Evidence of re-osseointegration after electrolytic cleaning and regenerative therapy of peri-implantitis in humans: a case report with four implants.

OBJECTIVE: To evaluate re-osseointegration after electrolytic cleaning and regenerative therapy of dental implants with peri-implantitis in humans. MATERIAL AND METHODS: Four dental implants that developed peri-implantitis underwent electrolytic cleaning followed by regenerative therapy with guided bone regeneration. All four implants developed recurrent peri-implantitis and were therefore explanted 6 to 13 months later. Radiographic bone level, probing depth, and bleeding on probing were determined at the time of surgery, 6 months later, and before implant retrieval. The peri-implant tissues were histologically and histomorphometrically analyzed. RESULTS: All four implants demonstrated radiographic and histological bone gain, reduced probing depth, and bleeding on probing. Radiographic bone gain was 5.8 mm mesially and 4.8 mm distally for implant #1, 3.3 mm and 2.3 mm for implant #2, 3.1 mm and 0.5 mm for implant #3, and 3.5 mm and 2.8 mm for implant #4. The histometric mean and maximum vertical bone gain for implant #1 to #4 was 1.65 mm and 2.54 mm, 3.04 mm and 3.47 mm, 0.43 mm and 1.27 mm, and 4.16 mm and 5.22 mm, respectively. The percentage of re-osseointegration for implant #1 to #4 was 21.0%, 36.9%, 5.7%, and 39.0%, respectively. In one implant, the newly formed bone was deposited directly onto calculus on the implant surface. CONCLUSIONS: We found that (1) re-osseointegration is possible on a formerly contaminated implant surface and (2) the electrolytic cleaning process seems to be effective enough at sites with calculus residues. CLINICAL RELEVANCE: Since re-osseointegration can be achieved by electrolytic cleaning, this decontamination technique may be considered as a future treatment concept.

Successful Treatment of a Resistant Subclone in ALK-Rearranged NSCLC.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are established effective therapies in patients with ALK-rearranged advanced non-small-cell lung cancer (NSCLC). Upon progressive disease, patients normally receive a subsequent ALK TKI. However, when disease progression occurs in a limited number of sites, an oligoprogressive approach is a treatment option. In our case, FDG-PET/CT scan detected a progressive site in a patient with ceritinib therapy. Biopsy of the lesion was not possible because of its location. Progression was therefore confirmed by liquid biopsy with identification of the resistant subclone ALK G1202R. Definitive radiotherapy of the progressive site led to the disappearance of the ALK-resistant mutation. Meanwhile, ceritinib therapy was continued. The absence of disease both on repeated imaging and liquid biopsy indicates that eradication of a resistant subclone with an oligoprogressive treatment approach might be possible.

Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene).

BACKGROUND: A minority of breast cancer (BC) patients suffer from severe reaction to adjuvant radiotherapy (RT). Although deficient DNA double-strand break repair is considered the main basis for the reactions, pretreatment identification of high-risk patients has been challenging. METHODS: To retrospectively determine the etiology of severe local reaction to RT in a 39-year-old woman with BC, we performed next-generation sequencing followed by further clinical and functional studies. RESULTS: We found a -4 intronic variant (c.2251-4A>G) in trans with a synonymous (c.3576G>A) variant affecting the ATM DNA-repair gene (NG_009830.1, NM_000051.3) which is linked to autosomal recessive ataxia-telangiectasia (A-T). We verified abnormal transcripts resulting from both variants, next to a minor wild-type transcript leading to a residual ATM kinase activity and genomic instability. Follow-up examination of the patient revealed no classic sign of A-T but previously unnoticed head dystonia and mild dysarthria, a family history of BC and late-onset ataxia segregating with the variants. Additionally, her serum level of alpha-fetoprotein (AFP) was elevated similar to A-T patients. CONCLUSION: Considering the variable presentations of A-T and devastating impact of severe reactions to RT, we suggest a routine measurement of AFP in RT-candidate BC patients followed by next-generation sequencing with special attention to non-canonical splice site and synonymous variants in ATM.

Skeletal muscle mass correlates with increased toxicity during neoadjuvant radiochemotherapy in locally advanced esophageal cancer: A SAKK 75/08 substudy.

