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Lectin cytochemistry was used to determine whether phase-specific changes could be detected in the smears of mouse vagina taken during the different phases of the estrous cycle. The strongest and most specific lectin reactivity was seen in the proestrus phase of the cycle. Several lectins reacted with mucinous cells typical of the proestrus phase and stained either diffusely the entire cytoplasm or only the cytoplasmic granules of desquamated cells. Nucleated squamous epithelial cells showed reactivity of the cell membrane or the entire cytoplasm in late metestrus and diestrus phase. Cornified squamous cells were essentially unreactive with the lectins tested in this study. Lectin cytochemistry is a reliable method for identification of mucinous cells in mouse vaginal smears and for establishing the cyclicity of the mouse estrous cycle.

As a member of the Committee on Publication Ethics (COPE), the Croatian Medical Journal (CMJ) endorses COPE guidance on retractions (1), which has been an important editorial tool for ensuring the integrity of the published record in their journals. The CMJ editors have used article retraction as a way to protect the journal’s integrity, and welcomed the help from experts from the COPE and the World Association of Medical Editors (2). Our experience has shown that guidelines and best practices for editors could serve as tools for editorial work and protection for editorial independence, especially for editors of small, scholarly journals, whose editorial posts are usually based on good will, enthusiasm, and limited professional skills in publishing (3). The awareness of the importance of editorial independence is growing among editors of scholarly journals, as can be seen from several recent examples. For example, the European National Society Cardiovascular Journals published a statement asking the editors and their national societies to “jealously safeguard the editorial independence of their respective national journals” (3). Independence is a great privilege for editors, but it also brings responsibility and occasionally even some unpleasant tasks, such as handling allegations about submitted or published articles and making decision on the correction of the published record (4,5).

The readers who came to this editorial from the Croatian Medical Journal’s (CMJ) web-page as well as those who regularly read the CMJ on line, already most likely know that Professor Matko Marusic has stepped down as one of the Journal’s co-editors. Herewith we are pleased to announce that the CMJ will be edited by Ana Marusic and Ivan Damjanov, serving as co-editors in chief in the editorial leadership of the Journal. Professor Ana Marusic will continue performing her editorial duties from the Split University School of Medicine, Split, Croatia, whereas the new co-editor in chief, Professor Ivan Damjanov, will take on editing the Journal electronically from the University of Kansas, Kansas City, Kansas, USA.

We report a 28-year-old man who presented with intestinal pseudo-obstruction as the initial manifestation of thymoma, myasthenia gravis, and dysautonomia. The patient's autoantibody profile was characteristic of this constellation of disorders, being positive for both muscle and ganglionic nicotinic acetylcholine receptor antibodies and striational antibody. Inflammatory cell infiltrates were found in the myenteric plexus of the stomach and small intestine. Review of 12 previously reported cases suggests that patients with both myasthenia gravis and dysautonomia in the context of thymoma respond poorly to therapy.

Primary neuroectodermal tumors of the ovary are rare monophasic teratomas composed exclusively or almost exclusively of neuroectodemal tissue. Approximately 60 neuroectodermal tumors of the ovary have been reported in the literature. These tumors were classified as ependymoma, astrocytoma, glioblastoma multiforme, ependymoblastoma or as primitive neuroepithelial tumors such as medullo-blastoma, medulloepithelioma and neuroblastoma. Most tumors were diagnosed in the third and fourth decades of life, but occasionally they were first discovered in children, adolescents or older women. Microscopically, they are identical to equivalent neuroectodermal tumors of the central nervous system. The review of the literature shows that most patients with clinical stage I and II were treated surgically, whereas those with stage III or IV tumors received additional radiation or chemotherapy, or both. The clinical stage at the time of diagnosis is the most important prognostic parameter of these tumors.

