Anaplastic lymphoma kinase status in lung cancers: An immunohistochemistry and fluorescence in situ hybridization study from a tertiary cancer center in India.

BACKGROUND AND OBJECTIVES: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) have shown good concordance for the detection of echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (ALK) rearrangement. Since studies reporting FISH/IHC concordance, clinicopathological features, and clinical outcomes of ALK-positive patients from India are lacking, this study was undertaken. MATERIALS AND METHODS: This is a retrospective, observational study of patients with adenocarcinoma of the lung on whom ALK test was performed between March 2013 and December 2015. ALK status was assessed in 341 patients by FISH using Vysis ALK Dual Color Break Apart Rearrangement Probe and IHC using ALK D5F3 clone. Clinicopathological features were noted. Patients were managed as per the standard guidelines. Clinical outcomes - response rate (RR) and progression-free survival (PFS) - were measured. RESULTS: ALK rearrangement was positive in 37 patients (10.9%). ALK positivity was observed more commonly in younger patients with no predilection for any gender or any specific histological subtype. ALK by IHC was highly sensitive (100%), compared to FISH with concordance rate of 94.4%. Thirty one of thirty seven (31 of 37) patients received therapy of which 3 patients received palliative chemotherapy and 28 patients received tyrosine kinase inhibitors (crizotinib/ceritinib). Overall RR observed was 77.4%, and median PFS had not been reached at a median follow-up of 12.5 months. INTERPRETATION AND CONCLUSIONS: We report higher frequency of ALK positivity (10.9%) in patients with adenocarcinoma of the lung. ALK by IHC is more sensitive than FISH for ALK detection with high concordance. These patients had good clinical outcome with TKIs targeting ALK fusion protein.

An audit of postoperative radiotherapy after non-curative resection for cancer of the oesophagus.

AIMS: The role of postoperative radiotherapy (PORT) after non-curative resections for cancer oesophagus is not well defined. A policy of offering PORT after non-curative resections for cancer oesophagus has been followed at our institution, and we report an audit of our experience. MATERIAL AND METHODS: Between March 1990 and September 2002, 139 patients underwent resections for cancer oesophagus. Of these, 86 patients received PORT to a dose of 45-50.4 Gy/25-28 fractions. Eleven of these patients also received concurrent and adjuvant 5-fluorouracil (5-FU). Disease-free survival and overall survival were computed from the day of surgery using the Kaplan-Meier method. RESULTS: Seventy-six per cent (65/86) of patients had squamous cell carcinoma and 69% (59/86) of patients had tumours in the lower-third of the oesophagus. The median interval between surgery and PORT was 41 days, and 93% of patients received doses as planned. Strictures at the anastomotic site and ulcerations in the stomach mucosa were seen in 17% and 5% of patients, respectively. The median and 5-year disease-free survival was 12 months (95% CI 9.9-14.1) and 14%; whereas the median and 5-year overall survival was 17 months (95% CI 12.4-21.6) and 17%, respectively. Local and distant failures were seen in 29% and 45% of patients, respectively. CONCLUSIONS: PORT, after a non-curative resection of cancer oesophagus, is well tolerated with acceptable morbidity and survival.

Problems and uncertainties with multiple point A's during multiple high-dose-rate intracavitary brachytherapy in carcinoma of the cervix.