BACKGROUND: Sarcopenia, the critical depletion of skeletal muscle mass, is an independent prognostic factor in several tumor entities for treatment-related toxicity and survival. In esophageal cancer, there have been conflicting results regarding the value of sarcopenia as prognostic factor, which may be attributed to the heterogeneous patient populations and the retrospective nature of previous studies. The aim of our study was therefore to determine the impact of sarcopenia on prospectively collected specific outcomes in a subgroup of patients treated within the phase III study SAKK 75/08 with trimodality therapy (induction chemotherapy, radiochemotherapy and surgery) for locally advanced esophageal cancer. METHODS: Sarcopenia was assessed by skeletal muscle index at the 3rd lumbar vertebra (L3) in cross-sectional computed tomography scans before induction chemotherapy, before radiochemotherapy and after neoadjuvant therapy in a subgroup of 61 patients from four centers in Switzerland. Sarcopenia was determined by previously established cut-off values (Martin et al., PMID: 23530101) and correlated with prospectively collected outcomes including treatment-related toxicity, postoperative morbidity, treatment feasibility and survival. RESULTS: Using the published cut-off values, the prevalence of sarcopenia increased from 29.5% before treatment to 63.9% during neoadjuvant therapy (p < 0.001). Feasibility of neoadjuvant therapy and surgery was not different in initially sarcopenic and non-sarcopenic patients. We observed in sarcopenic patients significantly increased grade ≥ 3 toxicities during chemoradiation (83.3% vs 52.4%, p = 0.04) and a non-significant trend towards increased postoperative complications (66.7% vs 42.9%, p = 0.16). No difference in survival according to sarcopenia could be observed in this small study population. CONCLUSIONS: Trimodality therapy in locally advanced esophageal cancer is feasible in selected patients with sarcopenia. Neoadjuvant chemoradiation increased the percentage of sarcopenia. Sarcopenic patients are at higher risk for increased toxicity during neoadjuvant radiochemotherapy and showed a non-significant trend to more postoperative morbidity.

3-weekly or weekly cisplatin concurrently with radiotherapy for patients with squamous cell carcinoma of the head and neck - a multicentre, retrospective analysis.

BACKGROUND: Concurrent chemoradiotherapy with cisplatin is standard for patients (pts) with loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) and for patients with resected SCCHN with high-risk features. The standard regimen includes 3-weekly cisplatin, but weekly regimens are often used to lower toxicity. Reaching a cumulative dose of ≥200 mg/m2 cisplatin was shown being associated with improved outcome. We herein investigated cumulative dose reached and toxicities between the 3-weekly and weekly cisplatin regimens with concurrent radiotherapy. METHODS: Multicentre, retrospective analysis of all patients undergoing combined RCT with cisplatin treated at 3 centres in Switzerland between 06/2008 and 12/2015. RESULTS: Three hundred fourteen pts. were included (3-weekly, N = 127; weekly, N = 187). Median cumulative cisplatin dose was 200 mg/m2 (IQR 150-300) for pts. treated with a 3-weekly schedule and 160 mg/m2 (120-240) for the weekly schedule, consequently more pts. treated with a 3-weekly schedule reached a cumulative dose ≥200 mg/m2 (75.6% vs. 47.1%, p < 0.001). This association was also observed in multivariable analysis adjusted for age and sex (OR 3.46, 95% confidence interval [CI], 2.1-5.7). The 3-weekly regimen led to a higher rate of acute renal toxicity (33.1% vs. 20.9%, p = 0.022). In the landmark analysis, we could not confirm that a cisplatin dose ≥200 mg/m2 is associated with better survival (HR 1.3, 95% CI 0.8-1.9). CONCLUSIONS: Significantly more patients receive a cumulative cisplatin dose of ≥200 mg/m2, when treated with a 3-weekly schedule compared to weekly dosing. The previously reported association between a cumulative cisplatin dose ≥200 mg/m2 and improved outcome could not be shown in our study.

Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08).

BACKGROUND: KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. RESULTS: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). CONCLUSIONS: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease.

BACKGROUND: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. METHODS: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. RESULTS: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. CONCLUSION: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.

Avoiding glucocorticoid administration in a neurooncological case.

