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Purpose: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated., Experimental Design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated., Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for "high"-HA patients (n = 6), and 3.5 and 5.7 months for "low"-HA patients (n = 11), respectively., Conclusions: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848-54. ©2016 AACR., (©2016 American Association for Cancer Research.)

The objective of this study was to improve the immediate and long-term results of combined treatment of patients with locally advanced rectal cancer. The study included 128 patients with morphologically confirmed diagnosis and clinical stage cT3/T4 and N-/N+, treated from 1998 to 2009. The comparison group had 64 patients, combined treatment included prolonged preoperative radiotherapy 4 Gy and 40 Gy, surgery was performed after 4 weeks. In the study group--also 64 patients--combined treatment consisted of preoperative chemoradiotherapy (continuous a-120 hour infusion of 5-fluorouracil at a dose of 500 mg/m2 in the first and last week of radiotherapy in 2 Gy to 50 Gy), surgery was performed through 6 weeks after chemoradiotherapy. Excision of the primary tumor was performed in 40 (62.5%) patients in the control group and in 53 (82.8%) patients in the study group. Wherein R-0 resections were performed in 32 (67%) patients and in 41 (73%), and R-1 resections--in 1 (2%) patients, and 7 (13%) patients in the control and study groups respectively. A 5-year survival rate was 43.6 ± 7.2% control and 62.7 ± 5.1 % in the study group.

Spread of the tumor in the distal direction is an important factor that must be considered when performing organ-serving surgery for rectal cancer. Particular relevance it has acquired in recent years due to the general tendency to expand the indications for the preservation of natural reflex-apparatus in patients with medium- and lower-ampullar part of the rectum.

The pathomorphism of rectal cancer (RC) was studied in 99 patients who received neoadjuvant chemoradiotherapy using two drugs (5-fluorouracil and xeloda). A morphological study indicated the qualitatively similar manifestations of pathomorphism (tumor necrosis, inflammation, and sclerosis) which were more pronounced in the use of xeloda. Three degrees of the pathomorphism of RC have been identified: the tumor was unchanged, changed, and undetectable.

Results of randomized studies and meta-analyses of the long-term results of surgical treatment of the gastric cancer with lymphadenectomy were compared. The D2 lymphadenectomy permits low indices of postoperative morbidity and mortality. The further lymphadenectomy volume increase does not lead to the significant improvement of the long term treatment results. The splenectomy and pancreas resection are not obligatory by the gastric cancer treatment and should be performed only by certain indications. The prevailing volume of surgical resection is considered to be gastrectomy; the indications to the subtotal gastric resection should be limited for the reduction of the local recurrence rate. Thereby, the optimal algorithm of the gastric cancer treatment includes the gastrectomy and D2 lymphadenectomy, accomplished by the neo- and adjuvant chemotherapy.

Immediate results of 100 D2 lymphadenectomies, performed for gastric cancer, were analyzed. The combined treatment included preoperative radiotherapy (n=39), combinations of pre- and postoperative radiotherapy (n=18) and adjuvant chemotherapy (n=18). The majority of patients had tumors of the lower third of the stomach, histologically low- and non-differentiated adenocarcinomas. Gastrectomy was performed in majority of cases. Achieved results showed, that pre- and postoperative radiotherapy led neither to lethality nor to complication rate or to hospital stay time increase. Thus, D2 lymphadenectomy for surgical and combined treatment of the gastric cancer, is a safe procedure with an acceptable rate of postoperative complications. It does not prevent neo- and adjuvant chemo- or radiotherapy conduction. D2 lymphadenectomy allows a more thorough cancer staging, according both to international and Japanese classifications.

Data on examination of 192 patients radically operated for stomach cancer at the Center's Clinic were analyzed vis-a-vis postoperative recurrences. Marked dependence of metastatic spread features and pathway on histological pattern of tumor was established. This can be used in working out therapeutic strategies. Most patients revealed different patterns of relapse. High incidence of peritoneal tumorigenesis unaccompanied by invasion of serous membrane was reported patients with primary signet-cell and undifferentiated cell tumor among others. Considering high frequency of local relapse in signet-cell and mixed cell cancer, gastrectomy should be regarded as operation of choice irrespective of site and size of tumor.

The paper reports the demographic and clinical data on more than 1,100 stomach cancer patients who underwent radical surgery in 1970-2007. Significant changes in structure and histological pattern of that pathology and primarily the growing fraction of signet ring and undifferentiated cell cancer (30%) are evident. It was matched by similarly important changes in the demographic and clinical data on patients with different morphological patterns and extent of tumor cell differentiation. Precise correlations between morphological pattern and loco-regional extent, site, size, pattern of growth and polyneoplasia rate were identified. Such characteristics should be taken into account when devising diagnostic and therapeutic strategies.

