Chromogranin A as a biomarker of disease activity and biologic therapy in inflammatory bowel disease: a prospective observational study.

OBJECTIVE: To access the correlation of Chromogranin A (CgA) with inflammatory bowel disease (IBD) activity and responsiveness to medical therapy. MATERIAL AND METHODS: A prospective observational study was conducted in 56 patients with moderate ulcerative colitis (UC) or Crohn's disease (CD) (UC, n = 29, CD, n = 27), 17 patients with irritable bowel syndrome and predominant diarrhea (IBS-D) and 40 healthy volunteers. IBD patients were treated by biologics (infliximab or adalimumab) or conventional agents (aminosalicylates, thiopurines or methotrexate and steroids) and were classified according to their treatment in two groups. Serum CgA was measured at baseline and 4-week posttreatment period. RESULTS: Serum CgA was significantly higher in IBD patients than in those with IBS-D or healthy volunteers (p < 0.01). Furthermore, serum CgA was markedly increased in CD patients than in UC patients (p < 0.01). CgA value was significantly reduced in 'biologic' group (24 IBD patients, UC, n = 15, CD, n = 9) at 4-week posttreatment period (p < 0.01), while 18/24 (72%) patients were already in remission during that time. In contrast, CgA value was significantly increased in the 'conventional' treatment group (32 IBD patients, UC, n = 14, CD, n = 18) between the two visits (p < 0.01), although 22/32 (69%) patients were in remission during the 4-week posttreatment period. CONCLUSION: CgA appears to be a reliable marker of disease activity in IBD patients and especially in those who received biologic therapy. IBS-D patients presented normal CgA values.

Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis.

Delta-like ligand 4 (DLL4) is a ligand of the notch pathway. In tumor angiogenesis, DLL4 switches to vascular maturation by providing a negative feedback on VEGFR2 activity. We investigated the expression of DLL4 in the plasma and cancer tissues from breast cancer patients. Plasma samples were collected from 18 women with localized breast cancer, six women with benign breast disease and from six patients with widespread metastatic disease. DLL4 was assessed using ELISA and in cancer tissues using immunohistochemistry. Patients with metastatic breast cancer had significantly higher levels (median 6.7 ± 0.81 ng/ml) compared to patients with localized tumors (median 5.4 ± 0.70 ng/ml) (p = 0.005) and to patients with benign breast disease (median 4.3 ± 0.28) (p = 0.0003). High histology grade was significantly linked with higher plasma DLL4 levels (median 5.59 ± 0.62 vs. 5.12 ± 0.44 ng/ml; p = 0.01). Surgical removal of high-grade breast cancer resulted in significant reduction in DLL4 plasma levels (p = 0.003). DLL4 was expressed in tumor-associated vessels and in cancer cells. The ratio of DLL4+/CD31+ vascular density (VD) ranged from 23 to 88% (median 49 %). High DLL4 cancer cell expression and high DLL4+ VD were significantly linked with nodal involvement (p = 0.004 and 0.01, respectively). Linear regression analysis showed a significant association of DLL4 plasma levels with the percentage of DLL4+ cancer cells (p = 0.03, r = 0.50) and with DLL4+ VD (p = 0.0007, r = 0.60). It is concluded that DLL4 is overexpressed in breast cancer cells and breast cancer vasculature and is linked with nodal and distant metastasis. DLL4 plasma levels measurement can reliably estimate the total DLL4 breast cancer/vasculature activity.

Development of primary malignant melanoma during treatment with a TNF-α antagonist for severe Crohn's disease: a case report and review of the hypothetical association between TNF-α blockers and cancer.

