Monoclonal gammopathy of undetermined significance. Natural history in 241 cases

Two hundred forty-one patients with a monoclonal protein in the serum but initially no evidence of multiple myeloma, macroglobulinemia, amyloidosis or lymphoma were followed up for more than five years. At the conclusion of the studies the patients were classified as follows: Group 1, patients without significant increase in monoclonal protein, 57 per cent; group 2, patients with more than 50 per cent increase in monoclonal serum protein or development of monoclonal urine protein, 9 per cent; group 3, patients who died without five-year serum studies, 23 per cent; and group 4, patients in whom myeloma, macroglobulinemia or amyloidosis developed, 11 per cent. Initially, the hemoglobin level, size of serum monoclonal protein peak, number of plasma cells in the bone marrow and levels of normal immunoglobulins were not significantly different among the four groups. The median interval from recognition of the monoclonal protein to diagnosis of multiple myeloma was 64 months, of macroglobulinemia 103 months and of amyloidosis 92 months. A significant increase of the monoclonal protein or development of myeloma, macroglobulinemia or amyloidosis occurred in 18 per cent of the patients with monoclonal immunoglobulin G(IgG), in 28 per cent with immunoglobulin A (IgA) and in 25 per cent with immunoglobulin M (IgM). Retrospective analysis of age, sex, presence of organomegaly, hemoglobin level, size and type of serum monoclonal protein peak, presence of small amounts monoclonal light chain in the urine, serum albumin level, levels of uninvolved immunoglobulins, IgG subclass and level of plasma cells in the bone marrow did not show how to distinguish initially between stable benign disease and progressive disease. Therefore, periodic reexamination of patients with monoclonal gammopathy is essential.     

Familial myeloma. Report of eight families and a study of serum proteins in their relatives

During a 6 year period, eight instances of familial occurrence of myeloma involving siblings (16 cases of myeloma and 3 of probable benign monoclonal gammopathy) were encountered at the Mayo Clinic. No other monoclonal serum protein abnormalities were found in 70 relatives studied. In view of the infrequency of myeloma, the high familial occurrence of this disease suggests the possibility of genetic factors in its etiology. It is most important that a complete family history be obtained from patients with myeloma.     

From Bedside Back to Bench? A Commentary on: “The Future of Cognitive Behavioral Therapy for Insomnia: What Important Research Remains to Be Done?”

In this month's issue of the Journal of Clinical Psychology, Vitiello and colleagues articulate an important research agenda that will help advance cognitive‐behavioral therapy for insomnia (CBT‐I) research and clinical practice. In addition to this ambitious agenda, we also propose that pursuing a parallel research program, focusing on treatment mechanisms and process will help move the CBT‐I field forward and optimize therapeutic dissemination and uptake.     

Type I to Type II Ovarian Carcinoma Progression: Mutant Trp53 or Pik3ca Confers a More Aggressive Tumor Phenotype in a Mouse Model of Ovarian Cancer