AIMS: This study evaluates the consequences of point A as a dose prescription point during multiple high-dose-rate (HDR) intracavitary brachytherapy (ICBT) in cancer cervix. MATERIALS AND METHODS: Fifty patients who had received teletherapy were randomised into two groups of 25 to receive three HDR ICBT fractions of 6 Gy each at point A with either a flexible Ralstron (Shimadzu Corporation, Japan) or rigid Rotterdam (Nucletron, Netherlands) applicator. The orthogonal radiographs of the 150 applications were evaluated for applicator geometry and point A co-ordinates. RESULTS: Irrespective of the nature and rigidity of the applicators, its various components exhibited a highly significant variation during multiple fractionated HDR ICBT. The Cartesian co-ordinates of point A (left and right) for the applicator geometry also showed significant variation during multiple HDR ICBT procedures. This resulted in an average shift of 9.5 mm (SD= +/-4.4) and 11.1 mm (SD= +/-6.4) in right point A, 10.2 mm (SD= +/-4.5) and 10.8 mm (SD= +/-6.6) in left point A for Ralstron and Rotterdam applicator, respectively, during the three HDR ICBT. Consequently, doses to both right and left point A's showed significant variation during multiple ICBT application and were independent of the applicator type. CONCLUSION: Applicator variation in the components and spatial position in the pelvis during multiple HDR ICBT results in multiple point A's irrespective of the nature of applicator, leading to uncertainty in the dose prescription. These uncertainties, which have a bearing on clinical end points, could be minimised by shifting from point-based dose prescription to image-based target localisation and treatment planning in ICBT.

Multimodality image fusion in dose escalation studies of brain tumors.

This article examines the utility of integrating images from computed tomography (CT), magnetic resonance imaging (MRI), and single photon emission computed tomography (SPECT) for radiation treatment planning of brain tumors for dose escalation studies. The information obtained from these imaging modalities is complementary to each other and could provide anatomic (through CT and MRI) and metabolic (through SPECT) information of the target. This anato-metabolic target localization could be expected to facilitate precise radiation therapy planning for brain tumors by delineating the boundary between the tumor, edema, and the normal brain parenchyma and identify the viable tumor nidus with greater degree of certainty. This could in turn lead to minimize dose to the normal tissue and permit dose escalation to the region of interest. The utility of these anato-metabolic imaging modalities for defining the clinical target volumes along with planning target volumes for different phases of the radiation therapy is illustrated.

Electron beam therapy at extended SSDs: an analysis of output correction factors for a Mitsubishi linear accelerator.

The effects of extended source-to-surface distance (SSD) on the electron beam dose profiles were evaluated for various electron beam energies--6, 9, 12, 15 and 20 MeV-and the accuracy of various output correction methods was analysed on a Mitsubishi linear accelerator using a radiation field analyser (RFA). The dose fall-off region of the central axis depth-dose curves was nearly independent for SSDs up to 120 cm where as in the build-up region, a marginal reduction of surface dose was observed, particularly for lower energies and for smaller field sizes. Effective SSDs and virtual source distances were evaluated for field sizes ranging from 5 x 5 to 15 x 15 cm2 for various energies. Curve fitting was done with the measured outputs with various equations and coefficients were evaluated. The accuracy of the derived output correction factors by effective SSD, virtual source distance and curve-fit methods was assessed by evaluating correlation coefficients between the calculated and the measured values. The correlation coefficient was best with the linear-quadratic equation followed by the effective SSD method and the virtual source method. The output correction based on the linear-quadratic equation showed the best estimate of electron beam output at extended SSDs with an accuracy well within +/- 1%. The rapid reduction of dose due to the applicator-scattered component at d(max) point with an extended SSD was significant for the 5 x 5 cm2 applicator and lower energies.

Variations of intracavitary applicator geometry during multiple HDR brachytherapy insertions in carcinoma cervix and its influence on reporting as per ICRU report 38.