It is recognized that immunosuppression may lead to reduced immune surveillance and tumor formation. Because of the immunosuppressive properties of tumor necrosis factor (TNF)-alpha (TNF-α) antagonists, it is plausible that these biologics may increase the risk of the occurrence of malignancies or the reactivation of latent malignancies. TNF-α antagonists have gained momentum in the field of dermatology for treating rheumatoid arthritis and psoriasis, and they have revolutionized the treatment of other inflammatory autoimmune diseases such as refractory Crohn's disease. However, there is accumulating evidence that TNF-α inhibitors slightly increase the risk of cancer, including malignant melanoma (MM). The authors herein report the case of a 54-year-old female patient who developed a primary MM during treatment with adalimumab for severe Crohn's disease resistant to successive medical therapies. The patient had been receiving this TNF-α blocker therapy for 3 years before the occurrence of MM. After wide surgical excision of the lesion and staging (based on Breslow thickness and Clark level), evaluation with a whole-body computed tomography scan was negative for metastatic disease. The long duration of the adalimumab therapy and the patient's lack of a predisposition to skin cancer suggest an association between anti-TNF-α drugs and melanocytic proliferation. The authors also review the literature on the potential association between anti-TNF regimens and the occurrence of malignancies such as melanocytic proliferations. There is a substantial hypothetical link between anti-TNF-α regimens such as adalimumab and the potential for cancers such as melanoma. However, the risk of malignancy with biological therapy remains to be established, and most of the relevant studies have lacked the statistical power and randomization required for large clinical trials. Further long-term controlled clinical trials and registries are required to investigate this potentially serious association.

Interleukin-1 associations in inflammatory bowel disease and the enteropathic seronegative spondylarthritis.

PURPOSE: This study aims to investigate any associations of the proinflammatory cytokine IL-1 in treated patients with inflammatory bowel disease (IBD) and the enteropathic seronegative spondylarthritis (eSpA). METHODS: Thirty-four patients with Crohn's disease (CD), 26 with ulcerative colitis (UC) and 14 patients with SpA participated in the study. Valid clinical indexes, CRP values and the endoscopic and histologic examination were used for the determination of disease activity. IL-1α, IL-1ß, IL-1 receptor antagonist (IL-1Ra) were measured by ELISA. Nonparametric tests were used for continuous and categorical data. RESULTS: Enteropathic SpA diagnosed in 29.4 % CD and 30.8 % UC patients. Active disease had 58.8 % CD (aCD), 76.9 % UC and 50 % SpA patients. Active and inactive CD (iCD) significantly differ on IL-1α levels (11.2 vs. 3.9 pg/ml; p = 0.034). Active and inactive UC significantly differ on IL-1ß (3.7 vs. 2.3 pg/ml; p = 0.054) and IL-1Ra levels (15.9 vs. 12.7 pg/ml; p = 0.023). Active and inactive SpA (iSpA) significantly differ on IL-1Ra (16.9 vs. 14.8 pg/ml; p = 0.033) and marginally on IL-1α levels (20 vs. 3.9 pg/ml; p = 0.06). Patients with aCD/ieSpA exhibited significant differences on IL-1α (p = 0.022) compared to those with iCD/ieSpA. CONCLUSIONS: IL-1α is associated with CD activity, while IL-1ß and IL-1Ra are associated with UC activity in treated patients with IBD. Prominent cytokine in SpAs seems to be IL-1α.

Primary umbilical endometrioma: a rare case of spontaneous abdominal wall endometriosis.

Umbilical endometrioma is a rare condition, with an estimated incidence of 0.5%-1% in all patients with endometrial ectopia. Spontaneous abdominal wall endometriosis is an even rarer and more unusual condition with unclear pathogenetic mechanisms. A 44-year-old parous woman presented with an umbilical skin lesion, and no history of bleeding from the umbilical mass or swelling in the umbilical area. The initial clinical diagnosis was granuloma, and excision was planned. Pathology examination revealed endometrial glands with mucinous-type metaplasia surrounded by a disintegrating mantle of endometrial stroma. Clinical examination and magnetic resonance imaging did not reveal pelvic endometriosis lesions, and given that the umbilical endometrioma was totally excised, no further treatment with hormonal therapy was proposed for the patient. Three years after excision, she was free of disease and no recurrence has been observed. Complete excision and histology is highly recommended for obtaining a definitive diagnosis and optimal treatment in spontaneous abdominal wall endometriosis.

Benign post-radiation rectal stricture treated with endoscopic balloon dilation and intralesional triamcinolone injection.

