Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.

BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.

Open-label, phase II study of talimogene laherparepvec plus pembrolizumab for the treatment of advanced melanoma that progressed on prior anti-PD-1 therapy: MASTERKEY-115.

BACKGROUND: Treatment options for immunotherapy-refractory melanoma are an unmet need. The MASTERKEY-115 phase II, open-label, multicenter trial evaluated talimogene laherparepvec (T-VEC) plus pembrolizumab in advanced melanoma that progressed on prior programmed cell death protein-1 (PD-1) inhibitors. METHODS: Cohorts 1 and 2 comprised patients (unresectable/metastatic melanoma) who had primary or acquired resistance, respectively, and disease progression within 12 weeks of their last anti-PD-1 dose. Cohorts 3 and 4 comprised patients (resectable disease) who underwent complete surgery, received adjuvant anti-PD-1, and experienced recurrence. Cohort 3 were disease-free for < 6 months and cohort 4 for ≥ 6 months after starting the adjuvant anti-PD-1 therapy and before confirmed recurrence. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included complete response rate (CRR), disease control rate (DCR) and progression-free survival (PFS) per RECIST v1.1 and irRC-RECIST, and safety. RESULTS: Of the 72 enrolled patients, 71 were treated. The ORR (95% CI) was 0%, 6.7% (0.2-32.0), 40.0% (16.3-67.7), and 46.7% (21.3-73.4) in cohorts 1-4, respectively; iORR was 3.8% (0.1-19.6), 6.7% (0.2-32.0), 53.3% (26.6-78.7), and 46.7% (21.3-73.4). iCRR was 0%, 0%, 13.3%, and 13.3%. Median iPFS (months) was 5.5, 8.2, not estimable [NE], and NE for cohorts 1-4, respectively; iDCR was 50.0%, 40.0%, 73.3%, and 86.7%. Treatment-related adverse events (TRAEs), grade ≥ 3 TRAEs, serious AEs, and fatal AEs occurred in 54 (76.1%), 9 (12.7%), 24 (33.8%), and 10 (14.1%) patients, respectively. CONCLUSION: T-VEC-pembrolizumab demonstrated antitumor activity and tolerability in PD-1-refractory melanoma, specifically in patients with disease recurrence on or after adjuvant anti-PD-1. TRIAL REGISTRATION: ClinicalTrials.gov identifier - NCT04068181.

Long-term benefit of sotorasib in patients with KRAS G12C-mutated non-small-cell lung cancer: plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial.

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 106 plaque-forming units (PFU)/mL in week 1, followed by 108 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported.At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297.

Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the longest follow-up, to our knowledge, for a KRASG12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies. Patients (N = 174) received sotorasib 960 mg once daily with the primary end points for phase I of safety and tolerability and for phase II of objective response rate (ORR). Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 months, and 2-year OS rate of 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 40 (23%) patients across PD-L1 expression levels, in a proportion of patients with somatic STK11 and/or KEAP1 alterations, and was associated with lower baseline circulating tumor DNA levels. Sotorasib was well tolerated, with few late-onset treatment-related toxicities, none of which led to treatment discontinuation. These results demonstrate the long-term benefit of sotorasib, including in subgroups with poor prognosis.

Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study.

PURPOSE: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. PATIENTS AND METHODS: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety. RESULTS: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3-24.2). One DLT of T-VEC-related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0-5.8] and 5.8 months (95% Cl, 2.9-11.4), respectively. CONCLUSIONS: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).

Transoral robotic surgery: radical tonsillectomy.

OBJECTIVE: To describe and show the feasibility of a new surgical technique for transoral robotic surgery (TORS) radical tonsillectomy. DESIGN: A prospective, phase 1 clinical trial. SETTING: Academic, tertiary referral center. PATIENTS: A total of 27 participants were prospectively selected using a volunteer sample. All eligible patients agreed to participate in the study. INTERVENTIONS: Patients underwent TORS radical tonsillectomy for previously untreated invasive squamous cell carcinoma of the tonsillar region without free-flap reconstruction, staged neck dissection, and adjuvant therapy. MAIN OUTCOME MEASURES: Outcome measures included final pathologic margin status, need for short- and long-term tracheotomy tube placement, and need for gastrostomy tube feedings among patients with a minimum 6-month follow-up. The incidence of significant postoperative complications was recorded. RESULTS: No mortality occurred. Final margins found to be negative for cancer were achieved in 25 of 27 patients (93%). Surgical complications included 1 case each of postoperative mucosal bleeding, delirium tremens, unplanned tracheotomy for temporary exacerbation of sleep apnea, and hypernasality and 2 cases of moderate trismus. Twenty-six of 27 patients (96%) were swallowing without the use of a gastrostomy. CONCLUSIONS: Radical tonsillectomy using TORS is a new technique that offers excellent access for resection of carcinomas of the tonsil with acceptable acute morbidity. Future reports will focus on long-term oncologic and functional outcomes.