PURPOSE: This paper examines the extent of variation in the applicator geometry during multiple high dose rate (HDR) intracavitary brachytherapy (ICBT) applications and its impact on reporting as per ICRU report 38. MATERIALS AND METHODS: Eighty orthogonal radiographs from 20 consecutive patients of carcinoma cervix (FIGO stages, IIA-IIIB) having four HDR ICBT applications of 6 Gy each at weekly intervals following teletherapy were evaluated. The applicator consisted of a flexible intrauterine tandem (IUT) independent of the ovoid assembly. The applicator geometry was evaluated in terms of: alpha angle, beta angle, intrauterine length (IUTL), interovoid (IOV), os to right ovoid (ORT) and os to left ovoid (OLT) distances along with vertical (VDL) and anteroposterior displacements (ADL) of the os with respect to the ovoids. The Cartesian co-ordinates (X, Y, and Z) of the IUT tip, centre of both ovoids and os were also measured. Doses to right point A (ARD), left point A (ALD), along with a reference volume of 6 Gy for ICRU height (IRH), width (IRW), thickness (IRT) and volume (IRV) were estimated for each application. RESULTS: Highly significant differences (P<0.001) between four insertions in any given patient across 20 patients for alpha angle, beta angle, IUTL, IOV, ORT, VDL, co-ordinates of the IUT, ovoids and os were observed, except for ADL (P=0.041) and OLT (P=0.247). As a consequence, variations were observed in ARD (P=0.027), ALD (P=0.017); IRH, IRW, IRT and IRV (all P<0.001). Applicator factors which influenced the various dose specification parameters were: beta angle and ORT for both ARD and ALD; UTLN, VDL and ORT for IRH; UTLN and IOV for IRW; UTLN for IRT and VDL for the 6 Gy IRV. CONCLUSIONS: A significant variation of the applicator geometry and its movement was observed in patients undergoing multiple HDR ICBT. This could have implications for reporting dose and volume specifications as required by ICRU report 38.

Biological integral dose: an alternate method for numerical scoring of rival plans.

Numerical scoring of rival plans (NSRP) are usually based either on basis of dose-volume histograms (DVH) or the relative values of corresponding normal tissue complication probabilities (NTCP) and tumor control probabilities (TCP). An alternative method for NSRP based on biological integral dose (BID) is being proposed, which is illustrated using a case of pituitary tumor planned to receive a dose of 50 Gy in 25 fractions over 5 weeks. BID for the various alternate plans -2-field (2F), 3-field (3F), 220 degrees arc (ARC) and 3-field static multileaf collimator (MLC) were calculated using the integration of the product of extrapolated response dose and the corresponding mass of the tissue enclosed separately for tumor and the normal brain in the entire planned target volume or a selected range of dose (approximately 90% and above of the normalized dose). Ratios of the BID for the brain versus the tumor were obtained and the plans were ranked on the basis of the least value of this ratio. In all of these plans, although the DVHs for normal brain were different, the DVHs for tumor were almost identical. However, the BID values for brain for 2F, 3F, ARC, and MLC were 22.53 Joules (J), 21.176 J, 21.991 J, and 10.608 J, respectively, and for tumor 0.561 J, 0.552 J, 0.555 J, and 0.556 J, respectively. The corresponding brain/tumor values were 40.16 (2F), 38.36 (3F), 39.62 (ARC), and 19.08 (MLC), thus ranking the plans in order of merit as MLC, 3F, ARC, and 2F. The BID for volumes encompassed by 90% and more of the normalized dose magnified the differences between the plans, with 2F being 29.99, compared to 3.82 for MLC. Rankings of rival plans could be based on the concept of BID. It requires a lesser number of uncertain variables and therefore could be used as an alternative technique in evaluation of the different plans in routine clinical practice.

Primary CNS lymphoma: an audit of cases treated over a nine year period and review of the literature.

Primary CNS lymphoma is a rare tumor comprising around one percent of all brain tumors. This report is an audit of eight cases [5 males, 3 females, age range: 17-55 years] which were accrued over nine years. All patients underwent surgical decompression, followed by radical Radiotherapy [RT]. Five out of eight patients received adjuvant chemotherapy in the form of CHOP or PCV. Of the patients who relapsed two received CHOP as a salvage therapy, one received PCV therapy and lomustine with intrathecal methotrexate. At a median follow up of 16 months [range 1 to 39 months] the two year disease free survival and overall survival were 13 percent and 38 percent respectively, which is in accordance with the literature. High dose RT to whole skull with boost therapy is indicated for all the cases. However, the role of chemotherapy and the appropriate regime needs to be defined with certainty.

