J. Appl. Cryst.の発刊に際して

Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011

Purpose The exact definition of pathologic complete response (pCR) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain. Methods Tumor response at surgery and its association with long-term outcome of 6,377 patients with primary breast cancer receiving neoadjuvant anthracycline-taxane–based chemotherapy in seven randomized trials were analyzed. Results Disease-free survival (DFS) was significantly superior in patients with no invasive and no in situ residuals in breast or nodes (n = 955) compared with patients with residual ductal carcinoma in situ only (n = 309), no invasive residuals in breast but involved nodes (n = 186), only focal-invasive disease in the breast (n = 478), and gross invasive residual disease (n = 4,449; P < .001). Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no invasive breast residuals but involved nodes ...

https://ascopubs.org/doi/pdf/10.1200/JCO.2011.38.8595

Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes

Summary Background Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. Methods In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m 2 , escalating, if tolerated, to 100 mg/m 2 every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Findings Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1–55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6–38·5]; p=0·0141). 23 of 96 (24·0% [15·8–33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3–25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15–20 serious adverse events per group in 10–17% of patients) but lower in group C (four serious adverse events in 4% of patients). Interpretation Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. Funding F Hoffmann-La Roche.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(11)70336-9.pdf

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial

Purpose To measure residual disease after neoadjuvant chemotherapy in order to improve the prognostic information that can be obtained from evaluating pathologic response. Patients and Methods Pathologic slides and reports were reviewed from 382 patients in two different treatment cohorts: sequential paclitaxel (T) then fluorouracil, doxorubicin, and cyclophosphamide (FAC) in 241 patients; and a single regimen of FAC in 141 patients. Residual cancer burden (RCB) was calculated as a continuous index combining pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size) for prediction of distant relapse-free survival (DRFS) in multivariate Cox regression analyses. Results RCB was independently prognostic in a multivariate model that included age, pretreatment clinical stage, hormone receptor status, hormone therapy, and pathologic response (pathologic complete response [pCR] v residual disease [RD]; hazard ratio 2.50; 95% CI 1.70 to 3.69; P .001). Minimal RD (RCB-I) in 17% of patients carried the same prognosis as pCR (RCB-0). Extensive RD (RCB-III) in 13% of patients was associated with poor prognosis, regardless of hormone receptor status, adjuvant hormone therapy, or pathologic American Joint Committee on Cancer stage of residual disease. The generalizability of RCB for prognosis of distant relapse was confirmed in the FAC-treated validation cohort. Conclusion RCB determined from routine pathologic materials represented the distribution of RD, was a significant predictor of DRFS, and can be used to define categories of near-complete response and chemotherapy resistance. J Clin Oncol 25:4414-4422. © 2007 by American Society of Clinical Oncology

https://ascopubs.org/doi/pdf/10.1200/JCO.2007.10.6823

Measurement of Residual Breast Cancer Burden to Predict Survival After Neoadjuvant Chemotherapy

Summary
• Changes in the physical state of cellular water and its interrelations with carbohydrate metabolism were studied during preplanting storage of tulip bulbs (Tulipa gesneriana‘Apeldoorn’).
• Magnetic resonance imaging, light and scanning electron microscopy and high-performance anion exchange chromatography with pulsed amperometric detection were used to follow time-dependent changes during bulb storage at 17 or 20°C (nonchilled) or 4°C (chilled).
• No visible differences in scale structure and central bud development were observed microscopically between chilled and nonchilled bulbs. However, the scales of the chilled bulbs exhibited higher water content, faster starch degradation and increased concentrations of sucrose and ethanol-soluble fructan. Quantitative measurements of magnetization transfer (MT) indicated a smaller fraction of a solid or a restricted-mobility proton pool in the scales of the chilled bulbs. By contrast, the MT effect was significantly higher in the central bud of the chilled than in the nonchilled bulbs.
• Degradation of storage polysaccharides to low-molecular-weight sugar molecules during release from dormancy could be accompanied by local release of water molecules tightly bound to the polysaccharide granules into the bulk water, or by an influx of free water molecules due to increased osmotic potential caused by the raised sugar concentration, or by a combination of both effects.