Restricting glucocorticoid (GC) use in the treatment of patients with a solid tumor may help improving outcome. Here, we report administration of celecoxib rather than dexamethasone to prevent brain edema in a patient with a cerebellar glioblastoma multiforme WHO grade IV (GBM) upon the patient's request, as well as determining cerebrospinal fluid (CSF) and serum concentrations. CSF concentration (0.04 microM) was 54 times below serum concentration (2.18 microM), or 2500 times below levels inhibiting GBM cells in vitro (100 microM), revealing a blood CSF barrier for celecoxib. The patient did not require dexamethasone for the entire treatment. GC administration hence was avoided successfully in this case. The role of COX-2 inhibitors in treatment of GBM is detailed, leading to the conclusion of a pressing need for a clinical evaluation of non-steroidal COX-2 inhibitors with the ability to penetrate into brain tumors.

Outbreak of Choanephora Blight Caused by Choanephora cucurbitarum on Green Bean and Pepper in Florida.

Severe outbreaks of Choanephora blight on green bean (Phaseolus vulgaris cvs. Bronco, Shade, and Gold Mine) and bell pepper (Capsicum annuum cvs. Aristotle, Crusader, and Sentry) were widespread in southwestern (Hendry and Collier counties) and northern Florida (Alachua County) in October and November 2002. Disease incidence, estimated by inspecting 100 randomly selected bean plants in each of four fields, was 40 to 100% and infected fruit ranged from less than 10 to 100%. Incidence estimated similarly on pepper plants in three fields was 35 to 40% with substantial fruit infection observed predominantly around the calyx. Zucchini fruit and a pigweed plant (Amaranthus sp.) were observed with sporulating lesions of Choanephora, indicating that other hosts were affected during the outbreak. Symptoms were blighted leaves, dieback of shoot tips, blighted blossoms, and black, soft-rot lesions on fruit. Choanephora sp. was sporulating in abundance on diseased tissue. Isolates of Choanephora sp. grew readily as pure cultures on acidified potato dextrose agar and malt yeast extract (MYE) agar. C. cucurbitarum (Berk. & Rav.) Thaxter was identified on the basis of shape and ornamentation of the sporangiola (1). The sporangiola of C. cucurbitarum are ellipsoid to broadly ellipsoid, and the wall is usually longitudinally striate. Pathogencity tests consisted of spray inoculation (5,000 spores per ml) of five 6-week-old plants each with and without wounding made by lightly scratching the leaf surface with a needle. Plants were placed in the greenhouse with temperatures ranging from 21 to 26°C, and symptom development was observed as early as 3 days after inoculation. The percentage of infected plants after wounding was 40% for bell pepper ('Enterprise'), 100% for green bean ('Opus'), 0% for watermelon (Citrullus lanatus 'Star Gazer'), 60% for cantaloupe (Cucumis melo 'Vienna'), and 20% for cucumber (Cucumis sativus 'Thunder CY'). Lesions on inoculated leaves were similar to those seen in the field on bean and pepper, and sporulation of C. cucurbitarum was present in the necrotic areas on all symptomatic plants. Pure cultures of C. cucurbitarum were reisolated. C. curcurbitarum was observed and isolated from a few noninoculated bean flowers and two noninoculated bean pods indicating spread to noninoculated plants; otherwise control plants were asymptomatic. Unwounded plants did not develop lesions, indicating that wounding was necessary for infection by this inoculation technique. The mating type was determined by juxtaposing several isolates on MYE agar, and zygospore formation was observed indicating both + and - strains occur in Florida. These outbreaks show that under the proper environmental conditions, such as long periods of high rainfall, high humidity, and high temperatures, crops like bean and pepper that are not usually affected by the disease may experience significant damage. Reference: (1) P. M. Kirk. Mycol. Pap. 152:1-61, 1984.

Xanthomonas Leaf Spot and Stem Canker on Blueberry in Nurseries in Florida.