A dualistic pathway model of ovarian carcinoma (OvCA) pathogenesis has been proposed: type I OvCAs are low grade, genetically stable, and relatively more indolent than type II OvCAs, most of which are high-grade serous carcinomas. Endometrioid OvCA (EOC) is a prototypical type I tumor, often harboring mutations that affect the Wnt and phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathways. Molecular and histopathologic analyses indicate type I and II OvCAs share overlapping features, and a subset of EOCs may undergo type I→type II progression accompanied by acquisition of somatic TP53 or PIK3CA mutations. We used a murine model of EOC initiated by conditional inactivation of the Apc and Pten tumor suppressor genes to investigate mutant Trp53 or Pik3ca alleles as key drivers of type I→type II OvCA progression. In the mouse EOC model, the presence of somatic Trp53 or Pik3ca mutations resulted in shortened survival and more widespread metastasis. Activation of mutant Pik3ca alone had no demonstrable effect on the ovarian surface epithelium but resulted in papillary hyperplasia when coupled with Pten inactivation. Our findings indicate that the adverse prognosis associated with TP53 and PIK3CA mutations in human cancers can be functionally replicated in mouse models of type I→type II OvCA progression. Moreover, the models should represent a robust platform for assessment of the contributions of Trp53 or Pik3ca defects in the response of EOCs to conventional and targeted drugs.Surgical pathologists continue to use traditional morphology-based schemes for classifying ovarian carcinomas (OvCAs). The schemes are based largely on the degree of resemblance of the OvCAs to non-neoplastic epithelia in the female genital tract. However, mounting clinicopathologic and molecular data have led Kurman and Shih¹ to propose a “dualistic” model of OvCA pathogenesis in which OvCAs are divided into two main categories, type I and type II.^1–3 Type I OvCAs are suggested to be low-grade, relatively indolent and genetically stable tumors that typically arise from recognizable precursor lesions such as endometriosis or so-called borderline (low malignant potential) tumors. Type I OvCAs frequently harbor somatic mutations (eg, KRAS, BRAF, CTNNB1, PTEN) that dysregulate specific cell signaling pathway factors or certain chromatin remodeling complexes (eg, ARID1A). Type I OvCAs include most endometrioid, clear cell, and mucinous carcinomas and low-grade serous carcinomas. In contrast, type II OvCAs are proposed to be high-grade, biologically aggressive tumors from their outset, with a propensity for metastasis from small-volume primary lesions. Most type II OvCAs are high-grade serous carcinomas, virtually all of which harbor mutant TP53 alleles.⁴ These tumors have a high level of chromosomal instability.⁵ Although varied gene defects besides TP53 mutation have been identified in type II tumors, with the exception of frequent genetic/epigenetic inactivation of BRCA1/2 and NF1, RB1, and CDK12 mutations, each of the somatic gene defects is found in a small fraction of tumors.^6–8 Notably, recent data suggest that many (and perhaps most) high-grade serous carcinomas arise from epithelium in the fallopian tube, rather than the ovarian surface epithelium (OSE).^9–11 The identification of precursor lesions with p53 protein overexpression and clonal TP53 mutations in the fallopian tube epithelium (including “p53 signature lesions” and tubal intraepithelial carcinomas) suggests TP53 mutation is an early event in the pathogenesis of most type II OvCAs.¹²The dualistic pathway model represents an advance in conceptualizing OvCA pathogenesis, but the model is likely an oversimplified view of a complex group of cancers. For example, there are uncertainties about classification of clear cell carcinomas as type I versus type II, because their molecular features are more in keeping with type I tumors, but cytologic grade and clinical behavior are often more like type II tumors.³ As another example, there is significant overlap in the morphologic and molecular features of high-grade serous and high-grade endometrioid OvCAs (hereafter referred to as EOCs) such that some pathologists now default the majority of gland-forming or near-solid cytologically high-grade OvCAs to the serous category and consider “true” high-grade EOCs to be rare or nonexistent.¹³ In this scenario, all low-grade EOCs would be classified as type I, and the category of high-grade EOCs would be eliminated.In a prior analysis of a substantial number of primary human EOCs, we found that mutations predicted to activate the canonical Wnt and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways frequently co-occur in low-grade EOC, a prototypical type I OvCA.¹⁴ Activation of Wnt signaling typically occurs as a consequence of oncogenic CTNNB1 mutations, or rarely bi-allelic APC inactivation, whereas PI3K/AKT/mTOR signaling is usually activated because of PTEN inactivation and/or oncogenic PIK3CA mutations. Notably, we identified 4 of 21 tumors with gene expression and/or mutational profiles like type I EOCs, but the tumors had also acquired TP53 mutations, suggesting type I→type II progression may occur in a sizeable subset (nearly 20%) of EOCs.¹⁴ Similarly, we identified four EOCs with mutations in both PTEN and PIK3CA, rather than a single mutation dysregulating PI3K/AKT/mTOR signaling. Importantly, TP53 mutation has been associated with adverse outcome in women with endometrioid carcinomas of the endometrium and ovary,^15–18 and PIK3CA mutation has been linked to poor outcome in patients with several types of cancer, including carcinomas of the endometrium, breast, and colon.^19–22 The effect of PIK3CA mutations on the prognosis of patients with OvCA is unclear, because some studies have shown an adverse effect on outcome, whereas others showed no or even a favorable effect.^23–25 The notion that type II tumors can progress from type I tumors is not unique to EOCs. Indeed, type I→type II progression in serous carcinomas has also been described and is often associated with acquisition of TP53 mutation.^26–29We previously described a murine model for type I human EOC in which concurrent dysregulation of Wnt and PI3K/AKT/mTOR signaling is achieved through conditional inactivation of the Apc and Pten tumor suppressor genes in the OSE.¹⁴ In this model, ovarian bursal injection of recombinant adenovirus expressing Cre recombinase (AdCre) in Apc^flox/flox;Pten^floxf/flox mice results in the development of EOC-like tumors with complete penetrance. The purpose of the present study was to determine the effect of mutant Trp53 and Pik3ca on the Apc^−/−;Pten^−/− murine EOC tumor phenotype as models of type I→type II progression.