Post-radiation stricture is a rare complication after pelvis irradiation, but must be in the mind of the clinician evaluating a lower gastrointestinal obstruction. Endoscopy has gained an important role in chronic radiation proctitis with several therapeutic options for management of intestinal strictures. The treatment of rectal strictures has been limited to surgery with high morbidity and mortality. Therefore, a less invasive therapeutic approach for benign rectal strictures, endoscopic balloon dilation with or without intralesional steroid injection, has become a common treatment modality. We present a case of benign post-radiation rectal stricture treated successfully with balloon dilation and adjuvant intralesional triamcinolone injection. A 70-year-old woman presented to the emergency room complaining for 2 weeks of diarrhea and meteorism, 11 years after radiation of the pelvis due to adenocarcinoma of the uterus. Colonoscopy revealed a stricture at the rectum and multiple endoscopic biopsies were obtained from the stricture. The stricture was treated with endoscopic balloon dilation and intralesional triamcinolone injection. The procedure appears to have a high success rate and a very low complication rate. Histologic examination of the biopsies revealed non-specific inflammatory changes of the rectal mucosa and no specific changes of the mucosa due to radiation. All biopsies were negative for malignancy. The patient is stricture-free 12 months post-treatment.

Is Post-ERCP Pancreatitis a Genetically Predisposed Complication?

Background/Objectives. Pancreatitis remains the most common complication of ERCP. History of post-ERCP pancreatitis is an independent risk factor for a new episode, suggesting a genetic background. The N34S mutation in serine protease inhibitor Kazal type 1 (SPINK 1) gene may downregulate the threshold for the development of pancreatitis. The aim of the present study is to evaluate the presence of this mutation among patients with post-ERCP pancreatitis. Methods. During a period of four years, thirty patients with post-ERCP pancreatitis entered the study. Patients and procedural data were collected, focusing on risk factors for pancreatitis. Blood samples were taken for genetic testing for the presence of N34S mutation in SPINK 1 gene. After DNA extraction, we used an allele-specific polymerase chain reaction as an initial screening method for the N34S mutation, and in order to confirm the results and to determine the hetero- and homozygosity genotype status, we used a restriction fragment length polymorphism (RFLP) method. Results. None of the thirty patients was found to carry the N34S mutation, with both of the applied methods. Patients had an average of two of the known risk factors. Conclusion. SPINK1 N34S mutation does not seem to play a role in post-ERCP pancreatitis, but larger studies needed to confirm our results.

Multiple-checkpoint inhibition of thymic stromal lymphopoietin-induced TH2 response by TH17-related cytokines.

BACKGROUND: The interplay between allergy and autoimmunity has been a matter of long debate. Epidemiologic studies point to a decreased frequency of allergy in patients with autoimmune diseases. However, recent studies suggest that IL-17 and related cytokines, which play a central role in autoimmunity, might also promote allergy. OBJECTIVE: To address this controversy, we systematically studied the interactions between T(H)17-related cytokines and the thymic stromal lymphopoietin (TSLP)-mediated proallergic pathway. METHODS: We used human primary dendritic cells (DCs), T cells, and skin explants. A novel geometric representation and multivariate ANOVA were used to analyze the T(H) cytokine profile. RESULTS: We show that IL-17A specifically inhibits TSLP production but increases proinflammatory IL-8 production in human skin explants exposed to TNF-α and IL-4. This inhibitory activity was confirmed in cultured skin explants of atopic dermatitis lesions. At the T-cell level, T(H)17-polarizing cytokines (IL-1ß, IL-6, TGF-ß, and IL-23) inhibited T(H)2 differentiation induced by TSLP-activated DCs. This led to a global dominance of a T(H)17-polarizing environment over TSLP-activated DCs, as revealed by clustering and computational analysis. CONCLUSIONS: Our data indicate that T(H)17-related cytokines are negative regulators of the TSLP immune pathway. This might explain the decreased frequency of allergy in patients with autoimmunity and suggests new means of manipulating proallergic responses.

Endoscopic treatment of a gastrocutaneous fistula using the over-the-scope-clip system: a case report.

The over-the-scope-clip (OTSC; Ovesco Endoscopy GmbH, Tuebingen, Germany) system is a newly designed method for the mechanical compression of large areas in the gastrointestinal tract. So far, indications for OTSC application are hemostasis of primary or postinterventional bleeding, closure of iatrogenic full-thickness or covered perforations. Recently closure of gastrointestinal tract fistulas using this device has been described. A 44-year-old man developed a gastrocutaneous fistula after surgical treatment for a perforated gastric ulcer. We describe the successful endoscopic closure of the fistula using the OTSC system. The patient's clinical followup was uneventful. Fistula closure was successfully implemented as it was documented by imaging and endoscopic examinations performed on the 2nd day and 6th week after the application of the clip. Endoscopic application of the OTSC device was safe and effective for the treatment of a gastrocutaneous fistula.

