Twenty-four years lucerne (Medicago sativa L.) breeder seed production in India: a retrospective study.

Lucerne (Medicago sativa L.) is the second most significant winter leguminous fodder crop after berseem in India. Breeder seed (BS) is the first stage of the seed production chain, as it is the base material for producing foundation and certified seeds. In India, lucerne BS demand has been reduced by 85.58% during the last 24 years (1998-1999 to 2021-2022), declining from 2150 kg to 310 kg. Out of 14 varieties released and notified so far, only nine varieties entered the seed chain since 1998-1999. It shows narrow varietal diversification and, hence, needs robust breeding programs towards enriching genetic variability and varietal development. The present study also highlights the disparity in BS demand and production over the years and puts forth the possible reasons behind the reduction in BS demand and production in the country. Out of the nine varieties, the BS demand of Anand-2 (53.11%) was highest, followed by Type-9 (19.44%) and RL-88 (13.60%). Varietal replacement rate (VRR) was found to be moderate, i.e., 23.67% for the varieties having <5 years old age in the last 3 years (2019-2020 to 2021-2022). It has also been estimated that BS produced (233 kg) during 2021-2022 can cover the approximate area of 6,300 ha at farmers' fields in 2024-2025 if the seed chain functions 100%, effectively. The present study provides a holistic overview of lucerne BS demand and production, challenges in BS production, and the way forward to develop more varieties and surplus BS production in the country.

Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer.

PURPOSE: Previous studies of hypofractionated adjuvant whole-breast radiotherapy for early breast cancer established a 15- or 16-fraction (fr) regimen as standard. The FAST Trial (CRUKE/04/015) evaluated normal tissue effects (NTE) and disease outcomes after 5-fr regimens. Ten-year results are presented. METHODS: Women ≥ 50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) were randomly assigned to 50 Gy/25 fr (5 weeks) or 30 or 28.5 Gy in 5 once-weekly fr of 6.0 or 5.7 Gy. The primary end point was change in photographic breast appearance at 2 and 5 years; secondary end points were physician assessments of NTE and local tumor control. Odds ratios (ORs) from longitudinal analyses compared regimens. RESULTS: A total of 915 women were recruited from 18 UK centers (2004-2007). Five-year photographs were available for 615/862 (71%) eligible patients. ORs for change in photographic breast appearance were 1.64 (95% CI, 1.08 to 2.49; P = .019) for 30 Gy and 1.10 (95% CI, 0.70 to 1.71; P = .686) for 28.5 Gy versus 50 Gy. α/ß estimate for photographic end point was 2.7 Gy (95% CI, 1.5 to 3.9 Gy), giving a 5-fr schedule of 28 Gy (95% CI, 26 to 30 Gy) estimated to be isoeffective with 50 Gy/25 fr. ORs for any moderate/marked physician-assessed breast NTE (shrinkage, induration, telangiectasia, edema) were 2.12 (95% CI, 1.55 to 2.89; P < .001) for 30 Gy and 1.22 (95% CI, 0.87 to 1.72; P = .248) for 28.5 Gy versus 50 Gy. With 9.9 years median follow-up, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) have occurred. CONCLUSION: At 10 years, there was no significant difference in NTE rates after 28.5 Gy/5 fr compared with 50 Gy/25 fr, but NTE were higher after 30 Gy/5 fr. Results confirm the published 3-year findings that a once-weekly 5-fr schedule of whole-breast radiotherapy can be identified that appears to be radiobiologically comparable for NTE to a conventionally fractionated regimen.

Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial.

BACKGROUND: The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity. METHODS: SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat. ClinicalTrials.gov NCT00003893. FINDINGS: Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43-0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26-0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). INTERPRETATION: Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemo-radiation was in patients treated with anthracycline-CMF. FUNDING: Cancer Research UK (CR UK/98/001) and Pharmacia.

Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy. METHODS: IMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1-3, with a tumour size of 3 cm or less (pT1-2), none to three positive axillary nodes (pN0-1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634. FINDINGS: Between May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7-83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5-2·3) of patients in the control group, 0·2% (0·02-1·2) in the reduced-dose group, and 0·5% (0·2-1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were -0·73% (-0·99 to 0·22) for the reduced-dose and -0·38% (-0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the whole-breast radiotherapy group). Photographic, patient, and clinical assessments recorded similar adverse effects after reduced-dose or partial-breast radiotherapy, including two patient domains achieving statistically significantly lower adverse effects (change in breast appearance [p=0·007 for partial-breast] and breast harder or firmer [p=0·002 for reduced-dose and p<0·0001 for partial-breast]) compared with whole-breast radiotherapy. INTERPRETATION: We showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. FUNDING: Cancer Research UK.

Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.

BACKGROUND: Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. METHODS: In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. FINDINGS: From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. INTERPRETATION: We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. FUNDING: Cancer Research UK, Amgen, Pfizer, and Roche.

Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial.

BACKGROUND: The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHODS: tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546). FINDINGS: Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86-1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]). INTERPRETATION: The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup. FUNDING: Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

Bioinformatics analyses reveal age-specific neuroimmune modulation as a target for treatment of high ethanol drinking.

BACKGROUND: Use of in silico bioinformatics analyses has led to important leads in the complex nature of alcoholism at the genomic, epigenomic, and proteomic level, but has not previously been successfully translated to the development of effective pharmacotherapies. In this study, a bioinformatics approach led to the discovery of neuroimmune pathways as an age-specific druggable target. Minocycline, a neuroimmune modulator, reduced high ethanol (EtOH) drinking in adult, but not adolescent, mice as predicted a priori. METHODS: Age and sex-divergent effects in alcohol consumption were quantified in FVB/NJ × C57BL/6J F1 mice given access to 20% alcohol using a 4 h/d, 4-day drinking-in-dark (DID) paradigm. In silico bioinformatics pathway overrepresentation analysis for age-specific effects of alcohol in brain was performed using gene expression data collected in control and DID-treated, adolescent and adult, male mice. Minocycline (50 mg/kg i.p., once daily) or saline alone was tested for an effect on EtOH intake in the F1 and C57BL/6J (B6) mice across both age and gender groups. Effects of minocycline on the pharmacokinetic properties of alcohol were evaluated by comparing the rates of EtOH elimination between the saline- and minocycline-treated F1 and B6 mice. RESULTS: Age and gender differences in DID consumption were identified. Only males showed a clear developmental increase difference in drinking over time. In silico analyses revealed neuroimmune-related pathways as significantly overrepresented in adult, but not in adolescent, male mice. As predicted, minocycline treatment reduced drinking in adult, but not adolescent, mice. The age effect was present for both genders, and in both the F1 and B6 mice. Minocycline had no effect on the pharmacokinetic elimination of EtOH. CONCLUSIONS: Our results are a proof of concept that bioinformatics analysis of brain gene expression can lead to the generation of new hypotheses and a positive translational outcome for individualized pharmacotherapeutic treatment of high alcohol consumption.

The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.

BACKGROUND: 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. METHODS: From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0-10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7-8·5 vs 7·4%, 5·5-10·0; hazard ratio [HR] 0·91, 95% CI 0·59-1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7-11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79-1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5-10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2-5·9) and the 50 Gy group (5·5%, 95% CI 4·2-7·2; HR 0·77, 95% CI 0·51-1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. INTERPRETATION: Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health.

Osteonecrosis of the jaw and oral health-related quality of life after adjuvant zoledronic acid: an adjuvant zoledronic acid to reduce recurrence trial subprotocol (BIG01/04).

PURPOSE: In patients with early breast cancer, adjuvant zoledronic acid (zoledronate) may reduce recurrence and improve survival. However, zoledronate is associated with the occasional development of osteonecrosis of the jaw (ONJ). We report on the frequency of ONJ and investigate oral health-related quality of life (Oral-QoL) in a large randomized trial (Adjuvant Zoledronic Acid to Reduce Recurrence [AZURE]). PATIENTS AND METHODS: Three thousand three hundred sixty women with stage II or III breast cancer were randomly assigned to receive standard adjuvant systemic therapy alone or with zoledronate administered at a dose of 4 mg for 19 doses over 5 years. All potential occurrences of ONJ were reported as serious adverse events and centrally reviewed. Additionally, we invited 486 study participants to complete the Oral Health Impact Profile-14 (OHIP-14) to assess Oral-QoL around the time the patients completed 5 years on study. Multivariable linear regression was used to calculate mean scores and 95% CIs in addition to identifying independent prognostic factors. RESULTS: With a median follow-up time of 73.9 months (interquartile range, 60.7 to 84.2 months), 33 possible cases of ONJ were reported, all in the zoledronate-treated patients. Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the OHIP-14 questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients. CONCLUSION: Adjuvant zoledronate used in the intensive schedule studied in the AZURE trial is associated with a low incidence of ONJ but does not seem to adversely affect Oral-QoL.