In June and July 1998, in nurseries in south Florida, lesions were observed on the foliage and stems of three southern high-bush cultivars of blueberry hybrids (Vaccinium coryumbosum). Plants were approximately 1.5 to 2 years of age (0.6 to 1 m high). Disease incidence ranged from 95 to 50%, depending on cultivar. Lesions on leaves were roughly round, 5 to 20 mm in diameter, reddish brown surrounded by a yellow halo, and frequently coalesced to form large blighted areas. Stem cankers were soft, dark brown-to-black, and often resulted in the death of the entire branch. Microscopic examination of free-hand sections through lesion margins revealed bacterial streaming. Isolation of bacteria on nutrient agar consistently recovered mucoid, yellow bacteria typical of a xanthomonad. A pure culture of the bacteria was gram negative, oxidase negative, nonfluorescent, and proteolytic and produced a hypersensitive reaction on tobacco. Strains had fatty acid profiles with 88.5% similarity to Xanthomonas campestris pv. maniotis and 84.6% similarity to X. campestris pv. fici. Koch's postulates were fulfilled by spray-inoculation of 18-month-old blueberry cv. Sharpblue with a bacterial suspension (1 × 108 CFU/ml) in sterile water. Control plants were sprayed with sterile distilled water. Plants were covered with plastic for 24 h and kept in a growth chamber at 25°C with a 12-h photoperiod. Symptoms were reproduced on inoculated plants, and bacteria were reisolated from lesions. Control plants were asymptomatic. The disease was controlled by applications of copper compounds, increased plant spacing, rouging of infected plants, reduction of leaf wetness, and elimination of overhead irrigation.

Reduction of Phytophthora Blight of Madagascar Periwinkle in Florida by Soil Solarization in Autumn.

Three field experiments were conducted in southwest and west-central Florida in 1993 through 1995 to evaluate the effectiveness of soil solarization during autumn in reducing Phytophthora blight of Madagascar periwinkle (Catharanthus roseus) caused by Phytophthora nicotianae. Plots (3.6 by 3.6 m) were infested by incorporating winter wheat seed containing P. nicotianae in the upper 15 cm of soil. Solarization was then conducted for 21 to 41 days, primarily during October, using clear, 25- or 50-µm low-density polyethylene mulch. The progress of Phytophthora blight, monitored for 31 to 42 days following planting, was significantly reduced by solarization in all experiments, and final blight incidence was reduced in two of three experiments. Solarization also reduced population densities of P. nicotianae.

First Report of Aerial Blight Caused by Pythium myriotylum on Tomato in Florida.

In September 1996 and 1997, diseased tomato seedlings were observed with symptoms of an aerial watery rot on leaves, petioles, and stems. Tomato cvs. Sanibel and 10097 from commercial fields in southwest Florida (Collier and Lee counties) and west central Florida (Manatee County) exhibited similar symptoms that occurred at an incidence of 15 to 18% about 4 weeks after transplanting and resulted in plant death. Microscopic examination of symptomatic tissue revealed the presence of mycelium and oogonia typical of Pythium spp. A fungus was consistently isolated from four plants sampled from each site onto a medium selective for Pythium spp. and maintained in pure culture on V8 juice agar at 28°C. The isolates were identified as Pythium myriotylum Drechs. based on the following morphological data: lobate sporangium, 12 to 13 µm wide; vesicle 15.4 to 19.4 µm in diameter; exit tube 54 to 90 µm long, oogonium 23 to 30 µm in diameter; and oospore 21 to 26 µm in diameter (1,2). Pathogenicity tests were conducted with two isolates from diverse regions within Florida by spray inoculating the leaves and shoots of 6- to 8-week-old tomato seedlings with a sporangial suspension of 1 × 104 sporangia per ml. Noninoculated plants served as controls. Plants had 24 h of pre- and post-dark period, day/night temperatures of 28/21°C, a 14-h photoperiod, and near 100% relative humidity in a growth chamber. The foliage of inoculated tomato plants exhibited symptoms identical to those observed in field samples 24 h after inoculation and 100% mortality within 72 h. The reisolated fungus was morphologically identical to the original isolate. Noninoculated plants remained asymptomatic. The unusual rainfall recorded at some sites, such as in Manatee County in September 1997, was 36% higher than the 40-year average and may have contributed to the incidence of this previously undescribed foliar blight. References: (1) Anonymous. C.M.I. Descriptions of Pathogenic Fungi and Bacteria No. 118. (2) T. Watanabe. Pictorial Atlas of Soil Fungi. Lewis Pub., London. p. 71.