The effects of ethanol and closely related alcohols on the cell-substrate adhesion of embryonal carcinoma cells were studied in microtiter wells using the enzyme cytochemical alkaline phosphatase technique and an ELISA reader. Three embryonal carcinoma cell lines (NF-1, NE and F9) were used. Prior to plating of cells the wells were coated with laminin, fibronectin or collagen type I. NF-1 cells adhered only to laminin; NE adhered to all substrata and uncoated wells equally well; F9 adhered only to fibronectin and laminin coated wells. Ethanol reduced the binding of cells to laminin and collagen type I but did not affect the binding of NE or F9 cells to fibronectin. The effect of ethanols was dose dependent; it lasted as long as an adequate concentration of this alcohol was maintained in vitro, and it was reversible. Other short chain alcohols inhibited the binding of cells to laminin proportionately to their membrane/buffer partition coefficients. These data show that various embryonal carcinoma cells differ with regards to their capacity to adhere to different extracellular matrix components. Cell adhesion to some but not all substrates can be prevented by ethanol and related short chain alcohols. The effects of alcohols on the adhesion of embryonal carcinoma cells to various substrates may be relevant for the elucidation of the fetal alcohol syndrome.

Hepatocyte retinoid X receptor alpha (RXRalpha)-deficient mice are more sensitive to ethanol toxicity than wild-type mice. Because RXRalpha-mediated pathways are implicated in lipid homeostasis and the inflammatory response, we hypothesized that a compromise in lipid metabolism and associated production of proinflammatory mediators are responsible for the hepatotoxicity observed in ethanol-treated hepatocyte RXRalpha-deficient mice. Wild-type and hepatocyte RXRalpha-deficient mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks. After ethanol treatment, serum ALT levels increased significantly (4-fold) in hepatocyte RXRalpha-deficient mice, but not in the wild-type mice. Hepatic liver fatty acid binding protein (L-FABP) mRNA and protein levels were reduced due to RXRalpha deficiency. Ethanol induced L-FABP mRNA and protein in wild-type mice and provided protection against nonesterified fatty acid toxicity; however, this effect was absent in the mutant mice. Accordingly, hepatic nonesterified fatty acid level was increased in ethanol-fed mutant mice. Ethanol increased nuclear factor (NF)-kappaB binding activity in hepatocyte RXRalpha-deficient mice, but not in wild-type mice. In agreement, hepatic mRNA levels of proinflammatory cytokines and chemokines were increased to a greater extent in the mutant than in wild-type mice. Furthermore, signal transducer and activator of transcription factor (STAT) 3 and associated Bcl-xL induction was observed in ethanol-fed wild-type mice but not in ethanol-fed hepatocyte RXRalpha-deficient mice. Taken together, after ethanol treatment, hepatocyte RXRalpha deficiency results in lack of L-FABP induction, increased hepatic free fatty acids, NF-kappaB activation, and proinflammatory cytokines production and a lack of STAT3 activation, which in part may contribute to alcohol-induced liver damage.

This unit describes protocols on how to assess the developmental potency of human embryonic stem cells (hESCs) by performing xenografting into immunodeficient mice to induce teratoma formation. hESCs can be injected under the testis capsule, or alternatively into the kidney or subcutaneously. Teratomas that develop from grafted hESCs are surgically removed, fixed in formaldehyde, and paraffin embedded. The tissues in the teratoma are analyzed histologically to determine whether the hESCs are pluripotent and form tissues derived from of all three embryonic germ layers (ectoderm, mesoderm, and endoderm). Teratomas can also be fixed in Bouin's or cryosectioned for analysis, and they can be analyzed by immunohistochemistry for tissue markers. Methods for these procedures are included in this unit.

Over 30 years ago Skakkebaek was the first to characterize a noninvasive precursor lesion (intratubular germ cell neoplasia or carcinoma in situ) that would progress to invasive testicular tumors. In this article we discuss the molecular changes thought to cause this malignant transformation, various conditions that predispose to the development of testicular germ cell tumors, diagnostic strategies, and treatment options. Additionally we discuss the current patterns of contralateral testicular biopsy to identify intratubular germ cell neoplasia, as well as the incidence and management of bilateral testicular tumors.

The grading of endocrine gland tumors has been difficult, inconsistent, and unrewarding. While the reasons for these problems vary from organ to organ, and from one tumor type to another, in general grading has been hampered by the following issues: In many endocrine organs, the transition of hyperplasia to benign neoplasia and then to malignancy includes a spectrum of morphologic changes that are not always easily defined. The proposed grading systems are often complex and include a number of variants that are not acceptable to all pathologists. The lack of consensus among pathologists has been one of the main hindrances to grading endocrine tumors. The correlation between the microscopic grading and the prognosis of tumors is often poor, and therefore with a few notable exceptions, clinicians do not find the pathologic grading of endocrine tumors to be as useful as that for tumors of other organs systems.