Overall 194 patients with signet ring cell carcinoma of stomach were treated, 124 (64%) of them underwent combined treatment (preoperative radiotherapy with subsequent operation), 70 (36%) - only surgical treatment. There were no differences in survival rate between two groups at early (pT1) cancer. The combined method has advantages over isolated surgical at T2 tumors (both with and without regional lymphatic metastases) and at T3 tumors without regional lymphatic metastases (p=0.03). At T3N1-2 tumors with regional lymphatic metastases and T4 tumor neither combined no surgical method demonstrated positive results of treatment. Generally combined treatment with preoperative radiotherapy has statistically significant advantage (p=0.007) over surgical treatment at the patient with signet ring cell carcinoma of stomach.

The 30-year experience with combined and surgical treatment of gastric cancer gained at the Center is discussed. The results of surgery were improved due to use of intensive preoperative radiotherapy, metronidazole and dynamic fractionated treatment. There was no correlation between intensive preoperative radiotherapy and postoperative complication incidence or lethality, irrespective of extent of surgery or lymph node dissection. Moreover, radiotherapy was followed by a considerable decrease in postoperative incidence of pancreatitis due to inhibition of secretory function by the pancreas. Use of modern technology of radiotherapy planning and implementing left virtually no serious damage. Considering the recent changes introduced to standards for surgical treatment of gastric cancer, our findings point to a safe combination of preoperative radiotherapy with extended surgical and combined treatment.

Long-term results of treatment of 175 patients with early cancer of the stomach are analyzed. Recurrences of the disease (local, regional recurrences and distant metastases) were diagnosed in 14 (8.2% of all operated) patients. Duration of recurrence-free period ranged from 2-3 months to 9.5 years; median was 12 months. Tumor spread, regional nodes affection, tumor morphological structure, age of patients were the main prognostic factors for recurrences. Extent of surgery and lymphodissection did not correlate with recurrences rate. It is concluded that extended lymphodissection in patients with early cancer of the stomach should not be regarded as a real method for an increase of treatment efficacy.

The end-results of combined and surgical treatment of gastric cancer are compared. Survival rates were sufficiently high in both procedures in cases without extension through the serosa (T1-2) or regional metastases with adenocarcinoma cells were well differentiated (NO). However, combined treatment proved more effective in cases of the opposite situations (p=0.04-0.0001). Considering the possibility of inadequate staging, the following indications for preoperative radiotherapy are suggested: low cell differentiation, signet-cell or undifferentiated gastric tumor of 3-10 cm in diameter. In other words, early cancer of the stomach and total involvement must be excluded.

Cases of primary multiple malignant tumors, with one localized in the stomach, have been studied. In cases of radical surgery, second tumors were detected in 6.2% while in patients with early gastric cancer--twice as many (12.5%). Among second tumors, most frequent were neoplasms of large bowel, urogenital system, head and neck, lung, skin and breast. Radical surgery for gastric cancer was carried out in 94%, palliative resection--6%. Radical surgery for second tumors was performed in 53 (82%), palliative--7 (11%). Surgery for second tumors was used in 38%, combined treatment--27%. Synchronous and, in particular, metachronous tumors were mostly responsible for deaths among those radically treated for stomach cancer. In general, second tumors failed to significantly impact the end results of that pathology (p=0.13). Hence, primary multiple tumors should not be regarded as counterindications for radical treatment, a combined one included, of the either neoplasm, nor does it contribute to postoperative lethality rates. Prior to surgery and during clinical course, it is important to make sure that there are no synchronous or metachronous tumors in sites where they generally occur.

Characteristics of recurrence and metastatic development of signet ring cell carcinoma of the stomach were studied in 59 cases after combined and surgical treatment. Peritoneal dissemination appeared to be the most frequent pattern of tumor progression. It accounted for 55% of all relapses and occurred in 27% of patients even without extension through serous membrane (pT2). Metastasizing through the lymphatic viae was fairly frequent mostly in cases of peritoneal carcinomatosis while blood flow-related dissemination was not. Subtotal resection in patients with early-stage signet ring cell carcinoma (pT1) was justified because local recurrences are extremely rare in that pathology. Since (pT2-4) stump relapse is fairly frequent (14-16%), the operation of choice was gastrectomy, whatever site of tumor. Regional metastasis recurrence was 20% among patients with relapsing tumor. It usually co-occurred with distant metastases and, therefore, was less clinically significant. However, when concomitant with local recurrence, it ruled out radical treatment. Preoperative radiotherapy was followed by a significant drop in regional metastasis recurrence rate (4.5 and 13.3%, p = 0.04).

