Targeting BTK has profoundly changed the face of CLL treatment over the past decade. Iterative advances in the cat and mouse game of resistance and redesign have moved BTK inhibitors from covalent to non-covalent and now targeted protein degraders. However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKis.

We studied the intramitochondrial localization of several multiprotein complexes involved in U-insertion/deletion RNA editing in trypanosome mitochondria. The editing complexes are located in one or two antipodal nodes adjacent to the kinetoplast DNA (kDNA) disk, which are distinct from but associated with the minicircle catenation nodes. In some cases the proteins are in a bilateral sheet configuration. We also found that mitoribosomes have a nodal configuration. This type of organization is consistent with evidence for protein and RNA interactions of multiple editing complexes to form an ~40S editosome and also an interaction of editosomes with mitochondrial ribosomes.

Background

The results of RTOG-MRC randomized trial of photon (n=15) versus neutron (n=17) therapy in the 1980's reported an improved local control (LC) with neutron radiotherapy for unresectable salivary gland tumors. Due to increased severe toxicity with neutron radiotherapy and the paucity of neutron-therapy centers, we analyzed our institution's results of photon radiotherapy for unresectable salivary gland tumors.

Patients and methods

From 1990 to 2009, 27 patients with unresectable salivary gland cancer underwent definitive photon radiotherapy at our institution. Nodal involvement on presentation was found in 9 patients. Median dose of radiotherapy was 70 Gy. Chemotherapy was given to 18 patients, most being platinum-based regimens. Local control (LC), locoregional control (LRC), distant metastasis-free survival (DMFS), overall survival (OS), and toxicity outcomes were assessed.

Results

With a median follow-up of 52.4 months, the 2/5-year actuarial LC was 69% (95%CI ± 21.0%)/55% (± 24.2%), LRC was 65% (± 21.4%)/47% (± 21.6%), and DMFS was 71% (± 21.8%)/51% (± 22.8%), respectively using competing risk analysis. The median OS was 25.7 months, and the 2/5-year OS rates were 50% (± 19.0%)/29% (± 16.6%), respectively. Higher histologic grade was significant for an increased rate of DM (intermediate grade vs. low grade, p=0.04, HR 7.93; high grade vs. low grade, p=0.01, HR 13.50). Thirteen (48%) patient's experienced acute grade 3 toxicity. Late grade 3 toxicity occurred in three (11%) patients.

Conclusions

Our data compares favorably to neutron radiotherapy with fewer late complications. Photon radiotherapy is an acceptable alternative to neutron radiotherapy in patients who present with unresectable salivary gland tumors.

Background and objectives

To review clinical outcomes and toxicities in locally advanced differentiated thyroid cancer patients treated with external beam radiotherapy (EBRT) with or without concurrent chemotherapy (CCRT).

Methods

Between 1990 and 2012, 66 patients with gross residual/unresectable non-anaplastic non-medullary thyroid cancer were treated with EBRT.

Results

The median overall survival was 42.0 months. The overall locoregional progression-free survival (LPFS) at 3 years was 77.3%. CCRT resulted in a non-significant improvement in LPFS (90.0% vs. 73.0%, P = 0.347). Poorly differentiated histology had significantly improved LPFS (89.4% vs. 66.1%, P = 0.020), despite a significantly worse distant metastasis-free survival (43.9% vs. 82.5%, P = 0.023). Acute treatment-related toxicity included dermatitis, mucositis, and dysphagia with grade three rates of 12.1%, 19.7%, and 16.7%, respectively. The incidence of late toxicity was low. CCRT was only associated with a significant greater rate of acute grade 3 hoarseness (10.0% vs. 0.0%, P = 0.033), but with no difference in the rate of grade 2 late toxicity.

Conclusions

EBRT is a safe and effective treatment modality with 90% LPFS at 3 years in patients with gross residual or unresectable non-anaplastic, non-medullary thyroid carcinoma treated with CCRT. Further incorporation of EBRT with concurrent chemotherapy may result in improved disease control.

Purpose

Minor salivary gland cancers are rare and account for roughly 2% to 3% of all head and neck tumors. This is a retrospective review in a modern cohort of patients treated for this rare cancer with surgery and adjuvant radiation therapy.

Materials and methods

Between February 1990 and December 2010, 98 patients with cancer of the minor salivary glands were identified and treated at a single institution. The median radiation dose was 63 Gy. Outcomes assessed included local control (LC), locoregional control (LRC), and overall survival (OS). Toxicity was graded using the Common Terminology Criteria for Adverse Events, version 3.0. Competing-risk analysis using the Gray test was performed, with death as the competing risk. OS was calculated by the Kaplan-Meier method.

Results

With a median follow-up of 7.3 years, the 5- and 10-year LC and LRC rates were 87.9% and 83%, and 80.5% and 73.7%, respectively. Higher T stage and adenocarcinoma histology were the significant negative prognostic factors for both LC and LRC. Freedom from distant metastasis at 5 and 10 years were 83% and 63%, respectively. The median OS was 19.6 years. Overall, no grade 4 or 5 toxicities occurred, and 20% of the cohort experienced an acute grade 3 toxicity, and 6% with a grade 3 late toxicity.

Conclusions

In a modern cohort treated with surgery and radiotherapy, excellent outcomes can be achieved with lower toxicity rates compared with older published series.

Objectives

We previously reported inferior outcomes for locally advanced head and neck cancer treated with cetuximab (C225) versus cisplatin (CDDP). We now examine if this difference persists when accounting for HPV status and update outcomes on the entire cohort.

Materials and methods

From 3/106 to 4/1/08, 174 locally advanced head and neck cancer patients received definitive treatment with RT and CDDP (n=125) or RT and C225 (n=49). Of these, 62 patients had tissue available for HPV analysis.