Adalimumab - an effective and promising treatment for patients with fistulizing Crohn's disease: a case series.

INTRODUCTION: Crohn's disease is a chronic inflammatory bowel disease of unknown etiology which may affect any part of the bowel. Fistulas are a common and often serious complication of Crohn's disease. The treatment for fistulizing Crohn's disease can be medical, surgical or a combination of the two. Recently, adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, has been suggested as a safe and effective treatment for the induction and maintenance of remission in adult patients with moderate to severe Crohn's disease, who are refractory to conventional therapy or intolerant to infliximab. However, large studies focusing on evaluating the efficacy of adalimumab in fistulizing Crohn's disease have not yet been published. CASE PRESENTATION: We report the cases of three patients, of European Caucasian ethnicity and Greek nationality, with active luminal and fistulizing Crohn's disease. All of the cases were treated successfully with adalimumab. Patient 1 (a 44-year-old man) and patient 2 (an 18-year-old woman) developed early post-surgical enterocutaneous fistulas, while patient 3 (a 20-year-old woman) had peri-anal fistulizing Crohn's disease. Adalimumab treatment (160 mg subcutaneously at week zero, 80 mg at week two, and 40 mg every other week) was used for three different indications: (1) after the failure of other conservative medical treatments for Crohn's disease (patient 1); (2) as a monotherapy in treating a naive patient (patient 2); (3) after an intolerance to infliximab (patient 3). A remission of the active luminal and fistulizing disease was achieved soon after the initiation of adalimumab and sustained thereafter with maintenance doses. No further surgical intervention was required and no adverse effects were observed in any of the cases. CONCLUSIONS: Fistulizing Crohn's disease remains a challenge in clinical practice. Adalimumab seems to be an effective, well-tolerated and safe treatment option for the induction and maintenance of remission in patients with moderate to severe peri-anal fistulizing Crohn's disease. Furthermore, adalimumab seems to be a promising treatment option for patients with moderate to severe fistulizing Crohn's disease with enterocutaneous fistulas. However, this clinical observation needs to be investigated in further clinical trials.

Massive intestinal ischemia, a rare complication of oral contraceptive-induced mesenteric venous thrombosis: a case report and review of literature.

Intestinal necrosis and perforation is a clinical and pathological presentation of the infrequently seen mesenteric venous thrombosis in women using oral contraceptives.We report a case of a previously healthy 31-year-old female patient, who presented with a 3-day history of abdominal pain.Although chest and abdomen radiographs showed small bowel obstruction, conservative treatment failed and the patient developed peritonism. Contrast-enhanced Tomography of the abdomen revealed free air associated with dilated and thickened small bowel. A laparotomy was performed and segmental resection of both small and large bowel was required. The pathological examination showed intestinal ischemia and mesenteric venous thrombosis. There were no further predisposing factors and mesenteric venous thrombosis was ascribed to oral contraceptives.

The efficacy and safety of total thyroidectomy in the management of benign thyroid disease: a review of 932 cases.