The paper discusses the end results of combined treatment of stomach cancer (radical surgery plus pre- and intraoperative radiotherapy). A randomized evaluation showed that it might be used for loco-regional monitoring. Five-year rates and median of survival rose significantly, as compared with surgery alone, in tumor extension through the stomach wall (T3-4), metastatic dissemination to lymph nodes (N1-2), combinations of such pathologies as well as in cases of low-differentiated, undifferentiated and signet- cell cancer.

Results of surgical treatment of 156 patients were analyzed. There were no metastases to the lymph nodes in patients with invasion of mucous membrane only. In patients with invasion of the tumor into a submucous layer regional metastases were revealed in 18 (19%) cases. Number of affected lymph nodes varied from 1 to 7 (2.7, on the average). Metastases to 1 lymph node were revealed in 9 (50%) patients, to 2-3 nodes -- in 5 patients, to 5-7 nodes -- in 4 patients. In 14.78% patients metastases were only to perigastric lymph nodes, in 4 cases -- to nodes of the second level (N2). Invasion of the tumor into submucous layer, location and size of the tumor were the main factor of risk of lymphatic cancer spread. Frequency of lymphatic cancer spread does not exceed 10% in any variant. In patients with proximal tumor, infiltrative growth and size more than 4 cm, tumor lymphatic metastases are diagnosed in each third person. It is concluded that gastrectomy or distal subtotal resection of the stomach with modified D2 lymphatic dissection is the method of choice in treatment of patients with invasion of stomach cancer into submucous layer.

The paper discusses our findings on a phase II clinical study of an original procedure for therapy of locally advanced gastric cancer including pre- and intraoperative radiotherapy (IORT) and extended lymph node dissection. Out of 24 patients, none had intraoperative complications while postoperative ones developed in 16%; lethality rate was 4%. As far as immediate results are concerned, intensive pre- and intraoperative radiotherapy proved fully compatible with any surgical procedure including extended and extended-combined ones. Survival rates (Kaplan-Meier) were: 1 yr--90 +/- 6%; 2-, 3-year--74 +/- 9%. Indications of adjuvant radiotherapy and approaches to its effective use are discussed.

Experience in surgical treatment of gastric cancer with distant metastases was analyzed. Distant metastases were located most often in the peritoneum (19 patients), distant lymph nodes (16), liver (10) and ovaries (5). Surgery was performed as gastrectomy (27 patients), subtotal resection of the stomach (25) and extirpation of the gastric stump (4); metastatic tumors were removed in half of the patients. During the last years number of extended gastrectomies increased, but rate of postoperative complications and lethality decreased to 11 and 3.5% respectively. Median of survival was 9.0 months. Cumulative survival was 80% in 6 ms, 39% in 12 ms, 11% in 24 ms. The highest median of survival was in metastatic affection of the lymph nodes (13.7 months), the lowest -- in canceromatosis of the peritoneum (7.1 months). It is concluded that main goal of surgeries is fight with fatal complications of tumors. But today, extended surgeries can be performed in uncomplicated forms of gastric cancer to improve quality of patients' life and to carry out drug therapy more successfully.

The immediate and end results of surgical and combined treatment of cancer of the body of the stomach have been evaluated. The combined therapy used intensive preoperative procedures. No significant differences in mortality and postoperative complication rates between combined treatment and surgery were reported. The joint use of preoperative irradiation and radical surgery was followed by better end results in therapy of such locally advanced malignancies as invasion through the stomach wall, metastases to the regional lymph nodes, stage III and infiltrative growth.

Aim: Surgery remains the main treatment of stomach carcinoma. Poor long-term survival mandates the study of other techniques. An original treatment scheme with preoperative radiotherapy and metronidazole as a radiosensitizer is reported here., Methods: Between 1982 and 1988, MRRC RAMS carried out a prospective clinical trial of preoperative radiotherapy (20 Gy/5 days) in combination with metronidazole (given orally, 3 times, 5 gms per metre(2)). Of 91 patients who received preoperative radiotherapy, 67 patients were operated on with curative intent and were eligible for further analysis., Results: Acute gastro-intestinal toxicity was significant but manageable without surgery delay in most cases. There were 4 postoperative deaths. Overall 5-year, 10-year survival and median survival were 46%, 36% and 46 months. Serosal and nodal involvement were the most significant adverse prognostic factors. Tumours confined to the gastric wall, node negative cases, middle and distal location, differentiated tumours, female sex and age more than 50 years were associated with relatively good long-term results: overall 5-year survival was 50% or better, overall 10-year survival was 40% or better., Conclusion: The combined treatment showed significant but manageable acute toxicity. The long-term results seem encouraging and support further investigations in multimodal treatment of gastric cancer., (Copyright 2002 Elsevier Science Ltd.)

