Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Animal Models of Barrett's Esophagus and Esophageal Adenocarcinoma–Past,Present, and Future

Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long‐standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5‐year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett''s esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett''s esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett''s esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett''s carcinogenesis.     

The history of ideas of Nordic midwives’ excursions from the early 19th century to the millennium

The midwifery art has emphasised the uniqueness of human beings throughout its Nordic history. The educated Nordic midwife has in the last decade celebrated several hundred years of memories. This article studies how the key ideas of the midwifery art and patterns of ideas become evident in the zeitgeist from the beginning of the 19th century to the millennium in the Nordic countries. The legacy and pattern of ideas of the art of midwifery are interpreted in relation to the texts of the selected historical sources and based on Ricoeur's phenomenological-hermeneutic approach to the text and further to the dedication of understanding and interpretation. The historical sources refer to unprinted primary sources from historical archives and printed secondary and tertiary sources. The patterns of ideas include a tripartite whole: the true cultivation of the head, the philosophy and aesthetics of the hand, the strength of the heart and the drive of calling. These ideas open for unique visions and attest to the evident in modern midwives. Today's midwives have academic training with examinations, and the education is based on scientific evidence. The midwife profession is authorised by the state and supervised by the authorities.     

The surgical management of resistant club foot by rotation skin flap and extensive soft tissue release

Summary Resistant club foot remains an unsolved problem because of the complex aetiological and pathological factors, and is still seen quite frequently, especially in developing countries. The posteromedial skin contracture is a potent deforming force which is responsible for many failures or relapses. I report the results of an operation in which a rotation skin flap was combined with an extensive soft-tissue release. The age of the children was from 9 months to 10 years. The follow-up period was from one to 9 years with an average of 43 months, and in 50 cases for more than 5 years. I consider that the outcome has been excellent or good in 94 out of 100 feet.

---

Résumé Le pied bot invétéré demeure un problème mal résolu en raison de la complexité des facteurs étiologiques et anatomiques et il est encore bien souvent rencontré, notamment dans les pays en voie de développement. La rétraction cutanée postéro-interne représente un puissant élément de la déformation, qui est responsable de bon nombre d'échecs ou de récidives. Nous rapportons les résultats d'une opération qui associe un lambeau cutané de rotation à la libération des parties molles. L'âge des enfants était compris entre neuf mois et dix ans. Le recul est de un à neuf ans, avec une moyenne de 43 mois. Cinquante enfants ont été suivis plus de cinq ans. Les résultats sont excellents ou bons dans 94% des cas.

     

Dysphagia aortica

Three patients with dysphagia caused by compression of the distal esophagus by a tortuous nonaneurysmal atherosclerotic aorta are described. All three patients were elderly women; systemic hypertension and cardiomegaly were present in two patients. Barium studies of the esophagus showed displacement and compression of the distal esophagus by the thoracic aorta. Debilitating dysphagia was treated surgically in one patient. The other two patients had milder symptoms and were managed conservatively. Esophageal manometry in these three patients showed superimposed pulsations and elevated intraluminal pressure just proximal to the lower esophageal sphincter. To evaluate the significance of these manometric findings and their correlation with clinical symptoms, we reviewed manometric tracings in 47 normal subjects. Ten of these subjects had an elevation of baseline intraluminal esophageal pressure as a result of superimposed vascular pulsations. We conclude that (1) compression of the distal esophagus by a tortuous atherosclerotic aorta in the appropriate setting can lead to clinically significant dysphagia and (2) a manometric finding of vascular compression of the esophagus does not necessarily correlate symptomatic dysphagia.     

Role of immediate versus delayed nephrectomy for failed renal transplants

The role of timing of transplant nephrectomy after renal transplantation has not been well defined. This report compares the morbidity, mortality, and hospitalization costs of 37 patients undergoing transplant nephrectomy within 14 days after graft failure and return to dialysis, with 31 patients undergoing delayed transplant nephrectomy (less than 14 days after graft failure and return to dialysis). This analysis revealed that there were no significant (P greater than .05) differences in patient morbidity and mortality between these groups. There was, however, a substantial increase (P less than .05) in the cost of hospitalization in the delayed nephrectomy group. For this reason, we recommend early nephrectomy after renal transplant failure in order to minimize the cost of health care for these patients undergoing failed cadaver donor transplant nephrectomy.     

Comparison of morphologic and immunohistochemical features of cervical microglandular hyperplasia with low-grade mucinous adenocarcinoma of the endometrium.

Twenty cases of microglandular hyperplasia (MGH) of the uterine cervix and 14 cases of low-grade (nuclear) mucinous adenocarcinoma of the endometrium (MA) were compared morphologically and immunohistochemically. Subnuclear vacuoles were seen in 10 cases of MGH but were absent in all MA. Luminal squamous metaplasia was seen in only 10% of MGH cases versus 65% of MA cases. Stromal foam cells were present in 36% of MA but were absent in MGH cases. Both MGH and MA had minimal variation in nuclear size and inconspicuous nucleoli. As many as 8 mitoses/10 high-power fields (MF/10 HPF) were found in MA compared with 3 or fewer MF/10 HPF in MGH. Vimentin was expressed in 90% of MA but was absent in MGH. A significantly higher percentage of MA cells stained with MIB-1 than did those of MGH (mean 11% versus 0.5%). Both MA and MGH lacked CEA and p53 staining, whereas both had variable expression of ER and PR with no significant differences except that PR was absent in 40% of MGH cases. Our findings indicate that in the differential diagnosis of MGH versus MA, the presence of subnuclear vacuoles favors the former, whereas luminal squamous metaplasia, stromal foam cells, mitotic activity, vimentin expression, and MIB-1 expression favor the latter.