvant chemoradiotherapy (CRT) had at least a pathologic partial response: three of seven sinonasal undifferentiated carcinomas and two of two sinonasal neuroendocrine carcinomas had complete pathological responses. All five patients with pathologic complete responses were alive without disease at a median follow-up of 43 (29-67) months. CONCLUSIONS: Having a complete response pathologically to CRT was a favorable prognostic indicator. Neoadjuvant CRT followed by surgery seems to be an efficacious sequence of multimodality therapy.

Matched cohort analysis of the effect of pretreatment positron emission tomography on clinical outcomes of patients with head and neck cancer treated with definitive chemoradiotherapy.

BACKGROUND: Pretreatment positron emission tomography (PET) has been shown to be useful for patients with head and neck squamous cell carcinoma (HNSCC) after definitive chemoradiotherapy (CRT). METHODS: We conducted a retrospective analysis of a matched cohort of 116 patients with HNSCC that underwent CRT treatment at our institution. Pretreatment PET was performed in 58 patients and omitted in the other 58 patients. The 2 cohorts were matched for T classification, N classification, primary site, and smoking history. Kaplan-Meier 2-year estimates of local control (LC), regional control (RC), freedom from distant metastasis (FFDM), cause-specific survival (CSS), and overall survival (OS) were compared with log-rank tests. RESULTS: There were no differences between the 2 cohorts for 2-year endpoints of LC, RC, FFDM, CSS, and OS. On multivariate analysis pretreatment PET imaging did not influence any endpoint. CONCLUSIONS: PET imaging before definitive CRT may not significantly improve outcomes in patients with HNSCC.

Phase II trial of hyperfractionated intensity-modulated radiation therapy and concurrent weekly cisplatin for Stage III and IVa head-and-neck cancer.

PURPOSE: To investigate a novel chemoradiation regimen designed to maximize locoregional control (LRC) and minimize toxicity for patients with advanced head-and-neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Patients received hyperfractionated intensity modulated radiation therapy (HIMRT) in 1.25-Gy fractions b.i.d. to 70 Gy to high-risk planning target volume (PTV). Intermediate and low-risk PTVs received 60 Gy and 50 Gy, at 1.07, and 0.89 Gy per fraction, respectively. Concurrent cisplatin 33 mg/m(2)/week was started Week 1. Patients completed the Quality of Life Radiation Therapy Instrument pretreatment (PRE), at end of treatment (EOT), and at 1, 3, 6, 9, and 12 months. Overall survival (OS), progression-free (PFS), LRC, and toxicities were assessed. RESULTS: Of 39 patients, 30 (77%) were alive without disease at median follow-up of 37.5 months. Actuarial 3-year OS, PFS, and LRC were 80%, 82%, and 87%, respectively. No failures occurred in the electively irradiated neck and there were no isolated neck failures. Head and neck QOL was significantly worse in 18 of 35 patients (51%): mean 7.8 PRE vs. 3.9 EOT. By month 1, H&N QOL returned near baseline (mean 6.2, SD = 1.7). The most common acute Grade 3+ toxicities were mucositis (38%), fatigue (28%), dysphagia (28%), and leukopenia (26%). CONCLUSIONS: Hyperfractionated IMRT with low-dose weekly cisplatin resulted in good LRC with acceptable toxicity and QOL. Lack of elective nodal failures despite very low dose per fraction has led to an attempt to further minimize toxicity by reducing elective nodal doses in our subsequent protocol.

Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors.

In mice, Lkb1 deletion and activation of Kras(G12D) results in lung tumors with a high penetrance of lymph node and distant metastases. We analyzed these primary and metastatic de novo lung cancers with integrated genomic and proteomic profiles, and have identified gene and phosphoprotein signatures associated with Lkb1 loss and progression to invasive and metastatic lung tumors. These studies revealed that SRC is activated in Lkb1-deficient primary and metastatic lung tumors, and that the combined inhibition of SRC, PI3K, and MEK1/2 resulted in synergistic tumor regression. These studies demonstrate that integrated genomic and proteomic analyses can be used to identify signaling pathways that may be targeted for treatment.