Tumors of the female genital organs are often biopsied or surgically resected and thus form a significant part of surgical pathology material in most institutions. Invasive tumors and premalignant or borderline lesions are routinely graded, and in many instances, the grade assigned by the pathologist is an important determinant of future treatment of these conditions. The parts of the female genital organs that are covered with squamous epithelium, namely, the vulva, vagina, and the cervix uteri, give rise to squamous cell carcinomas. Squamous cell carcinomas and their precursors of the female genital organs are graded like the homonymous lesions in other anatomic sites. The mucosa of the endocervix, endometrium, fallopian tubes, and probably the surface epithelium (mesothelium) of the ovary give rise to adenocarcinomas. These tumors are graded more or less the same way as adenocarcinomas in other anatomic locations. Some ovarian tumors that are unique to that organ are graded according to generally accepted schemes.

Tumors of the soft tissues and bones form a heterogeneous group that includes common benign neoplasms as well as other less common, variably malignant neoplasms (sarcomas). Recent advances in molecular and cell biology have influenced considerably the present clinical approach to these tumors. As the classifications of these tumors, most notably that of soft tissue sarcomas, are constantly refined by the addition of new data, the grading of soft tissue and bone sarcomas remains a work in progress (1, 2). Accordingly, only the most established grading systems used in daily surgical pathology practice are presented here.

The relationship between the tumor morphology and the clinical behavior of tumors has been known since the early studies of Rudolf Virchow (1821–1902) and the scientific beginnings of microscopic pathology. From the historical point of view, however, the first attempts to correlate the microscopic features of tumors with their biology and clinical behavior are traditionally attributed to David Paul von Hansemann (1858–1920) [1–3]. This German pathologist, who was a student of Virchow, studied systematically the microscopic pathology of tumors and in the 1890s published his pioneering observations on abnormal mitotic figures. He also introduced the terms anaplasia and dedifferentiation (German: Entdifferenzirung) and was the first to suggest that the clinical behavior of tumors could be predicted from their microscopic characteristics. His novel observations on microscopic tumor cell atypia, anaplasia, and asymmetrical mitoses were summarized in an 1897 book [3]. Von Hansemann’s teaching and his book were at that time considered revolutionary and quite controversial, stimulating many scientific discussions [4]. Nevertheless, the book was apparently widely read, and it reappeared 5 years later in its second edition (Fig. 1.1). In contrast to many theoretical textbooks dominating the field of pathology, this treaty was based on meticulous microscopic study of tumors and could be considered “evidence based.” It was illustrated with original drawings supporting the author’s views of cancer (Fig. 1.2). The clarity of these illustrations is fascinating even today.

Urogenital tumors are among the most common human tumors. Malignant tumors predominate, and the most important malignant neoplasms in this group are renal cell carcinoma, urothelial carcinoma of the urinary bladder, testicular carcinoma, and prostatic carcinoma. Testicular cancer is not generally assigned a microscopic grade, but the other 3 tumors are routinely graded according to well-established principles (Mostofi et al., 1998; Amin et al., 2004; Eble et al., 2004; Foster and Ross, 2004).

Breast carcinomas are graded according to the “Nottingham modification of the Bloom–Richardson system” (SBR). The system is hindered, however, by lack of precision in assessing all three parameters including nuclear grade, mitosis, and tubular formation, leading to an element of subjectivity. Our objective was to evaluate a new grading system [the nuclear grade plus proliferation (N+P) system] for subjectivity, ease, and better representation of tumor biology. Its components are nuclear grade and automated proliferation index. Invasive ductal carcinomas, consisting of 137 SBR grade I, 247 grade II, and 266 grade III, were re-evaluated by the N+P system. The two systems were compared with each other and correlated with patients’ overall survival, tumor size, angiolymphatic invasion, lymph node status, and biomarker status including estrogen receptor, progesterone receptor, p53, epidermal growth factor receptor, BCL-2, and Her-2. Although there was an agreement between the two systems with histologic and prognostic parameters studied, there was 37% disagreement when grading individual tumors. Fifty-three percent of SBR grade II tumors were “down-graded” to N+P grade I, and 7% were “up-graded” to N+P grade III. Distinction among the different histologic grades for overall survival curves was better indicated by the N+P than the SBR system.