Visual attention circuitry in schizophrenia investigated with oddball event-related functional magnetic resonance imaging.

OBJECTIVE: Schizophrenia patients have problems directing attention. Sustained attention requires ensuring that brain resources are focused on a selected target (top-down task) while ignoring irrelevant distractors (bottom-up interference). Whether patients have too little ability to focus or too much interference from distraction has not been clarified. The oddball paradigm embeds infrequent targets and distractors into the stimulus train, and schizophrenia deficits have been linked to diminished responses to both. Cerebral activity underlying abnormal attention can be examined with event-related functional magnetic resonance imaging. METHOD: A visual oddball task was presented to 22 patients with schizophrenia and 28 comparison subjects. Statistical probability maps reflecting blood-oxygenation-level-dependent changes were generated for infrequent targets and novel distractors relative to frequent standard stimuli. Activation was related to performance and symptoms. RESULTS: Activation specific to targets and distractors was associated with faster performance. For targets, patients had diminished activation in superior temporal and frontal gyri, cingulate, thalamus, and basal ganglia. They had increased activation in right insula, mid-frontal gyrus, posterior cingulate, and left inferior parietal lobule. For distractors, patients showed less activation in occipital regions and left inferior parietal lobule but increased activation in parietal-occipital, right mid-frontal, and left inferior frontal gyri. Abnormal activation correlated with positive and negative symptoms. CONCLUSIONS: Abnormal activation in schizophrenia in response to attentional demands reflects both insufficient recruitment of brain systems required for target detection and overcommitment of resources for processing irrelevant distractors. Schizophrenia patients appear to have an inability both to focus on targets and ignore distraction.

Transoral robotic surgery: supraglottic partial laryngectomy.

OBJECTIVES: We assessed the feasibility of performing transoral supraglottic partial laryngectomy with robotic instrumentation. METHODS: Transoral robotic surgery (TORS) was performed on 3 human patients with supraglottic carcinoma in a prospective human trial. The study was approved by our institutional review board and involved the da Vinci Surgical Robot (Intuitive Surgical, Inc, Sunnyvale, California). RESULTS: All procedures were completed robotically. The median overall operation time to perform the robotic procedure was 120 minutes (range, 1:32:48 to 2:58:18), including 18 minutes (range, 00:6:07 to 00:30:39) for exposure and robotic positioning. There were no intraoperative or postoperative complications or surgical mortality. CONCLUSIONS: The preliminary results of our series suggest that application of the da Vinci robotic surgical system for TORS to supraglottic partial laryngectomy is technically feasible and relatively safe. Furthermore, TORS provides excellent surgical exposure that allows complete tumor resection. Most importantly, TORS provides an alternative to open approaches and "conventional" transoral supraglottic partial laryngectomy.

Hemodynamic responses in neural circuitries for detection of visual target and novelty: An event-related fMRI study.

The oddball paradigm examines attentional processes by establishing neural substrates for target detection and novelty. Event-related functional imaging enables characterization of hemodynamic changes associated with these processes. We studied 36 healthy participants (17 men) applying a visual oddball event-related design at 4 Tesla, and performed an unbiased determination of the hemodynamic response function (HRF). Targets were associated with bilateral, albeit leftward predominant changes in frontal-parietal temporal and occipital cortices, and limbic and basal ganglia regions. Activation to novelty was more posteriorly distributed, and frontal activation occurred only on the right, while robust activation was seen in occipital regions bilaterally. Overlapping regions were left thalamus, caudate and cuneus and right parietal precuneus. While robust HRFs characterized most regions, target detection was associated with a negative HRF in the right parietal precuneus and a biphasic HRF in thalamus, basal ganglia, and all occipital regions. Both height of the HRF and longer time to peak in the right cingulate were associated with slower response time. Sex differences were observed, with higher HRF peaks for novelty in men in right occipital regions, and longer time to peak in the left hemisphere. Age was associated with reduced peak HRF in left frontal region. Thus, indices of the HRF can be used to better understand the relationship between hemodynamic changes and performance and can be sensitive to individual differences.