Adjuvant therapy in invasive thymoma: an audit of cases treated over an 8 year period.

Invasive thymomas comprise 0.1%-0.2% of all malignancies in India. This report is an audit of 11 cases (10 males and 1 female) at a mean age of 36.6 years (range 25-52 years) of invasive thymoma accrued over an eight year period treated by combined modality treatment. Nine of these presented with myaesthenia gravis. All patients underwent initial surgery (3 partial and 8 total resections) and postoperative radiotherapy. Two of the three partially resected patients received one course of chemotherapy prior to radiotherapy consisting of cyclophosphamide, vincristine, procarbazine and prednisolone. At a median follow up of 28 months (range 2-87) there have been no local relapses, one distant metastasis and one death due to uncontrolled myaesthenia. The treatment strategies with invasive thymomas would depend upon the extent of resection. Postoperative radiotherapy appears to be indicated in all cases, however the role of chemotherapy may be limited to those with partial resection.

A non-randomized comparison of two radiotherapy protocols in inoperable squamous cell carcinoma of the oesophagus.

We report an audit of two different telebrachytherapy schedules in inoperable carcinoma of the oesophagus. Between October 1990 and December 1996, 108 patients with a Karnofsky performance status > or = 50 were selected from our database on the basis of intention to treat by telebrachytherapy. Teletherapy in the low dose group L (55 patients) consisted of 35 Gy in 15 fractions over 3 weeks, while that in the high dose group H (53 patients) consisted of 50 Gy in 25 fractions over 5 weeks. The choice of teletherapy dose was based on physician preference. The high dose rate intraluminal radiotherapy that followed 2 weeks later was identical in both groups and consisted of two applications of 6 Gy, a week apart. The pretreatment disease characteristics of the patients in both arms were similar. Relief of dysphagia was obtained in 49% of the patients in group L and in 75% of those in group H (chi2: P = 0.004). The median dysphagia-free interval was 0 and 7 months in groups L and H respectively (log-rank: P = 0.06), while the median overall survival was identical at 8 months (log-rank: P = 0.21) for both groups. The probability of survival at 1, 2 and 5 years was 34.8% versus 35.8%, 14.5% versus 13.9% and 0% versus 10% for groups L and H respectively. Morbidity in the form of ulcers, strictures and fistulae were observed in 9%, 7% and 5% of patients in group L compared with 8%, 8% and 13% in groups H respectively. This audit suggests that the protocol used in group H, when compared with group L, results in a greater proportion of patients being rendered dysphagia free, with a statistical trend towards a greater sustainment of dysphagia relief on follow-up.

The familial incidence of benign paroxysmal positional vertigo.

The goal of this investigation was to determine whether there is a familial tendency in the development of benign paroxysmal positional vertigo (BPPV). We hypothesized an increased frequency of BPPV among relatives of patients with the same diagnosis. BPPV is caused by dislodged otoconia from the utricular macula floating in the semicircular canals. At least half of BPPV cases are idiopathic and most pathological associations provide no clue as to the reason otoconia become dislodged. We have noted a number of BPPV patients with family histories of BPPV, suggesting a genetic predisposition to the condition. We surveyed 120 successive BPPV patients and 120 successive dizzy patients without BPPV regarding the frequency of dizziness and BPPV (diagnosed by a physician) among family members. Patients in our group with BPPV were 5 times as likely to have relatives with BPPV compared to the dizzy control group (chi2=5.95, DF=1, p=0.015). We have demonstrated that there is a familial tendency for the occurrence of BPPV. There is nothing in our data that would distinguish between a hereditary or environmental influence in the development of the disease, however.

Partial transmission block for optimization of anterior supraclavicular-posterior axillary boost in the radiation therapy of carcinoma breast.