Publisher Summary Human embryonic stem cells (hESCs) are developmentally pluripotent as shown by their ability to differentiate into various somatic cell types in vitro. The differentiation abilities of hESC lines can explored further by injecting them into immunodeficient mice, where they differentiate into highly organized tissues that resemble the structures found in fully developed organs. This chapter focuses on recognition and identification of the tissues arising from hESCs in experimental teratomas. For experimental teratoma production, hESCs are typically transplanted to skeletal muscle, testes, or kidney capsule of immunodeficient mice. Teratomas are usually harvested 6-7 weeks after the injection of hESCs and are histologically composed of tissues derived from all three germ layers. The histology of teratomas is remarkable; the teratoma tissues often have the microscopic features of equivalent adult human somatic tissues, or fetal.

In this paper we have reviewed the publications dealing with primary neuroectodermal tumors of the ovary.These rare monophasic teratomas are composed exclusively or almost exclusively of neuroectodemal tissue and are thus an important paradigm of a type of malignancy that develops from ovarian germ cells. Approximately 60 neuroectodermal tumors of the ovary have been reported in the literature. Histologically, the tumors were classified as gliomas, such as ependymoma, ependymoblastoma, astrocytoma, glioblastoma multiforme, or as primitive neuroepithelial tumors such as medulloblastoma, medulloepithelioma, and neuroblastoma. Microscopically, they are identical to equivalent neuroectodermal tumors of the central nervous system. Most tumors were diagnosed in the third and fourth decades of life. Neuroectodermal tumors are rarely diagnosed in other age groups, although there are published reports of such tumors in children, adolescents or older women. The review of the litarature shows that most patients with clinical stage I and II were treated surgically, whereas those with stage III or IV tumors received additional radiation or chemotherapy, or both. The clinical stage at the time of diagnosis is the most important prognostic parameter of these tumors.Patients whose tumors were recognized early in the course of the neoplastic disease and treated appropriately had a good prognosis, but those with tumors in advanced stages advanced tumors had poor prognosis., U ovom smo radu pregledali objavljenu literaturu o primarnim neuroektodermalnim tumorima jajnika. Ovi rijetki monofazični teratomi, sastavljeni isključivo ili gotovo isključivo od neuroektodermalnog tkiva, predstavljaju važnu paradigmu tumora koji se razvijaju iz zametnih stanica jajnika. Do sada je u literaturi opisano oko 60 slučajeva neuroektodermalnih tumora jajnika. Većinom se dijagnosticiraju u žena u trećem i četvrtom desetljeću života, a rijetko se pojavljuju u djece, adolecenata i starijih žena. Ovi se tumori dijele na gliome, kao što su ependimom, ependimoblastom, astrocitom, glioblastom, te na primitivne neuroepitelne tumore, kao što su meduloblastom, meduloepiteliom i neuroblastom. Histološka slika ovih tumora identična je tumorima koji se pojavljuju u središnjem živčanom sustavu. Većina bolesnica s niskim kliničkim stadijem bolesti (I i II) liječena je kirurški, dok su bolesnice s višim kliničkim stadijem (III i IV) dodatno liječene zračenjem, kemoterapijom, ili s oba modaliteta. Klinički stadij bolesti pri dijagnozi najznačajniji je prognostički pokazatelj kod ovih tumora. Bolesnice kod kojih je tumor dijagnosticiran i odstranjen u ranom kliničkom stadiju imaju dobru prognozu, dok je prognoza u uznapredovalim stadijima bolesti loša.

Polyomavirus nephropathy is commonly seen in the renal allograft setting but is uncommon in native kidneys. This paper describes polyomavirus nephropathy that developed in the native kidneys of a patient following immunosuppressive therapy for rheumatoid arthritis/Sjogren's syndrome associated lung disease. The patient presented with dyspnoea and a slow steady rise in serum creatinine. Owing to chronic immunosuppression, calcineurin-inhibitor toxicity was suspected. However, renal biopsy revealed polyomavirus nephropathy. The treatment of choice, lowered immunosuppression, was complicated by exacerbation of the patient's lung disease. This case highlights features of polyomavirus nephropathy in the native kidney, as well as the difficulty in its treatment when immunosuppressive treatment is necessary for medical comorbidities.