Transoral robotic surgery (TORS) for base of tongue neoplasms.

OBJECTIVE: To develop a minimally invasive surgical technique for the treatment of base of tongue neoplasms using the optical and technical advantages of robotic surgical instrumentation. STUDY DESIGN: Ten experimental procedures including tongue base exposure and dissections were performed on three cadavers and two mongrel dogs. Transoral robotic surgery (TORS) was then performed on three human patients with tongue base cancers in a prospective human trial. METHODS: Using the da Vinci Surgical Robot (Intuitive Surgical, Inc., Sunnyvale, CA), we performed a total of 10 base of tongue resections on edentulous and dentate cadavers as well as live mongrel dogs. In the cadaver models, exposure was evaluated using three different retractors, the Dingman, Crowe Davis, and FK retractors. The three human patients underwent TORS surgery of their tongue base cancers under an institutional review board approved prospective clinical trial. The ability to identify and preserve or resect key anatomic structures such as the glossopharyngeal, hypoglossal, and lingual nerves as well as techniques for identifying the lingual artery and achieving hemostasis were developed. RESULTS: The da Vinci Surgical Robot provided excellent visualization and enabled removal of the posterior one third to one half of the oral tongue in cadavers, dogs, and human patients. Among the three retractors evaluated, the FK retractor offered the greatest versatility and overall exposure for robotic instrument maneuverability. Complete resection to negative surgical margins with excellent hemostasis and no complications was achieved in the live patient surgeries. CONCLUSIONS: TORS provided excellent three-dimensional visualization and instrument access that allowed successful surgical resections from cadaver models to human patients. TORS is a novel and minimally invasive approach to tongue neoplasms that has significant advantages over classic open surgery or endoscopic transoral laser surgery.

Evaluation of photopoint photosensitizer mv6401, indium chloride methyl pyropheophorbide, as a photodynamic therapy agent in primate choriocapillaris and laser-induced choroidal neovascularization.

PURPOSE: To assess the potential of a new photosensitizer, indium chloride methyl pyropheophorbide (PhotoPoint MV6401), for ocular photodynamic therapy (PDT) in normal choriocapillaris vessels and experimentally induced choroidal neovascularization in New-World monkeys (Saimiri sciureus). METHODS: PhotoPoint MV6401 (Miravant Pharmaceuticals, Inc., Santa Barbara, CA) was activated at 664 nm using a DD3-0665 (Miravant Systems, Inc., Santa Barbara, CA) 0.5 W diode laser. The efficacy of MV6401 was evaluated by indirect ophthalmoscopy, fundus photography, fluorescein angiography, and histology. The drug and light doses were 0.10 micromoles/kg to 0.3 micromoles/kg and 10 J/cm to 40 J/cm, respectively, and post-injection activation times ranged from +10 minutes to +120 minutes. RESULTS: Best closure of normal choriocapillaris was achieved at a dosage level of 0.15 micromoles/kg in primates. Histology demonstrated that increased post-injection activation times (+60 minutes to +90 minutes) and low laser light doses (10 J/cm to 20 J/cm) in the primate model resulted in selective closure of the choriocapillaris and medium sized choroidal vessels with minimal effect to the retina. Histology from neovascular lesions PDT-treated with MV6401 revealed significant diminution of vascularity, correlating with diminution of leakage observed on angiography. CONCLUSION: PhotoPoint MV6401, indium chloride methyl pyropheophorbide, is a potent photosensitizer that demonstrates both efficacy and selectivity in primate choriocapillaris and laser-induced choroidal neovascularization occlusion. Maximum selectivity was achieved using a post infusion interval of +60 to +90 minutes.

The squirrel monkey: characterization of a new-world primate model of experimental choroidal neovascularization and comparison with the macaque.