The results of clinical application of an original method of operable gastric cancer treatment including pre- and intraoperative irradiation (IORT) and radical intervention are presented. According to a randomized study, combination treatment did not involve intra- and postoperative complication rates higher than those of surgery alone. Moreover, a significant decrease in postoperative pancreatitis was registered. IORT is a highly effective method of adjuvant treatment of operable gastric cancer. Due to its application in conjunction with preoperative irradiation and radical surgery, the end results of locally-advanced gastric cancer improved.

Theoretical, experimental and clinical rationale is discussed for selection of targets and main parameters of intraoperative radiotherapy for gastric cancer. Topometric and dosage research has been carried out. Original technological equipment has been developed for safe treatment using the domestic accelerator Mikrotron-M. Procedures for continuous relay pre- and intraoperative radiotherapy of gastric tumors in conjunction with radical surgery have been devised and adapted to operation of a specialized clinical facility.

Introduction: Worldwide, gastric cancer remains one of the most common malignancies. Discouraging survival rates after surgical treatment promote the study of adjuvant therapy. A prospectively, randomized, controlled clinical trial was performed in order to determine whether pre-operative and intraoperative radiotherapy improves treatment results of gastrectomy for stomach carcinoma., Methods: From 1993 to 1998, 112 patients were randomized and underwent exploratory laparotomy; among them 78 satisfied protocol requirements and entered in the trial. Patients in the experimental group were treated with pre-operative radiotherapy (20 Gy/5 days), gastrectomy and intraoperative radiotherapy (20 Gy using 8-12 electrons). Patients in the control group underwent surgery alone., Results: Incidence and distribution of post-operative complications were similar in both groups except significantly higher incidence of pancreatitis after surgical treatment. No late radiation-related morbidity was registered. There was no significant difference in survival between the two treatment groups (Chi(2)=1.026, df=1, P=0. 311) as well as in N0 (Chi(2)=0.0029, df=1, P=0.956) and T1-2 subgroups (Chi(2)=0.1928, df=1, P=0.660). In contrast, combined treatment had marked survival advantage in more advanced stages: in the case of lymph-node involvement (Chi(2)=4.19, df=1, P=0.04) and extragastric tumour extension (Chi(2)=4.118, df=1, P=0.042)., Conclusion: The proposed intensive treatment programme is feasible, shows good acute and late tolerance and has the potential to improve survival in patients with locally advanced gastric cancer., (Copyright 2000 Harcourt Publishers Ltd.)

The analysis of end results of treatment of rectal cancer showed combined therapy to assure long survival in the whole group of radically operated cases, viz. two-third of them survived 10 years. Conversely, mean survival of non-operated or surgically palliated patients was as low as 10.1 and 26.7 months, respectively. Survival of radically operated cases was found to be related to various clinico-anatomic factors, the most close relationship being observed for extent, histology and growth pattern of tumor and regional nodal status. The influence of site and surgical procedure on patient survival proved far less significant.

The effectiveness of local hyperthermia was investigated in 56 patients with locally advanced carcinoma of the rectum (T4N0M0). All received combined heat and radiation therapy as a pre-operative treatment. The control group consisted of 59 patients with the same stage of disease as those who were only irradiated. Both groups of patients underwent the same surgical procedure. The total tumour dose of ionizing radiation was 40 Gy in 10 fractions, three times a week. The tumour was heated four or five times to a maximum of 42-43 degrees C by electromagnetic waves with a frequency of 905 MHz before irradiation. Each heating session lasted 60 min. Patients were selected on the principle of randomization: 16.1% of patients (n = 9; n: actual number of patients) showed complete response and 53.6% (n = 30) showed significant regression of the primary tumour compared with 1.7% (n = 1) and 33.9% (n = 20) in the control group, respectively. The differences were significant (p less than 0.05). It was found that thermoradiotherapy allowed the 5-year survival rate of patients to increase up to 35.6% (n = 12) compared with 6.6% (n = 7) in the control group (p less than 0.05).

