これ以下はぐっと頻度が下がり、また報告者によって疾患頻度がバラバラ。
このころはMFHが一番多い病名だったことが伺われる文献である。
流れを変えたのはFletcherという病理医。この人の↓の論文（1992年のAm J Surg Pathol)で流れが変わっていくようだ。Fact or Fictionなんて挑戦的だな。
American Journal of Surgical Pathology. 16(3):213-228, March 1992.
私のささやかな意見であるが、Enzinger & WeissによるMFHという概念があって初めて分類学としての病理学は大いに進んだんだと思う。そこから再分類が試みられ、次のより洗練された疾患分類ができるのなら、MFHというのはすぐれて優秀な作業仮説だったということだ。Fletcherの次の世代はmolecular biologyで肉腫を攻めているはずだ（私は詳細を知らないが）。molecular classificationなんて提言はいくらでもありそうだが、寡聞にして知らない。
Fletcherの次に何が待っているか？第二のEnzinger & Weissがやってくるかもしれない。Aufhebenなら良いわけだが。
あるいは全く違った分類体系が現れるかもしれない。
腫瘍のclinical behaviorと分子分類が一致するような新体系で現状の診断体系より洗練したもの。そこに病理形態組織が入り込む余地が全くないような分類（つまり顕微鏡をのぞいてもどうしてその診断名になるのか全くわからないような診断体系）が登場するかもしれない。それでも臨床には役に立つ分類。
病理学者はのんびりしている暇はないぞ！
Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.
In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.
Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.
By reviewing the current status of Wnt signaling, we realized how many questions in this field remain unanswered. We highlight ten of those questions, hoping to inspire future research.
(1) What is the evolutionary origin of Wnt signals? Wnt genes and signaling components are found in all metazoan animals, including sponges. Given that Wnts are intercellular signals, it is not surprising that they are not present in unicellular organisms. Although the recently established Wnt-Fz structure has not yet pointed to a particular evolutionary origin, one can speculate that Wnts have a more ancient origin, possibly derived from enzymes secreted by prokaryotes.
(2) What is the nature of Wnt as a signal? Is the protein active by itself, or is it packaged in membranes, together with possible cofactors? The importance of “Wnt delivery” needs to be understood.
(3) Where does Wnt signaling take place in cells? Whereas Hedgehog signaling is located at the primary cilium, the subcellular location of Wnt signaling events remains unknown, though the endosomal compartment has been implicated as a signaling center.
(4) Besides the well-studied Frizzled and LRP receptors, there are other mechanisms for Wnt reception that involve the tyrosine kinases ROR and RYK. There is very little insight into the mechanisms of action of these receptors, and they deserve more intense study.
(5) How is the stabilized form of β-catenin ferried into the nucleus? Is there a role for active microtubule-based transport?
(6) How does Wnt signaling coordinate cell fate changes with changes in cell shape and polarity? This is a key question in many developmental contexts of Wnt signaling, including stem cells.
(7) Many different kinds of stem cells are controlled by Wnts, in such a way that self-renewal and the developmental potential of the cells are preserved by the Wnt signal. Is there a universal “stemness” property conferred to cells by Wnts?
(8) How much of the genome is Wnt controlled across various cell types? Given the broad effects of Wnt signaling and many Wnt target cells, the total number of Wnt-controlled genes could be significant.
(9) Are cancer stem cell behaviors controlled by Wnt signaling? The definition of cancer stem cells as being able to self-renew the tumorigenic state but also able to differentiate suggests that their behavior is dependent on external signals, such as Wnts.
(10) Can we identify bona fide and effective Wnt inhibitors? Though several molecules have been described to inhibit Wnt signaling in cells, there is a great need for additional reagents interfering with the Wnt pathway.