PURPOSE: To evaluate and characterize the New-World squirrel monkey as a primate model for experimental choroidal neovascularization (CNV) studies and to compare it with the current Old-World macaque monkey model. METHODS: Fibrovascular tissues (FVT) were elicited in 12 maculae of seven squirrel monkeys by laser photocoagulation using optimized laser parameters (532 nm, 0.05 second, 75 micro m, 650 mW). Follow-up fundus and fluorescein angiography (FA) examinations were conducted on postlaser days 30 and 35, followed by euthanasia and histologic analysis of tissues. For comparative evaluations, FVT development also was induced and analyzed in eight maculae of four macaque monkeys with laser parameters previously used in this species (514 nm, 0.1 second, 50 micro m, 390 and 455 mW). RESULTS: FVT developed in both primate species, consisting of fibrous tissue that contained vessels that ranged from sparse but identifiable capillaries to well-established neovascular networks. Overall, 65% of the photocoagulation sites in the squirrel monkey and 37% of sites in macaque monkey elicited development of FVT. Localized FVT ranged from modest to extensive thickenings of the choriocapillaris layer. Unexpectedly, 76% of the FVT sites in squirrel monkey eyes and 27% of the sites in macaque eyes showed diffuse FVT that expanded beyond the original photocoagulation sites, accompanied by neovascular infiltration of the retina. CONCLUSIONS: Like the macaque, the squirrel monkey can be considered a useful primate model for experimental CNV investigations, while additionally offering certain species-specific advantages. Diffuse FVT permit studies of antiangiogenic therapies in areas distant from laser photocoagulative trauma sites.

Pre-migration trauma and HIV-risk behavior.

This study examined the relationship between pre-migration trauma and HIV-risk behavior in refugees from sub-Saharan Africa. The sample comprised 122 persons who had emigrated from sub-Saharan Africa and were currently residing in Sweden. Qualitative methods including individual interviews, focus groups, and interviews with key informants addressed questions regarding trauma experience and HIV-risk behavior. A history of pre-migration trauma was found to be associated with HIV-risk behavior. According to the participants, symptoms associated with post-traumatic stress disorder, depression, adjustment disorder, and substance use mediated the relationship between pre-migration trauma and sexual risk behavior. In contrast, a minority of the participants who reported pre-migration trauma but not psychological sequelae, or experienced post-traumatic growth, reported safer sexual practices. It appears that for some individuals, pre-migration trauma resulted in psychiatric sequelae, which may increase an individual's risk to be infected with HIV. Interventions targeted at individuals at increased risk (i.e. pre-migration trauma with unresolved psychiatric symptomatology) may facilitate the prevention of HIV and other sexually transmitted diseases in this population. Integration of multiple psychosocial and health issues is recommended for comprehensive treatment and prevention programs.

Age-related mutation accumulation at a lacZ reporter locus in normal and tumor tissues of Trp53-deficient mice.

Increased genomic instability has been found associated with cancer and aging. The p53 tumor suppressor protein is a major determinant of genomic instability as a regulator of cell cycle control and apoptosis in response to DNA damage. To investigate the rate of age-related mutation accumulation in the absence of p53, we crossed Trp53 null mice with transgenic mice harboring a lacZ mutational target gene. In the hybrid animals, lacZ mutation frequencies at early age (i.e. at about 2 months) were found to be the same as in the control lacZ animals. However, up until about 6 months, when the Trp53-knockout mice usually die from cancer, mutations were found to accumulate with age in the spleen, and to a lesser extent in the liver, at a more rapid rate than in the control Trp53(+/+) or Trp53(+/-), lacZ hybrid mice. Treatment of 2-3-month-old Trp53(-/-), lacZ hybrid mice with the powerful mutagen ethyl nitrosourea (ENU) resulted in a higher number of mutations induced in the liver but not in the spleen, as compared to the Trp53(+/+), lacZ mice. These results suggest that p53 is not an important determinant of gene mutation induction, either spontaneously during development or after treatment with a mutagen. The accelerated age-related accumulation of mutations in normal spleen and liver could be explained by the defect in apoptosis, which would prevent severely damaged cells from being eliminated.

Mutational fingerprints of aging.

Using a lacZ plasmid transgenic mouse model, spectra of spontaneous point mutations were determined in brain, heart, liver, spleen and small intestine in young and old mice. While similar at a young age, the mutation spectra among these organs were significantly different in old age. In brain and heart G:C-->A:T transitions at CpG sites were the predominant mutation, suggesting that oxidative damage is not a major mutagenic event in these tissues. Other base changes, especially those affecting A:T base pairs, positively correlated with increasing proliferative activity of the different tissues. A relatively high percentage of base changes at A:T base pairs and compound mutants were found in both spleen and spontaneous lymphoma, suggesting a possible role of the hypermutation process in splenocytes in carcinogenesis. The similar mutant spectra observed at a young age may reflect a common mutation mechanism for all tissues that could be driven by the rapid cell division that takes place during development. However, the spectra of the young tissues did not resemble that of the most proliferative aged tissue, implying that replicative history per se is not the underlying causal factor of age-related organ-specific differences in mutation spectra. Rather, differences in organ function, possibly in association with replicative history, may explain the divergence in mutation spectra during aging.