BACKGROUND: Total thyroidectomy is currently the preferred treatment for thyroid cancer, multinodular goitre and Graves disease; however, many surgeons choose not to perform total thyroidectomy to treat benign thyroid diseases owing to the associated risk of postoperative hypoparathyroidism and recurrent laryngeal nerve damage. We reviewed 932 total thyroidectomies performed for benign thyroid diseases when surgery was indicated. We sought to assess whether the results support the hypothesis that total thyroidectomy is safe and can be considered as the optimal surgical approach for treating benign thyroid diseases. METHODS: A total of 932 patients underwent thyroidectomy between 1985 and 2005. We excluded patients with thyroid cancer or suspicion of thyroid malignancy. We evaluated indications for total thyroidectomy, cancer incidence, complication rates, local recurrence rate and long-term outcome after total thyroidectomy. RESULTS: Diagnoses before surgery were multinodular goitre (n = 734, 78.8%), Graves disease (n = 166, 17.8%) and recurrent (after previous partial thyroidectomy) nodular goitre (n = 32, 3.4%). The incidence of permanent bilateral recurrent laryngeal nerve palsy was 0% and that of permanent unilateral recurrent laryngeal nerve palsy was 0.2%, whereas the incidence of temporary unilateral recurrent laryngeal nerve palsy was 1.3%. Permanent hypocalcemia occurred in 0.3% and overall temporary hypocalcemia occurred in 7.3% of patients. Hemorrhage requiring repeat surgery occurred in 0.2% of patients. There was no wound infection, and postoperative mortality was 0%. We observed no disease recurrences during a median follow-up of 9 (range 2-20) years. CONCLUSION: Total thyroidectomy is safe and is associated with a low incidence of disabilities. Complication rates for recurrent laryngeal nerve palsy and hypoparathyroidism are similar to results of specialist endocrine surgery units. Furthermore, total thyroidectomy seems to be the optimal procedure, when surgery is indicated, for Graves disease and multinodular goitre, as total thyroidectomy has the advantages of immediate and permanent cure and no recurrences.

Asymptomatic brain finding results on MRI in a patient with Crohn's disease: a case report.

The association of inflammatory bowel disease with neurological involvement is unusual and often controversial. We report the case of a 39-year old man with Crohn's disease and an intracranial benign primary tumor, detected on MRI scan. The patient had been suffering from extensive perianal fistulas for 8 years, before inflammatory bowel disease was diagnosed six months ago. The patient, being enrolled in a research protocol, underwent brain MRI examination. Despite the absence of neurological symptoms and electromyography abnormalities, a meningioma was evidenced. Whether this is an incidental finding on brain MRI or whether it might be linked to Crohn's disease development as an extraintestinal, neurological disorder remains unclear. This information is especially important in view of the ethical and practical issues involved in the management of incidental findings in CD. This report might provide further confirmation of the hypothesis that central neurological disorders occur during CD.

Parathyroid apoplexy, the explanation of spontaneous remission of primary hyperparathyroidism: a case report.

Primary hyperparathyroidism due to parathyroid adenoma represents an endocrine disease that is usually treated by surgical intervention (parathyroidectomy). In a very few patients, primary hyperparathyroidism can be spontaneously remit either by infraction or hemorrhage of the adenoma,a fact that is almost certain that will not lead to complete and definite cure. We describe a similar case of a 59-year-old male patient who underwent surgery for a cystic degeneration of a parathyroid adenoma, with substantial preoperative reduction of parathyroid hormone and calcium serum levels,and the diagnostic and treatment modalities are discussed, with a brief review of the current literature.

Complicated Crohn's-like colitis, associated with Hermansky-Pudlak syndrome, treated with Infliximab: a case report and brief review of the literature.

INTRODUCTION: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive inherited disorder consisting of a triad of albinism, increased bleeding tendency secondary to platelet dysfunction, and systemic complications associated with ceroid depositions within the reticuloendothelial system. HPS has been associated with gastrointestinal (GI) complications related to chronic granulomatous colitis with pathologic features suggestive of Crohn's disease. This colitis can be severe and has been reported to be poorly responsive to medical therapies including antibiotics, corticosteroids, sulfasalazine, mesalamine and azathioprine. CASE PRESENTATION: We report a patient with HPS which was complicated by inflammatory bowel disease with clinical and pathologic features of Crohn's disease, refractory to antibiotics, corticosteroids and azathioprine. A trial of infliximab was attempted and repeated infusions produced a complete response. CONCLUSION: The occurrence of ileitis and perianal lesions and also the histopathological findings in our case suggest that HPS and Crohn's disease may truly be associated. Given this similarity and the failure of the standard medical therapy of corticosteroids and azathioprine, our patient received infliximab with marked clinical improvement.

Peptic ulcer perforation as the first manifestation of previously unknown primary hyperparathyroidism.

