Krebswissenschaft und -therapie

Objectives: Contribution of a case of unusual spread of cervical carcinoma mimicking iliopsoas abscess fifteen years after initial radiotherapy.

Method: A 65-year-old white woman with history of squamous cell carcinoma of uterine cervix treated 15 years ago, was referred to our department with clinical and imaging’s findings simulating a psoas abcess.

Result: Colposcopy and punch biopsy confirmed the diagnosis of carcinoma of the cervix. Needle aspirate of cystic mass yielded a watery chocolate-colored. Cytopathology revealed cells suggestive of squamous cell carcinoma consistent with the diagnosis of metastasis from carcinoma cervix. Consultations with radiation therapy and medical oncology suggested no additional therapy .The patient became increasingly cachectic and died with generalized metastasis 3 months after admission.

Conclusion: Through this case, the authors highlights the fact that metastasis from squamous cell carcinoma of the cervix can present as a psoas abscess and demonstrates certain difficulties in diagnosis even with the newer imaging modalities.

Problem Statement: Even after decades of scientific research, the application of chemotherapy in the management of neoplastic disease still presents numerous difficulties. Significant, amongst potential complications are numerous toxicity related side effects and the potential for chemoresistance. Despite the widespread tendency to include a variety of new chemotherapeutics in different combinations, progress in this area has proven slow going and unsatisfactory due to the aforementioned factors. 3

Approach: Seeking a new approach, we introduced the method of Insulin Potentiation Therapy (IPT) in our practice. The theoretical basis and the gathered experimental data on insulin’s mode of action, as well as its application in practice, show that IPT is a promising method with low toxicity. Moreover, it facilitates a selectively physiological approach to the management of neoplastic disease using chemotherapy.

In this report we present the results of our three-year experience applying Insulin Potentiation Targeted Therapy Low Dose (IPTLD) in the treatment of 196 patients diagnosed with a variety of neoplastic diseases

Results: Our results showed that patients tolerated IPTLD without difficulties, without serious side effects. Our laboratory tests demonstrated that the dose related toxicity of chemotherapeutics could be largely mitigated when applied in conjunction with insulin, at a fractionated dose in accordance with a dose dense regimen. Upon follow-up, eighty five of 106 patients (80%) with advanced metastatic disease reported a subjectively significant improvement in their quality of life.

Conclusions: Future extended experimental data and clinical trials would contribute to a more complete understanding of the therapeutic potential of IPTLD.

Background: Intensity Modulated Radiotherapy (IMRT) is being used increasingly for the radical treatment of oropharyngeal cancers. We have reviewed the evidence and summarised the data to enable readers to decide whether the dosimetric advantages of IMRT have been translated into clinical benefit in oropharyngeal cancer treatment.

Methods: We searched Medline and the Cochrane library for published studies investigating the role of IMRT in reducing rates of xerostomia, osteoradionecrosis and difficulties with swallowing.

Results: Despite heterogeneity in the assessment of xerostomia following radiotherapy, 20 out of the 22 studies reported lower xerostomia rates following parotid-sparing IMRT. There is only limited information on the consequences of sparing dose to the submandibular gland and emerging clinical information on the benefits of reducing dose to the pharyngeal constrictor muscles. Rates of osteoradionecrosis are lower with IMRT.

Conclusion: Rates of xerostomia are lower with IMRT than with conventional radiotherapy techniques. Prospective evaluation of IMRT techniques to assess whether lower doses to the submandibular glands and constrictor muscles are associated with clinical benefit is essential. Although there appear to be lower rates of osteonecrosis with IMRT, pre treatment evaluation of dental status and maintenance of dental hygiene remain important.