Radiation therapy of breast often involves an anterior supraclavicular-axillary (SC-AX) portal to irradiate the supraclavicular and axillary contents. However, the fall-off of the dose in this region leads to an inhomogeneity that could result either during the use of a single anterior SC-AX field or even with the concomitant use of a posterior axillary boost. An attempt has been made to circumvent this inhomogeneity by the use of a partial transmission block that could be placed in the anterior SC-AX portal corresponding to the posterior axillary boost field. The details of the quantum of partial transmission block to be used for different axillary separations and the reference depths of the dose prescription has been evaluated and presented.

Midline shield for radiation therapy of carcinoma of the uterine cervix: should it be "midline" or "individualized".

This study attempts to evaluate the advantage of individualized midline shield (IMLS) constructed on the basis of uterine geometry and applicator position in terms of the dosimetric consequences to points A-right (AR) and left (AL) as compared to standard midline shield (SMLS) in radiation therapy of carcinoma cervix. Twenty consecutive patients of carcinoma cervix (Stage I, II and III) were treated by external beam radiotherapy (EBRT) (50 Gy/5 weeks/25 fractions) and high-dose rate intracavitary brachytherapy (24 Gy/4 weeks/4 fractions) prescribed at point A. At the completion of 40 Gy by EBRT (phase I), IMLS (5 cm wide) at isocenter was fabricated on the basis of uterine geometry as ascertained by a dummy intracavitary application. The remaining 10 Gy of EBRT was delivered using IMLS (phase II) to effectively minimize and optimize the dose to point A. The dose profiles of IMLS were compared against the corresponding dose profile of a 5 cm SMLS and were found to be dependent on the positional variation of AR and AL with respect to the midline. With IMLS, the dose to AR and AL for the 10 Gy of phase II varied between 21.7-38.87% (30.01 +/- 4.87) and 22.42-35.72% (28.12 +/- 3.79) respectively. However with SMLS, the AR and AL doses would have ranged from 22.03% to 77.26% (34.55 +/- 15.94) for AR and from 20.59% to 96.2% (46.93 +/- 28.15) for AL leading to considerable inhomogeneity. Thus, in protocols incorporating midline shield for radiotherapy of carcinoma cervix, IMLS in place of SMLS could be preferred for achieving a definitive and homogeneous dose to the points AR and AL.

Primary gastrointestinal lymphoma--disease spectrum and management: a 15-year review from north India.

OBJECTIVE: To analyze retrospectively the disease spectrum and outcome of primary gastrointestinal lymphoma (PGIL) in a tertiary referral center in north India. MATERIAL: Seventy five patients presenting with PGIL between January 1971 and December 1985 were evaluated. RESULTS: The 49 males and 26 females were aged 3.5-69 years (mean 34) at presentation. Abdominal pain, weight loss and vomiting were cardinal symptoms at presentation; the stomach was the most common site of involvement. Histologically, a majority of patients were classified as having diffuse poorly-differentiated lymphocytic lymphoma (46.7%) and diffuse histiocytic type (30.7%). Twenty seven (36%) patients had stage I disease, 31 (40%) stage II, 11 (14.7%) stage III, and 6 (8%) stage IV. At laparotomy, primary resection and anastomosis was carried out in 66 patients, while only biopsies were taken in nine. Forty eight patients received adjuvant radiation with or without chemotherapy. The mean follow-up was 3.9 years (range 1-14). The 5-year actuarial survival was 34%, 25% and 16% for stages I, II, and higher-stage disease, respectively. The survival was significantly better (p < 0.01) for gastric location (44%) compared to other sites (24%). CONCLUSION: PGIL was more common in the 3rd and 4th decades of life, with the stomach being the predominant site of involvement. Survival was better among patients with stages I and II disease, and gastric location of lesion.

Results of treatment in endometrial carcinoma: ten years experience.