A patient admitted for acute abdomen was incidentally found with elevated serum calcium level. In surgery, under conservative treatment of the hypercalcemia, a perforated duodenal ulcer was found and simple closure was performed. Postoperatively, calcium level continued to rise, parathyroid hormone was elevated and ultrasonographic examination showed a lesion in the right anterior neck, while serum gastrin level was normal, thus documenting the diagnosis of primary hyperparathyroidism. Conservative treatment had no effect on calcium level and the patient was subjected to emergency neck exploration, where a large parathyroid adenoma was removed. After surgery, calcium and PTH levels were normalized and the patient was discharged on the 5th postoperative day. Peptic ulcer and its complications are usual manifestations of primary hyperparathyroidism, with or without increased gastrin level. On the other hand, cases of a perforation of peptic ulcer as the first clinical manifestation of primary hyperparathyroidism are extremely rare.

Perforated GIST of the small intestine as a rare cause of acute abdomen: Surgical treatment and adjuvant therapy. Case report.

A case of perforated gastrointestinal stromal tumor (GIST) of small intestine causing acute abdomen is described, with a brief review of the literature. A male patient presented with symptoms of acute abdomen. After evaluation, a laparotomy was performed, where perforation of a tumor in the ileum was found. The perforated part along with the tumor was resected and the cytopathological examination showed that the tumor was GIST. Postoperatively, the patient received treatment, using imatinib. Gastrointestinal stromal tumors are relatively rare and often present with vague symptoms. Their first clinical manifestation as acute abdomen due to their perforation is extremely rare. In emergency laparotomy, a R0 resection is required and adjuvant therapy with imatinib must be considered.

Enterolith small-bowel obstruction caused by jejunal diverticulosis: Report of a case.

We report the successful surgical treatment of intestinal obstruction caused by enteroliths formed in jejunal diverticula. A 78-year-old man with bowel obstruction of unknown etiology was initially managed conservatively, but suffered recurrence of the obstruction. Thus, we performed a laparotomy, which revealed multiple diverticula in the jejunum, with one enterolith inside a diverticulum and one enterolith in the terminal ileum. There was no abnormal communication between the gallbladder and the intestinal tract, excluding the possibility of a gallstone ileus. The stone in the terminal ileum could not be broken manually, so we performed an enterotomy to remove the stones. Intestinal obstruction caused by enteroliths in small-bowel diverticula is a rare event, which is difficult to diagnose and manage. To our knowledge, only 35 such cases have ever been reported.

Lateral subcutaneous internal sphincterotomy in the treatment of chronic anal fissure: our experience.

BACKGROUND: Chronic anal fissure is the most common cause of anal pain associated with internal anal sphincter hypertonia. Reduction of hypertonia favours fissure healing. Temporary reduction in sphincter tone can be achieved by conservative treatment. Surgical sphincterotomy achieves permanent reduction of sphincter hypertonia and is very successful at healing anal fissures, but requires an operation with associated small morbidity. METHODS: A study was undertaken on 246 patients (120 men, 126 women, mean age 48.3 years), undergoing subcutaneous lateral internal sphincterotomy for a chronic fissure-in-ano from January 1, 1981 to December 31, 2004. Therapeutical outcome, postoperative course and early and long-term results were recorded. RESULTS: During the study period, the 246 patients underwent total subcutaneous lateral internal sphincterotomy, 62 of them under general anesthesia (1981-1991), and the remainder under local anesthesia. Two-hundred-forty-two patients returned for their postoperative visits at 2, 6, 24 and 48 weeks, while four patients were lost to follow-up. At 3 months postoperatively, 97.5% of fissures had healed; 224 fissures were healed by 6 weeks, 10 by 7 weeks and 2 by 3 months. Pain was significantly reduced in all patients at Day 1 postoperative. Minor complications included hematoma (0.8%) and pain (0.4%). New minor incontinence was seen in 7.02% of patients at 48-week follow up. Patients' satisfaction was 91.7%. CONCLUSIONS: Total subcutaneous internal sphincterotomy is a safe and effective treatment for chronic anal fissures, that only rarely impairs continence to flatus.

Extrahepatic biliary obstruction due to a solitary pancreatic metastasis of squamous cell lung carcinoma. Case report.

A 53-year old male, with a history of squamous cell lung carcinoma, was presenting with jaundice. Examinations showed a pancreatic tumor infiltrating the common bile duct and a percutaneous biopsy proved that the lesion was metastatic from the lung carcinoma. The decision was taken to perform a laparotomy. During laparotomy, a palliative operation was performed to relieve the jaundice. According to the literature, symptomatic metastatic lesions of the pancreas from squamous cell carcinoma of the lung are infrequent.