Metastasis contributes to 90% of all breast cancer death. Several studies have highlighted the role of epigenetic events such as DNA methylation in promoter regions of genes as an important event in the process of metastasis in breast cancer. The promoter of the CXCL12 gene, encoding a chemokine, is silenced by methylation in gastric, colon as well as in the breast cancer. The aim of this work was to map methylated regions flanking the promoter of CXCL12 by cloning bisulfite treated DNA containing the distinct CpG regions and also correlate methylation pattern with the gene expression in different breast tumor cell lines. The results showed that the CpG islands 1, 3, 5 as well as the middle end of CpG 2 were more than 80% methylated in the cell lines that expressed the gene CXCL12 (HB4a, PMC42 and MCF7). Expression analysis indicates strongly that these regions do not regulate this gene expression. However, CpG island 4 (CGI 4) located approximately 1550 bp away from the transcription start region and outside the putative promoter region, was differentially methylated and it seems to promote CXCL12 gene silencing. In conclusion the CGI 4 is probably the last region to be methylated for silencing of CXCL12 gene and could be a suitable DNA region for the diagnostic and prognostic to breast cancer studies.

Background: Minimally invasive approach for cancer of esophagus and gastroesophageal junction (GEJ) is gaining more popularity in the developed world mainly because of its better cosmetic results, lesser pain and lesser postoperative stay without compromising the radicality of the cancer surgery and survival. The aim of this study is to review the early outcome of this approach at BP Koirala Memorial Cancer Hospital.

Methods: Resectable tumors of GEJ and esophagus were treated primarily with surgery. Locally advanced tumors were considered for multimodality approach. Three ports were used for Video-assisted thoracoscopic (VATS) esophageal mobilization. Five ports were used for laparoscopic mobilization of stomach. Depending upon the feasibility, either a totally minimally invasive approach or a combination of minimally invasive approach with open technique was used. A 5 cm minilaparotomy was performed to retrieve the specimen.

Results: 34 patients with mean age of 57 years were reviewed. 9%, 38%, 29.5% and 23.5% of patients had malignancies of upper esophagus, middle esophagus, GEJ - I (distal esophagus) and GEJ - II (cardia), respectively. Primary surgery was performed in 91% of cases, whereas 9% underwent preoperative chemoradiation followed by surgery. VATS-laparotomy-neck (3-incision), thoracotomy-laparoscopy-neck (3-incision), laparoscopy-thoracotomy (2-incision), laparoscopic transhiatal-neck (2-incision), VATS-laparoscopy-neck (3-incision) and laparoscopyassisted (1-incision) approaches were used in 15%, 56%, 3%, 12%, 12% and 3%, respectively. Mean number of dissected nodes was 22 and mean number of positive nodes was 6. R0 resection was achieved in 94% of cases. The major postoperative complications were in-hospital mortality (6%), anastomotic leak (12%) and recurrent laryngeal nerve injury (6%). The early (6 months) survival is 97%.

Conclusion: Our results show, minimally invasive surgery is feasible, safe and the early outcome is promising though a longer follow-up is required for its strong recommendation in Nepalese context.

TMPRSS2-Ets gene fusions were identified in prostate cancers where the promoter of transmembrane protease, serine 2 (TMPRSS2) fused with coding sequence of the erythroblastosis virus E26 (Ets) gene family members. TMPRSS2 is an androgen responsive transmembrane serine protease. Ets family members are oncogenic transcription factors that contain a highly conserved Ets DNA binding domain and an N-terminal regulatory domain.

Fusion of these gene results in androgen dependent transcription of Ets factor in prostate tumor cells. The ERG is the most common fusion partner with TMPRSS2 promoter in prostate cancer patients. The high prevalence of these gene fusions, in particular TMPRSS2-ERG, makes them attractive as potential diagnostic and prognostic indicators, as well as making them a potential target for tailored therapies.

This review focuses on the clinical and biological significance of TMPRSS2-ERG fusions and their role in PC development and progression.

Introduction: Breast cancer is the second most common cancer worldwide. Adequate evaluation of the specimen is essential for accurate diagnosis and prognosis.

Objective: To present a standardized protocol for the gross and microscopic examination of radical mastectomy specimens, despite the presence or absence of homolateral axillary dissection and irrespective of the type of the malignancy to provide the necessary information to guide potential adjuvant therapy and prognostic information.