Prosthetic rehabilitation of amputated hallux after distraction osteogenesis: one-year follow-up.

BACKGROUND: The great toe helps in maintaining body balance during standing, walking, running, dancing, and so on. CASE DESCRIPTION AND METHODS: A 22 year-old female patient reported to the department, one month after losing her left hallux in a road accident. Anatomical reconstruction was performed with distraction osteogenesis. The prosthesis was constructed using a wax pattern of the normal hallux to create a silicone prosthesis. The residual limb mold was altered to increase prosthesis retention. FINDINGS AND OUTCOMES: The procedure was economical, conserved materials, and produced lifelike anatomy without requiring artistic expertise. CONCLUSION: Distraction osteogenesis helped in improving function and retention of the prosthesis. Satisfactory esthetic and functional results were observed at the one-year follow-up. CLINICAL RELEVANCE: Distraction osteogenesis of the amputated hallux improved prosthetic prognosis by aiding retention. Modifications were made in the conventional prosthesis fabrication technique to increase retention, as the hallux is in constant movement and/or friction.

Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

An in vitro model for studying the effects of continuous ethanol exposure on N-methyl-D-aspartate receptor function.

Long-term ethanol exposure has deleterious effects on both glial and neuronal function. We assessed alterations in both astrocytic and neuronal viability, and alterations in N-methyl-d-aspartate receptor (NMDAR) function, in cocultures of rat cerebellar granule cells (CGCs) and astrocytes after continuous ethanol exposure (CEE). Treatment of cells with 100 mM EtOH once every 24 h for 4 days resulted in a mean ethanol concentration of 57.3 ± 2.1 mM. Comparisons between control and post-ethanol-treated cells were made 4 days after the last ethanol treatment. CEE did not alter glial cell viability, as indicated by the absence of either changes in astrocytic morphology, actin depolymerization, or disruption of astrocytic intracellular mitochondrial distribution at any day postethanol treatment. The CGCs were healthy and viable after CEE, as indicated by phase-contrast microscopy and the trypan-blue exclusion method. Whole-cell patch-clamp experiments indicated that NMDA-induced currents (I(NMDA)) were altered by CEE treatment. Similar to previous results obtained during the withdrawal phase from chronic ethanol exposure, I(NMDA) from CEE-treated cells were significantly larger than I(NMDA) from NMDARs in control CGCs, but returned to control values by the fourth day post-CEE. However, after the last ethanol dosing and during a time when ethanol concentrations remained high, I(NMDA) were significantly smaller than control values. Identical results were observed in CGCs expressing the NR2A or NR2B subunit. In summary, both neurons and astrocytes remained healthy following exposure to CEE with no signs of neurotoxicity at the cellular level, and modulation of NMDAR function is consistent with findings from prior experiments. Thus, we conclude that the CEE paradigm in glial-neuronal cocultures readily lends itself to long-term in vitro studies of ethanol effects that include glial-neuronal interactions and the ability to study ethanol withdrawal-induced neurotoxicity.

First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015).

BACKGROUND AND PURPOSE: Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. MATERIALS AND METHODS: Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. RESULTS: Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. CONCLUSIONS: At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.

Presurgical nasoalveolar molding for correction of cleft lip nasal deformity: experience from northern India.

CONTEXT: The cleft lip type nasal deformity presents one of the most complex surgical challenges. The long-term postoperative results are still not satisfactory despite an emphasis on primary nasal correction. This is attributed to tissue memory and healing. Nasoalveolar molding is used effectively to reshape the nasal cartilage and to mold the maxillary arch before cleft lip repair. AIMS: This study was undertaken to evaluate the role of presurgical nasoalveolar molding in correction of cleft lip nasal deformity for patients with unilateral and bilateral clefts of the lip. SETTINGS AND DESIGN: Twenty-three cases of clefts of lip and palate with nasal deformity were subjected to present study from May 2004 to May 2006. These cases were initially treated on outpatient basis, and they were admitted at the time of operation. All of these patients were children of less than 1 year of age, belonging to north Indian population. MATERIAL AND METHODS: Study consisted of patients of cleft lip and palate who were given presurgical nasoalveolar splints at early age. Lip repair was done after at least 2 months of molding. These patients along with control group (without presurgical nasoalveolar molding) were followed up for 1 year. Measurements were taken at different intervals in study over dental cast and on patients. Data obtained from comparison of 2 groups were analyzed using "MSTAT" analysis software (developed by Dr Russel Freed, Professor & Director, Crop & Soil Sciences Department, Michigan State University, East Lansing, Michigan). RESULTS: In our study, we found that nostril height was more in patients of experimental group (P = .18), while nostril width and alar perimeter were not changed significantly. Children with nasoalveolar molding had significant lengthening of columella (P = .02). Patients of unilateral cleft lip had more reduction in alveolar gap (P = .08) than bilateral group (P = .15). CONCLUSIONS: Nasoalveolar molding can be a useful adjunct for treatment of cleft lip nasal deformity. It is a cost-effective technique that can reduce the number of future surgeries such as alveolar bone grafting and secondary rhinoplasties.