From 1980 to 1989, 145 patients of histologically proven adenocarcinoma of the endometrium were seen and treated at the Department of Radiotherapy, Postgraduate Institute of Medical Education and Research, Chandigarh, Majority of the patients (84/145) presented with FIGO stage I disease. Relationship of myometrial invasion to grade was highly significant (p < 0.001). One hundred and seven patients were treated by surgery in combination with pre-operative or post-operative radiotherapy. The importance of various prognostic factors was assessed and grade of the tumour had statistically highly significant effect on survival (p < 0.005). Postoperative radiotherapy is recommended in patients with poor prognostic factors.

Primary lymphoma of the lung: a report of two cases.

Two cases of primary lung lymphoma B and T-cell type are reported. Their management with chemoradiotherapy is presented along with brief review of literature.

Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate.

Phenylbutyrate (PB), a novel lead compound for prostate cancer therapy, has molecular activities distinct from its metabolite, phenylacetate (PA). Both PB and PA promote differentiation in human prostate cancer cell lines, yet little data exist comparing the cytotoxic effects of each drug. We found that PB is more potent than PA in vitro; PB is 1.5-2.5 times more active at inhibiting growth and inducing programmed cell death than PA at clinically achievable doses against each human prostate cancer line studied. PB is equipotent to sodium butyrate, which induces apoptosis and differentiation through multiple mechanisms. Exposure of prostate cancer cell lines to PB reduces their DNA synthesis, leads to fragmentation of genomic DNA, and causes 50-60% of cells to undergo apoptosis. These PB-induced effects are 2-10 times greater than those of the control or PA. The stereotypical changes of apoptosis can be seen with sodium butyrate at similar concentrations, but not with PA. Prostate cancer cell lines overexpressing P-glycoprotein or possessing heterogeneous molecular alterations, including p53 mutations, are also sensitive to the effects of PB. In vivo, Copenhagen rats treated with oral PB had delayed growth of the androgen refractory Dunning R-3327 MAT-LyLu prostate cancer subline by 30-45% in a dose-dependent manner. These results demonstrate that PB induces cytotoxicity via apoptosis in human prostate cancer, in addition to its differentiating properties.

Spatial information on dose distribution using multisectional dose-volume histograms.

Dose-volume histograms are useful tools to summarize the information on the dose profiles resulting within a target volume. However, the spatial relationships of the hot and the cold spots are blunted in the dose-volume histograms. This study tries to circumvent this problem using multisectional dose-volume histograms and highlight the utility of these in the optimization of a radiation therapy plan.

Feasibility of non-cisplatin-based induction chemotherapy and concurrent chemoradiotherapy in advanced head and neck cancer.

The purpose of the present study was to determine the safety and efficacy of induction chemotherapy followed by concomitant chemoradiotherapy. Thirty-eight patients were randomised to receive induction chemotherapy, consisting of cyclophosphamide and methotrexate followed by concomitant 5-fluorouracil and irradiation (study group) or irradiation alone (control group). There were non-significant differences in the initial tumor clearance rates in the two groups. Median disease-free survival (in complete responders) was 17 months (6-60+) vs 11 months (5-60+) (p = 0.407) and overall survival 11 months (1-60+) vs 14 months (2-60+) (p = 0.428) in the study and control groups respectively. Acute morbidity and deaths during intervention were higher in the study group (p = 0.007). This study suggests that induction along with concomitant chemoradiotherapy is too toxic for routine use and also fails to provide a survival benefit.

Multisectional planning for external beam radiotherapy: a "poor person's" alternative to three-dimensional treatment planning.

Recent technical advances in the field of computers have led to the use of three-dimensional dose computation for optimizing a radiation therapy plan. However, in centers which lack such a state-of-the-art technology, one could explore the use of multisectional planning to obtain information about the dose profiles all along the target volume. This article highlights the utility of multisectional planning as an alternative to three-dimensional treatment planning systems for external beam radiation therapy.