Water status and carbohydrate pools in tulip bulbs during dormancy release

A specific physiological disorder, bronze speckle (J.P.A.'s nomenclature), was consistently induced in 'First Lady' and 'Voyager' marigold with Fe-DTPA concentrations greater than 0.018 m M Fe-DTPA (1 ppm) applied to a soilless medium. The disorder was characterized by specific symptomology distinguished visually by speckled patterns of chlorosis and necrosis, and downward curling and cupping of leaves. The percentage of total leaf dry weight affected with symptoms generally increased with increasing Fe-DTPA treatments. Symptomatic leaf tissue had a greater Fe concentration than corresponding asymptomatic leaf tissue. Leaf Mn concentrations in symptomatic and asymptomatic tissue were similar. In 'First Lady', older leaf tissue accumulated more total Fe and was associated with more severe symptoms than younger tissue. Media leachate Fe concentrations increased over 6 weeks and were larger at greater Fe- DTPA treatments. Adjustment of nutrient solution pH to 4.0, 5.25, or 6.5 did not alter media pH, nor did it prevent disorder symptoms. Application of Fe-DTPA containing nutrient solution to a soilless medium resulted in leachate Fe levels 3 times greater than for FeSO 4 treatments. Chemical names used: ferric diethylenetriaminepentaacetic acid, monosodium salt (Fe-DTPA).

/pdf/iron-toxicity-stress-causes-bronze-speckle-a-specific-2haeu24073.pdf

Iron Toxicity Stress Causes Bronze Speckle, a Specific Physiological Disorder of Marigold (Tagetes erecta L.)

Relationships between starch pattern indices and starch concentrations in four apple cultivars

We investigated the effects of a gibberellin synthesis inhibitor (ancymidol) and gibberellin (GA4+7) on carbohydrate metabolism and elongation in internodes of the tulip (Tulipa gesneriana L.) flower stalk during greenhouse growth. During the initial stages of flower stalk growth, the lowermost internode was mainly responsible for total flower stalk length, whereas the uppermost internode mostly contributed to total length during later stages. High concentrations of hexose sugar (mainly glucose) and increased activity of acid invertase were observed when internodes were rapidly elongating. Inhibition of gibberellin biosynthesis with ancymidol reduced the elongation rate of internodes, and inhibited the hexose sugar accumulation and acid invertase activity. Application of GA4+7 to ancymidol-treated plants reversed these effects. The degree of response to ancymidol and GA4+7 was, however, different in different internodes such that the lowermost internode was most responsive and the uppermost internode was least responsive. The results indicate that de novo biosynthesis of gibberellins is a requirement for expression of high acid invertase activity during the rapid elongation phase in tulip internodes which enables cleavage of imported sucrose to hexoses that can be readily utilized in elongating cells.

Gibberellin-mediated changes in carbohydrate metabolism during flower stalk elongation in tulips

High quality, in-vitro produced bulblets should grow rapidly and flower as fast as possible after transfer to soil. Fast growth occurred in large bulblets and in bulblets that formed a stem with several leaves instead of one or two leaf-bearing scales. Since stem formation occurred more often in large bulblets, we concluded that bulblet growth in vitro is an important factor for rapid growth of lily bulblets after planting. During in vitro culture, growth of the bulblets depended on sucrose concentration. Another important factor was the size of the explant: on a large explant, large bulblets regenerated. The presence of the explant was necessary during the whole regeneration period. When bulblets were excised from the explant after 5-6 weeks, and cultured onto the same medium, growth ceased. We studied changes in carbohydrate content during regeneration in vitro as influenced by explant size and sucrose concentration. We concluded that the contact area of the explant with the medium plays a key role in determining bulblet weight. Interestingly, the heaviest bulblets were regenerated on actively growing explants that accumulated starch.

William B. Miller

Papers

Water status and carbohydrate pools in tulip bulbs during dormancy release

Iron Toxicity Stress Causes Bronze Speckle, a Specific Physiological Disorder of Marigold (Tagetes erecta L.)

Relationships between starch pattern indices and starch concentrations in four apple cultivars

Gibberellin-mediated changes in carbohydrate metabolism during flower stalk elongation in tulips

Bulb growth in lily regenerated in vitro