Trigeminal neuralgia secondary to posterior fossa tumor.

Trigeminal neuralgia (TN) is by no means an uncommon entity presenting as typical or atypical pain syndrome with a standard treatment protocol consisting of medical and surgical therapies. The diagnosis of TN is mainly dependent on the characteristics of symptoms conveyed by the patient and the clinical presentation. Careful history taking, proper interpretation of the signs and symptoms and cranial nerve assessment are necessary for proper diagnosis. Here, we report a case of TN, treated for dental problems and then for neuralgia with only short-term relief. Subsequently, the patient underwent neuroimaging and was found to be having an uncommon space-occupying lesion in the posterior cranial fossa.

Intrathecal Catheterization by Epidural Catheter: Management of Accidental Dural Puncture and Prophylaxis of PDPH.

SUMMARY: Accidental or inadvertent dural puncture during epidural anaesthesia results in high incidence of post dural puncture headache (PDPH). Spinal or intrathecal catheter in such a situation, provides a conduit for administration of appropriate local anaesthetic for rapid onset of intraoperative surgical anaesthesia and postoperative pain relief. This procedure prevents PDPH if catheter left in situ for > 24 hrs and also avoids the associated risks with a repeat attempts at epidural analgesia. Primary aim of this study was to observe the effect of spinal catheter on incidence of PDPH, and to assess early and delayed complications of spinal catheterization by epidural catheter. In prospective clinical study 34 patients who had accidental dural puncture during epidural anaesthesia were included. The catheter meant for epidural use was inserted in spinal space and used for spinal anaesthesia and postoperative analgesia. Catheter was removed between 24-36hrs after surgery. The incidence of accidental dural puncture was 4%(34/846). Two patients 5.88% (2/34) had transient paresthesia during spinal catheter insertion. Post dural puncture headache occurred in 11.76% (4/34) patients. Two patients required epidural blood patch and two patients were managed with conservative treatment. No patient had any serious intraoperative or postoperative side effects. Epidural catheter can be used as spinal catheter to manage accidental dural puncture without serious complications, and it also prevents PDPH.

Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer. METHODS: In NEAT, we compared four cycles of epirubicin followed by four cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) with six cycles of CMF alone. In the BR9601 trial, we compared four cycles of epirubicin followed by four cycles of CMF, with eight cycles of CMF alone every 3 weeks. The primary end points were relapse-free and overall survival. The secondary end points were adverse effects, dose intensity, and quality of life. RESULTS: The two trials included 2391 women with early breast cancer; the median follow-up was 48 months. Relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups (2-year relapse-free survival, 91% vs. 85%; 5-year relapse-free survival, 76% vs. 69%; 2-year overall survival, 95% vs. 92%; 5-year overall survival, 82% vs. 75%; P<0.001 by the log-rank test for all comparisons). Hazard ratios for relapse (or death without relapse) (0.69; 95% confidence interval [CI], 0.58 to 0.82; P<0.001) and death from any cause (0.67; 95% CI, 0.55 to 0.82; P<0.001) favored epirubicin plus CMF over CMF alone. Independent prognostic factors were nodal status, tumor grade, tumor size, and estrogen-receptor status (P<0.001 for all four factors) and the presence or absence of vascular or lymphatic invasion (P=0.01). These factors did not significantly interact with the effect of epirubicin plus CMF. The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life. CONCLUSIONS: Epirubicin plus CMF is superior to CMF alone as adjuvant treatment for early breast cancer. (ClinicalTrials.gov number, NCT00003577 [ClinicalTrials.gov].).