Introduction Over the past twenty years, more than a hundred genes have been identified that can convert nontumorigenic tissue-cultured test cells from rodent cell lines to a transformed phenotype, that is, foci of piled-up and crisscrossed cells that grow in soft agar and form tumors when explanted into immunocompromised rodents. These dominant transforming genes, or oncogenes, encode proteins involved in signal transduction or cell cycle regulation and affect a variety of normal cellular functions, including apoptosis, proliferation, cell differentiation, and adhesion. When overexpressed or structurally altered by point mutation, deletion, or fusion, most oncogenic proteins selectively induce the proliferation of cells that express them. More recently, studies of families predisposed to specific types of cancers have yielded a growing number of recessive tumor suppressor genes. Loss of suppressor function by deletion or point mutation of both gene copies allows cells to proliferate unregulated or with reduced restraints. The discovery of both oncogenes and suppressor genes has proven pivotal in our understanding of the mechanisms of carcinogenesis by allowing scientists to focus on the genetic targets of carcinogens and thus finally link the details of carcinogen activation, adduct formation and repair, and neoplastic conversion and metastasis with definable molecular events. Furthermore, targeting of these genes with drugs that modulate their function has already led to effective therapies for human cancers.

In the previous chapter, the biology of malignancies and their caricature of normal tissue renewal suggested important principles that guide the development and use of treatment strategies. The current chapter presents how the treatment principles have been reduced to practice and how treatment principles relate to biological principles governing malignant growth. The chapter is organized around the four conventional treatment modalities available today: surgery, radiotherapy, cytotoxic chemotherapy and targeted therapy. (The term “conventional” refers to therapy accepted as the best available standard treatment.) Because of their different strategies, each modality is associated with specific risks and side effects, and this chapter builds a scientific understanding of the modalities' approved uses, successes, limitations, and toxicities. As explained in the preceding chapter, the goal of using the modalities is cytoreduction – hopefully the complete eradication of all cancer cells from the body. If not possible, then the goal becomes reducing the number of cancer cells in the body to the point that the time required for malignant stem cells to replace them is longer than the patient's life, giving rise to a cure. If sufficient cytoreduction is not achievable, then relapse ensues at some point in the future that depends on the amount of surviving malignant tissue and its rate of repopulation. The younger the patient at time of diagnosis, the more effective the treatment must be at eradicating malignant cells.

Introduction Notwithstanding physical removal of malignant tumors by surgery and regional control of malignant tumors by radiation, the concept of cancer as a disease of abnormal stem cell biology leads to three philosophies for treating the disseminated, metastatic disease that most patients will face. Only one of these philosophies has become clinically useful, whereas the others are developing or remain at the conceptual level. Therapies remaining at the conceptual level One treatment to attack this caricature of normal renewing biological tissue is conversion, or perhaps reversion, of the malignant phenotype to a benign state. As studies of the fate of micro-injected cancer cells in the embryo have revealed (detailed in Section 1.15, Chapter 1), it is possible for malignant cells to lose their malignant potential without losing their proliferative potential, such that they contribute to normal formation of chimeric organs in the developing embryo. The development of chimeras containing some functional tissue derived from the implanted malignant cells indicates that the cancer cells reacquire the capacity to properly respond to biological controls on tissue renewal even into adulthood after the embryonic environment disappears. The concept is that once converted back to normalcy by these embryonic control mechanisms, wherein the malignant phenotype is removed or suppressed, cancer-derived normal cells in the adult chimera can no longer cause disease. Therapeutic strategies harnessing this biological control might not be toxic in the adult patient, because they would target malignant, embryonic-like stem cells, converting them into normally functioning adult stem cells.

This is a revised and updated edition of a text used in undergraduate courses on cancer biology. It covers everything from the molecular basis of cancer to clinical aspects of the subject, and has a lengthy bibliography designed to assist newcomers with the cancer literature. An introduction acquaints students with the biological principles of cancer and the human dimensions of the disease by considering genuine cases of cancer in fictionalized letters. Other chapters discuss cancer pathology, metastasis, carcinogenesis, genetics, oncogenes and tumor suppressors, epidemiology, and the biological basis of cancer treatment. Also included are an appendix with descriptions of common forms of cancer, a glossary of cancer-related terms and colour plates to illustrate the pathology of many of the types of cancer discussed in the text. Upper-division undergraduates with a background in freshman biology and chemistry, as well as beginning graduate students will find this a valuable text.