Materials and methods: A standardized protocol was created for the examination of surgical specimens from radical mastectomies.

Results: The group of pathologists responsible for routine examination agreed that use of the standardized protocol reduced the time spent on macroscopic and microscopic examination of the radical mastectomy specimens and increased the accuracy of recording the information needed for diagnosis.

Conclusion: We believe that simplification of the protocol presented here for guidance of histological examination of surgical mastectomy specimens is easily applied, rapid, reliable and safe, and will contribute to the routine diagnostic practice.

Background/Aim: The anti-neoplastic agents are known to impair tissue healing which may lead to significant post-operative complications, like anastomotic leaks. There has been a number of studies that have shown the protective affects of glutamine on the enteric mucosa. Our study aimed to test whether the addition of enteral glutamine to 5-fluorouracil (5FU) used as immediate post-colectomy chemotherapy caused less anastomotic complications compared to 5-FU alone.

Materials and methods: Thirty-six female Wistar-Albino rats were initially divided into three groups of twelve rats. The first and the second twelve formed the control (CG) and the 5-FU groups respectively, and were fed on standard laboratory diet and water for seven days. The third group was the Glutamine group (GG) which had oral glutamine supplements in addition to the standard diet. All animals had a laparotomy on day 7. The left colon was transected and a hand sewn colocolic anastomosis was undertaken (hangi teknik, hand-sewn, single layer, sero-submucosal). All groups were further divided into two subgroups (a total of six groups). The first subgroup in each main group was sacrificed on post-operative day 3, the remainder were killed on day 7. Bursting pressures, tissue-hydroxyproline and histopathology were compared by Anova test.

Results: Bursting pressure values were significantly reduced by 5FU treatment, both at day 3 and day 7 postoperatively. Glutamine treatment prevented the reduction of bursting pressure in 5FU treated animals, which was not significantly different from animals not treated with 5FU. The lowest mean tissue hydroxyproline levels were found in the 5FU-day 3 & day 7 groups, histopathology was superior in 5FU-glutamine-day 7 group.

Conclusion: Glutamine neutralised the detrimental affects of 5-FU on tissue healing. This may enable the early inititiation of adjuvant chemotherapy.

Background: Mantle Cell Lymphoma (MCL) is an aggressive B cell malignancy accounting for 6% of non- Hodgkin’s lymphoma cases in the US. While various therapies are available to treat MCL, patients relapse within 3 to 4 years following treatment from therapy-resistant MCL, making MCL carry one of the worst prognoses of all non- Hodgkin’s B cell lymphomas. A better understanding of the biological mechanisms of relapse and therapy-resistance in MCL is vital for developing mechanisms to target relapsing MCL, and providing better care for patients. Recent studies implicate the NFκB pathway and survivin in promotion of aggressive, therapy-resistant MCL. Therefore, we tested the efficacy of inhibiting this pathway in three MCL lines (GP, recently-developed GRL, and JVM2) using the protease inhibitor ritonavir (Abbott Laboratories), which has been shown to downregulate NFκB targets, including survivin, in other hematological malignancies.

Methods: MCL cells were incubated with ritonavir then assessed for changes in proliferation, apoptosis, and activation of NFκB transcriptional targets. In addition, in vivo studies were performed to assess ritonavir’s utility as a single agent in MCL treatment using an immune-deficient mouse model of human MCL.

Results: When MCL cell lines were incubated with ritonavir in vitro, they exhibited reduced proliferation, increased apoptosis, and downregulation of NFκB pathway targets. However, no effect was seen when testing ritonavir as a single agent in vivo. Although, treatment with ritonavir plus vincristine in vitro revealed significant reduction in the proliferation of MCL compared to either treatment alone.

Conclusions: These studies suggest ritonavir is not suitable as a single-agent therapy for MCL. However, studies combining ritonavir plus vincristine in vitro suggest ritonavir may be effective in multi-pronged treatment approaches for MCL. These findings necessitate further studies to determine ritonavir’s utility within a multi-pronged treatment approach for treating therapy-resistant MCL.