Results

The median follow-up was 47 months. The 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.7% versus 40.2% (P<0.0001), 85.1% versus 35.4% (P<0.0001), and 90.0% versus 56.6% (P<0.0001), respectively. In the subset with tissue, there was no difference in rates of HPV or p16 positivity between the 2 groups. In this subset, the 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.3% versus 32.0% (P=0.01), 86.8% versus 43.2% (P=0.002), and 86.7% versus 76.9% (P=0.09), respectively. Multivariate analysis continued to show a benefit for CDDP.

Conclusions

With longer follow-up and the inclusion of HPV and p16 status for about one third of patients where tissue was available, we continued to find superior outcomes with concurrent CDDP versus C225.

p63, more specifically its ΔNp63α isoform, plays essential roles in squamous cell carcinomas (SCCs), yet the mechanisms controlling its nuclear transport remain unknown. Nucleoporins (NUPs) are a family of proteins building nuclear pore complexes (NPC) and mediating nuclear transport across the nuclear envelope. Recent evidence suggests a cell type-specific function for certain NUPs; however, the significance of NUPs in SCC biology remains unknown. In this study, we show that nucleoporin 62 (NUP62) is highly expressed in stratified squamous epithelia and is further elevated in SCCs. Depletion of NUP62 inhibits proliferation and augments differentiation of SCC cells. The impaired ability to maintain the undifferentiated status is associated with defects in ΔNp63α nuclear transport. We further find that differentiation-inducible Rho kinase reduces the interaction between NUP62 and ΔNp63α by phosphorylation of phenylalanine-glycine regions of NUP62, attenuating ΔNp63α nuclear import. Our results characterize NUP62 as a gatekeeper for ΔNp63α and uncover its role in the control of cell fate through regulation of ΔNp63α nuclear transport in SCC.

Background

The purpose of this study was to report the clinical outcomes and related prognostic factors of patients who underwent radiotherapy (RT) for the treatment of recurrent, never-irradiated oral cavity cancer (recurrent OCC).

Methods

The records of consecutive patients with nonmetastatic recurrent OCC who presented to and were treated with RT at our institution between 1989 and 2011 were reviewed. The Kaplan-Meier method was used to calculate overall survival (OS). The cumulative incidences of disease-specific death, local failure, regional failure, and distant metastasis were calculated with death as a competing risk.

Results

One hundred twenty-three patients were identified. Median follow-up for living patients was 54 months and 16 months for all patients. Ninety-one patients had salvage surgery followed by adjuvant RT. Definitive RT was utilized in the remaining 32 patients. The 5-year OS was 40%. The 5-year cumulative incidence of disease-specific death, local failure, regional failure, and distant metastasis was 55%, 34%, 22%, and 20%, respectively. Recurrent T classification and lack of salvage surgery were independently associated with worse disease-specific death and decreased OS, respectively. Subset analysis of patients who underwent salvage surgery demonstrated that age, recurrent T classification, and perineural invasion (PNI) were independently associated with decreased OS; recurrent T classification and thicker tumors were independently associated with worse disease-specific death; and positive/close margins and primary T classification were independently associated with increased local failure.

Conclusion

In this group of patients with recurrent OCC, clinical outcomes were similar or improved when compared with other recurrent OCC-specific reports. In the salvage surgery subset, tumor thickness and PNI are recurrent pathologic features associated with outcomes that were only previously demonstrated in studies of primary disease. Because of the relatively worse outcomes in patients receiving definitive or adjuvant RT for recurrent OCC, we advocate for the appropriate use of postoperative RT in the initial management of oral cavity cancers.

Background and purpose

Loco-regionally recurrent head and neck cancer (HNC) in the setting of prior radiotherapy carries significant morbidity and mortality. The role of re-irradiation (re-RT) remains unclear due to toxicity. We determined prognostic factors for loco-regional control (LRC) and formulated a nomogram to help clinicians select re-RT candidates.

Material and methods

From July 1996 to April 2011, 257 patients with recurrent HNC underwent fractionated re-RT. Median prior dose was 65 Gy and median time between RT was 32.4 months. One hundred fifteen patients (44%) had salvage surgery and 172 (67%) received concurrent chemotherapy. Median re-RT dose was 59.4 Gy and 201 (78%) patients received IMRT. Multivariate Cox proportional hazards were used to identify independent predictors of LRC and a nomogram for 2-year LRC was constructed.

Results

Median follow-up was 32.6 months. Two-year LRC and overall survival (OS) were 47% and 43%, respectively. Recurrent stage (P=0.005), non-oral cavity subsite (P<0.001), absent organ dysfunction (P<0.001), salvage surgery (P<0.001), and dose >50 Gy (P=0.006) were independently associated with improved LRC. We generated a nomogram with concordance index of 0.68.

Conclusion

Re-RT can be curative, and our nomogram can help determine a priori which patients may benefit.

Our understanding of the spatial variation in the chemical and microbial makeup of an entire human organ remains limited, in part due to the size and heterogeneity of human organs and the complexity of the associated metabolome and microbiome. To address this challenge, we developed a workflow to enable the cartography of metabolomic and microbiome data onto a three-dimensional (3D) organ reconstruction built off radiological images. This enabled the direct visualization of the microbial and chemical makeup of a human lung from a cystic fibrosis patient. We detected host-derived molecules, microbial metabolites, medications, and region-specific metabolism of medications and placed it in the context of microbial distributions in the lung. Our tool further created browsable maps of a 3D microbiome/metabolome reconstruction map on a radiological image of a human lung and forms an interactive resource for the scientific community.