Function of the hepatobiliary system in 35 patients with cholelithiasis of mild and average grave types and in 36 examinees after cholecystectomy without complaints and with the post-cholecystectomy syndrome was assessed with dynamic hepatocholescintigraphy which was shown to be an effective method for assessment of the hepatobiliary system in patients with cholelithiasis and after cholecystectomy. In some patients with cholelithiasis a degree of hepatobiliary disorders, including the frequency of dyskinetic disturbances, grows progressively with the severity of pathology (from a mild clinical type to an average grave one) and is most expressed in patients suffering from the postcholecystectomy syndrome.

In 90 patients with malignant neoplasia of larynx, stomach and cervix uteri the functional state of hemostasis was investigated within the process of radiotherapy and in radiotherapy and radiosensitization by metronidazole. Aim of this work is to answer the question if metronidazole affects the state of organism besides its effect on radiosensitivity of tumor tissue, especially the system of hemostasis, the impairment of which can not seldom result in thrombohemorrhagic complications in oncologic patients as is known. It was pointed out that the thrombophilic status of the blood of patients with stomach carcinoma continues to be unchanged and the patients are endangered for thrombosis potentially. In consequences of radiotherapy and doses of metronidazole the capacity for adhesion is decreased in thrombocytes of patients with laryngeal and cervical carcinomas to a high degree, whereby the thrombogenic potential of blood is reduced and with that the risk for origin of intravascular thrombosis.

In 48 patients with rectal carcinoma diagnostic means for ultrasound investigation USU were tested. The high quality of transrectal and transvaginal ultrasound scanning (US) facilitated a detailed evaluation. The stage of the malign tumor was correctly evaluated in 95.8% of the cases. In one case a false negative evaluation of the function of the muscular layer was given and in another inflammatory infiltration was seen as a tumour. Changes of the pararectal lymph nodes were found in 62% of the patients, of the regional lymph nodes in 5 patients (10.3%). Their metastatic status was proven with fine needle puncture aspiration biopsy (FNPAB) under sonographic and lymphographic control. In 10 patients with US-scanning the found focuses in the liver parenchyma. In 90% of the cases by aspiration biopsy the malignity was cytologically and histologically proven.

To assess the diagnostic value of ultrasonography in rectal carcinoma, the procedure was performed in 48 such cases. Stage was reliably established in the majority (95.8%) of patients. False--negative conclusion on the muscular layer integrity was made in one case and inflammatory infiltrate was misdiagnosed as cancer in another. Pararectal lymph nodes were visualized in 62% of patients whereas regional ones--in 5 (10.4%); their metastatic origin was confirmed with fine--needle aspiration biopsy and lymphography. Ultrasonic scintigraphy identified nodular lesions in the liver parenchyma in 10 cases; the malignant nature of those foci was verified in 90% by histo- and cytologic examination of samples obtained by fine--needle aspiration biopsy.

Analysis of the results of two methods used in the treatment of operable carcinoma of the rectum showed the advantages of the combined method over the purely surgical method: the survival of patients after combined treatment was practically twice that among patients subjected only to operation. No essential differences were found in the character and incidence of postoperative complications and postoperative lethality. All this allows the combined method of treatment to be recommended for wide use in clinical practice.

The authors present clinical results of enteral cozylate tube feeding diet in patients with malignant tumors following abdominal surgical interventions. They found a good tolerance to the drug, rapid recovery of gastrointestinal motility, lack of complications due to cozylate application.

Using histological and histochemical investigations and morphometric analysis the tumors and surrounding tissues of 70 rectal cancer patients were studied before and after preoperative radiotherapy with the total dose of 19.5 Gy and 40 Gy. Morphological changes proving the radiation damage of the tumors were determined. The extent of radiation damage depended on histological structure, degree of differentiation and radiation dose. The maximum damage was observed in poorly differentiated adenocarcinomas and the minimum--in colloidal cancer.

Myocardial diffuse dystrophic changes were recorded on the ECG of patients with stomach cancer of different site. After a preoperative course of radiation therapy in the summary focal dose up to 24 Gy these changes were aggravated in 63% of cases: changes in the voltage of the QRS complex waves, amplitudes of P and T waves, S-T intervals and the heart rate were noted. The most pronounced ECG changes developed in patients with tumors in the proximal part of the stomach when radiation exposure of the heart corresponded to 100% of a focal dose. The voltage of the QRS complex waves decreased, the amplitude of P waves increased, a rise of the S-T interval was noted, the amplitude of T waves decreased.